GI strand: metabolism Flashcards
what do we get glucose from
starch and glycogen
what do we get fructose from
sucrose (sugar)
what do we get galactose from
lactose (milk)
name 2 inherited disorders which are associated with absence of enzymes involved In the breakdown of sugars
hereditary fructose intolerence
galacrosaemia
NB- can be life threatening and cause sevre brain damage
is glycolysis an aerobic or aerobic process? what kind if cells does it take place in
anerorobic
all types of cells
what are the 2 phases to glycolysis
preparative phase
generating phase
what happens in the preparative phase of glycolysis? does this step require ATP
glucose –> fructose1,6biphosphate
ATP required
what happens in the generating phase of glycolysis ? what additional things are generated here
fructose1,6biphosphate –> 2x pyruvate
ATP and NADH generated here
what is generation of ATP in glycolysis called? how many ATPs are made in the aerobic and aerobic state of glycolysis
substrate level glycolysis
anaerobic: 2ATP
aerobic: 5-7 ATPs
in glycolysis what converts glucose –> glucose-6-phsopahte? why is this importnant
hexokinase in muscles and glucokinase in skeletal muscle
prevents glucose leaving the cell
name the molecules and enzymes which aid transition of glucose to pyruvate in glycolysis
glucose — (hexokinase/glucokinase)—> glucose-6-phosphate —–> fructose-6-phosphate —(phosphofructokinase)—-> fructose1,6biphosphate —>—->phosphoenolpyruvate —-(pyruvate kinase)—> pyruvate
in the absence of O2 what is pyruvate converted to and why is this important
pyruvate —> lactate
allows for regeneration of NAD
what is the Warburg effect ? what is this significant in and why?
high lactate productions in aerobic conditions
diagnostic of cancer as tumour cells absorb glucose more rapidly then normal cells but use aerobic glycolysis
where is glycogen mainly stored
liver and skeletal muscle
where are the glycosidic bonds made in glycogen, allowing it to be branched
1,4 and 1,6 glycosidic bonds
highlight the steps and enzymes involved in glycogen synthesis
glucose —-(hexokinase/glucokinase)—–>glucose-6-phosphate —(phosphoglucomutase)—-> glucose-1-phospahte + glucogenin +UDP-glucose —-(glycogen synthase enzyme) —-(branching enzyme) —-> glycogen
how does glucogen synthase enzyme work?
keeps adding UDP-glucose via 1,4 glycosidic bonds to make a long chain
how does branching enzyme work?
breaks of parts of the chain and adds it at the C6 of main chain =1,6 glycosidic chains
when do glycigenisis occur
in the fed state
when does glycogenlysis occur
in the fasting state
what hormones induce glycogenlysis
glucagon
noradrenaline
adrenaline
highlight the steps and enzymes involved which turn glycogen to glucose, in the liver and muscle cells
glycogen —(glucogen phosphorylase)—>. glucose-1-phosphate —-(phosphoglucomutase)—> glucose-6-phosphate
in muscle this goes into the glycolysis cylce
in the liver, kidneys and duodenum this is acted on by enzyme glucose-6-phosphatase –> turning it into glucose
where is the enzyme glucose 6 phosphatase found
in liver, kidneys and duodenum
highlight the steps that occur in the link reaction ? what other molecules are produced here ?
2 pyruvate —(pyruvate dehydrogenase)— 2 acetyl CoA
2NADH and 2CO2 produced
how does acetyl CoA get converted to fatty acids and what enzyme is required in this process
Acetyl CoA —-(Acetyl CoA carboxylase)—-> Maalonyl CoA —-> fatty acids
highlight the steps in the Krebs cycle and enzymes involved
Oxaloacetate + Acetyl CoA —(citrate synthase—> citrate —-(auto citrate)—-> isocitrate —-(isocitrate dehydrogenase) —>a-ketoglutarate —(a ketoglutarare dehydrogenase) —> succinyl —-(succinylCoA synthase) —-> sucinate —(complex 2/ sucinate deHgenase)—> fumate —-(Fumerase) —> malate —-(malate DH) —> OAA
highlight the steps in the electron transport chain
1) NADH into complex1, meanwhile FADH2 into complex 2
2) drop off electrons
3) e- from complex 1 and 2 to co-enzyme Q
4) e- to complex 3
5) e- to cytochrome C
6) e- to complex 4
7) e- donated to O2 and combine with H+ to H2O
8) H+ move through ATP synthase/F0F1ATPase
9) the movement of H+ combines ADP to ATP
what is the generation of ATP in Electron transport chain called?
oxidative phosphorylation
what can cause a lack of pyruvate dehydrogenase? how do we see this in and what can it cause
lack of thiamine seen in alcohol addicts can cause beriberi or Wernicke-Korsakoff syndrome
what activates and what deactivates pyruvate dehydrogenase?
activated by: sudden demands upon the cell- signalled by Ca2+
deactivated by: NADH, acetlyCoA, ATP, ADP (basically when energy levels are high)
what waste product is released from the Krebs cycle?
CO2
between isocitatre —> a-ketogluterate and —> succinyl
what do reduced NADH and FADH2 carry
electrons
when is the ATP made in the Krebs cycle
succinyl –> succinate
first GDP–>GTP then this turned into ATP
Why do diabetic patients synthesise ketones
cant use glucose effectively in the absence of insulin ….. so glycolysis is inhibited …. so pyruvate low …..
BUT STILL UNDERGO gluconeogensis … so oxaloacetate and malate being removed to form glucose
insulin low so fatty acids oxidised from adipose tissue = high levels acetlyCoA… lack of oxalactete prevents ACoA entering Krebs = ketones synthesised
how does cyanide effect ETC
blocks the formation of water at the end
how are protons able to move from a low [H+] in the maxtrix to a high [H+] in the intracellular membrane
each reduction step of electrons moving from complex to complex releases energy allowing H+ to pump across - like a game of hot potato
for one molecule of ATP how many protons cross the membrane
4 (should be 3 but an extra one for the movement of Pi)
what are uncouplers and what do they do
weak acids which are soluble in membrane and can associate with H+ at the inter membrane space and release the protons in the matrix
what is the aim of uncouplers
to dissipate the proton gradient and so the ETC can continue without ATP synthesis
what is the significance of high amounts of brown adipose tissue being found in newborns
has more mitochondria and contains thermogenin (uncoupling protein), when activated due to low body temps energy is released as heat
what happens when the ETC is uncoupled from ATP synthesis?
energy is released as heat
what is DNP? why is it dangerous
a ‘slimming’ pill
causes side effects: hyperthermia, tachycardia, excess sweating, blinding
other than energy what can fats be used to generate
phospholipds
cholesterol
same two essential fatty acids which are precursors for eicosanoids (prostaglandins, leukotrienes, thromboxanes)-ie. inflammatory and anti-inflammatory molecules
omega 3 and 6
what is cholesterol a precursor for?
membranes
vitamin D
steroid hormones
bile salts
what steroid hormones does cholesterol lead to the development of
- androgens
- oestrogen
- progesterone
- mineralocorticoids (eg.aldesterone)
- glucocorticoids (eg.cortisol)
how do chylomicrons make their way from the intestines to the liver
intestinal epithelial cells —> into lymph lacteals –> enter circulation via thoracic duct and subclavian vein
NB: not a direct from GI tract to liver
what does the liver do to. chylomicrons
turns them into VLDL
this them turns into LDLs and HDLs
what happens when fatty lipids (ie. chylomicrons,VLDLs, LDLs) arrive at peripheral tissues the fed state ?
released by lipoprotein lipase
what happens when fatty lipids arrive at peripheral tissues the fasting state ?
form adipose tissue: triacylglycerols broken down by hormone sensitive lipase —> fatty acids released into blood —> transported to tissues bound to albumin
can fatty acids be used by the brain?
no because cannot cross BBB
What stimulates fatty acid oxidation
long chain fatty acids
what is the first step in the oxidation of FAs
activation to fatty acyl CoA from the long chain fatty acids
how do we move acyl CoA into the mitochondria
carnitine transport system adds a carnitine and removes a CoA making fatty acid carnitine, done by carnitine palmitoyl transferase 1 = so can be transported
what inhibits the carnitine transport system
malonyl CoA (prevents the synthesis and degradation of FAs at the same time)
what happens when fatty acyl cartatine enters the mitochondria
carnitine palmitoyl 2 removes the carnitine and adds a CoA creating fatty acyl CoA
during the oxidation of fatty acids in the mitochondria what is produced and released in each oxidation
each turn releases one acetyl CoA and produces NADH and FADH2
what happens to the products of fatty acid oxidation
NADH and FADH2 are oxidised in the ETC and Acetyl CoA enters the Krebs
can the oxidation of fats be done in a anaerobic environment
no has to be aerobic
what is the main thing which regulates fatty acid synthesis ? how does it do this
conc malonyl CoA
inhibits carnitine acyl-transferase 1
why does malonyl CoA inhibit fatty acid synthesis
ensures that fatty acid breakdown is inhibited when energy is plentiful
why do we get formation of ketone bodies
excess acetyl CoA
where does ketogenesis occur
liver
where does ketolysis occur
brain and muscle
why would ketogenesis occur
when the body is reliant of fatty acid oxidation for energy
in what states would we get ketogensis occurring
fasting
uncontrolled diabetes
low blood glucose conc
why cant acetyl CoA be used in the Krebs cycle when glucose levels are low
because meanwhile gluconeogensis is occurring and so OAA is pumped and used out of the cell a so cannot react with Acetyl CoA
how does low levels of glucose lead to ketone body formation
decreased kerb cycle activity = decreased citrate levels = body joins 2 Acetyl CoA –(acetlyCoA acyltransferase) –> Acetoacetyl CoA —–(acetlyCoA acyltransferase)—–> HMG-CoA —-(HMG-CoA lyase)—> AcetoAcetate —> 3hydroxybutyrate and acetone
what is the job of acetlyCoA acyltransferase
joins 2 Acetyl CoA molecules and removes a CoA in the process
what are the main organs which synthesise cholesterol
intestines and liver
what are high levels of cholesterol associated with
CV disease and Alzheimers
highlight the steps in cholesterol biosynthesis
Acetyl CoA —> HMG CoA —–(HMG CoA reductase) —> Mevalonate —-phosphorlyated —-> isoprene units —– 6 isoprene units phosphorylated —> squalene ——cyclisation to form ring structure —-> lanosterol —> cholesterol
where does cholesterol synthesis take place
smooth ER
which step in cholesterol synthesis is the most importnant and why?
first step as HMG CoA reductase controls the rate of synthesis
what is cholesterol synthesis controlled by
- cholesterol levels (high levels = inhibit synthesis)
- energy levels (insulin stimulates and glucagon inhibits )
why would insulin stimulate and glucagon inhibit cholesterol synthesis
because insulin signals that there is energy availability whilst glucagon signals that there is a lack of energy and so energy is not ‘wasted’ on cholesterol synthesis
how do insulin and glucagon affect the activity of HMG CoA reductase
effect the phosphorylation enzyme which is inactivated at low energy levels
how does phosphorylation affect the activity of HMG CoA reductase
- controls the amount of enzyme present
- controls the transcription of enzyme (inhibited by high cholesterol)
- rate of degradation of enzyme (inhibited by high cholesterol)
how does high levels of cholesterol affect the transcription enhancing signals from the ER
inhibits the movement of SREBP (sterol regulatory binding protein) into the nucleas of the ER and so inhibits the binding od=f SREBP to SRE (sterol regulatory element) = decreasing the levels of transcription of HMG coA reductase and so cholesterol
how do we break down cholesterol
we cant ! can only excrete via faces
how do saturated fats affect cholesterol levels in the blood
raise the levels of LDL cholesterol
how do we get the formation of Trans Fats
formed from hydrogeneation of oils
how do Trans fats affect cholesterol levels
raise LDL and lower HDL
what effects do mono-unsaturated and poly-unstaurated fats have on disease prevalence?
reduce CHD risk and other benefits?
how does familial hyperccholesterolaemia affect and individual, what are they at increased risk of?
lack of LDL receptors
increased risk of CHD
what are high levels of LDL associated with
increased risk of atherosclerosis
what is Tangier disease
lack of HDL (so sufferers at higher risk of CHD)
describe the formation and consequence of an atherosclerotic plaque
damage to endothelial cells —> LDL access to subintimal space (space behind epithelium) —>accumulation of foam cells —> create bulge in vessel wall = plaque —> fibrous collagen ‘cap’ is formed —> restrict blood flow in coronary arteries = angina
how can thrombosis occur from a plaque
inflammatory response: macrophages produce proteinase enzymes —> degrade fibrous cap —> plaque ruptures —> activates clotting mechanisms —> blood clot
how has high levels of cholesterol been associated with alzieherms
high cholesterol = accumulation of AB peptide
what is alcoholic steatohepatitis and how is it caused
liver disease
metabolism of large amounts of Alcohol inhibit fatty acid oxidation and activate triglyceride synthesis = accumulation of triglycerides
what is non alcoholic steatohepatitis and how is it caused
chronic liver disease
insulin resistance leads to increased insulin secretion = FA synthesis = accumulation of FA on liver
what are excess sugars usually converted to
fatty acids
what are fatty acids converted to
- triacylglycerols (triglycerides) for storage
- other lipid synthesis (for membranes)
where does fatty acid synthesis mainly occur
liver , adipose tissue, breast tissue during lactation
how are is manlonyl CoA synthesised
citrate —(citrate lyase)—-> acetyl CoA —–(acetylCoA carboxylase) —–> malonyl CoA
how are FAs synthesised
x(malonyl CoA + Acetyl CoA) —-> palmitate —> longer chain FAs or unsaturated FAs
highlight the synthesis of triglycerols
3 fatty acids + glycerol-3-phosphate
what is a key modulator for metabolism
ATP availability: AMP-activated protein kinase
how does AMP-activated protein kinase work
phosphorylates key enzymes involved in metabolism in the heart, adipose tissue, liver, muscle
what are the overall effect of AMP-activated protein kinase
increase energy providing pathways and inhibit anabolic pathways (eg. FA synthesis, insulin secretion)
how does insulin influence glycolysis in muscle and adipose tissue
- increases expression of enzymes coding for glycolysis
- decreases expression of genes coding for glucosneogensis enzymes
how does glucagon influence glycolysis in muscle and adipose tissue
regulates levels of fructose2,6biphosphate which activate glycolysis and inhibits gluconeogeneiss
what happens when fructose2,6biphosphate is phosphorylated in high glucagon levels
enzyme degrades F26-BP
what happens when fructose2,6biphosphate is dephosphorylated in low levels of glucagon
enzyme synthesises F26-BP
what can we form from AA
- proteins
- nitrogen containing metabolites
- energy
- fatty acids
- ketones
- glucose/glycogen
what is kwashiorkor
disease in children of developing countries causing malnutrition, making them look fat
what are the symptoms of kwashiorkor
Poor growth Susceptibility to infection Changes in hair/skin colour Poor skin condition and poor nutrient absorption Abdominal bloating lower limb oedema
what kind of diet is kwashiorkor caused by
low protein high fibre diet
why does nitrogen have to be exerted
because ammonia from the AA can be converted to ammonium which can result it hyperammonaemia
what can hyperammonaemia cause
tremor vomiting cerebral oedema coma death
what is the main reason we get hyperammonaemia
liver disease: hepatitis or cirrhosis
which organ disposes of NH3 and which excretes it ?
liver disposes it as urea and kidney excretes it as urine
what are the 3 stages which convert NH3 to urea
- transamination
- deamination
- urea synthesis
highlight the steps in the process of transamination
1) AA combines with a-ketogluterate
2) amino group from AA and O2 from AKG swapped via pyrodoxial phosphate
3) AlanineAmino transaminase converts the AA to pyruvate and AKG is converted to glutamate
4) addition of another amino group to glutamate —> glutamine
where do transaminase reactions occur
muscle/peripheral tissue
where does demanination occur
in the liver
highlight the steps involved in deamination
1) glutamine acted on by glutamate dehydrogenase to form AKG
3) this releases NADPH from NADP+
4) NH3 is also released
what vitamin does pyrodoxial phosphate require
B6 - pyrodoxial phosphate is the active form of B6
what is pyrodoxial phosphate used in
- transamination and synthesis of AA
- decarboxylation of NTs
- haemorrhage synthesis
what can a lack of B6 lead to
- anaemia (lack of team synthesis)
- neurological conditions (lack of NT synthesis)
- poor growth and immune responses (lack of protein synthesis)
what happens to the AKG formed at the end of deamination
combines with aspartate —> OAA and glutamate
OAA can go into Krebs
what is the control step in urea synthesis
NH4+ enters the mitochondria + HC03- ——-(carbamoyl phosphate synthetase 1)—–> carbamoyl phosphate
what is carbamoyl phosphate synthesise 1 allosterically activated by? how is this formed
N acetyl glutamate
formed when glutamate levels are high (due to high levels of AA so protein)
what happens once carbamoyl phosphate enters the urea cycle
combines with ornithine to form citrulline via enzyme ornithine transcarbamoylase
what happens to citrulline
A second amino group from aspartate is added —> arginine —-> urea
how is uric acid different from urea
uric acid is derived from purine nucleotides rather than protein
what can excess uric acid in blood lead to
hyperuricaemia which can lead to deposition of Na crystals in kidneys (kidney stones) and joints (gout)
how can we get hyperuricaemia
over production of urate or poor excretion by the kidneys
high purine foods (red meat, seafood, yeast-containing -inc beer)
what can we use the carbon Skelton of AA for
Krebs cycle (via OAA)
- fatty acid and ketone synthesis
- gluconeogenisis
where does gluconeogensis occur
cytosol of liver and kidneys
when does gluconeogenesis occur
- low blood glucose : fasting or exercise
what are the precursors for gluconeogensis
keto acids
lactate
glycerol
how is lactic acid converted to glucose in gluconeogensis
lactic acid —> pyruvate —-> OAA —-> phodphornolpyruvate —> Frutose-1,6-biP —> fructose -6-phosphate—(glucose-6-phosphatase)—–>glucose
what effect does type 1 diabetes have on glyconeogenisis
glycolysis is inhibited as insulin allows tissue enters of glucose to muscle and adipose tissue so gluconepogensis is stimualted
= increases glucose conc a lot as body doest realise we have glucose
why does weight loss occur in individuals with diabetes type 1
muscle protein is broken down to provide AA for gluconeogenisis
what is the cori cycle
converts lactate rapidly from respiring cells to glucose via pyruvate
what does high levels of NADH cause
increases energy storage as triacylglycerol
why does alchohol make you hungry ? how does this work
inhibits gluconeogensis
ethanol metabolism creates lots of NADH which decreases levels of NAD+
this prevents convertion of glycerol to glyceraldenhyde 3 phosphate as NAD+ too low
high NADH causes conversion of pyruvate to alanine to lactate
so pyruvate and glyceraldehyde-3-phosphate cannot join create glucose = inhibition glycogenesis
what are glucocorticosteroids
class of steroid hormone
what is the active form of glucocovrticosteroids
cortisol
what is the pharmaceutical derivative of glucocorticosteroids
hydrocortisone
what are glucocorticosteroids produced by
adrenal / suprarenal glands
what part of the adrenal gland produces glucocorticoids
the zone fasiculata of adrenal - middle part of the adrenal cortex
what are the differnt layers of the adrenal gland (from outer to inner)
zona glomerulosa
zona fasciculata
zona reticularis
what are the 2 zones of the adrenal gland
medulla - the inner zone
cortex
what does the zona glomerulosa (the outer layer of the adrenal cortex produce)
mineralcorticosteroids : aldosterone and corticosterone
what does the zona fasciulata of the adrenal cortex ( the middle layer) produce
glucocorticoids : cortisol and cortisone
what does the zona reticularis of the adrenal cortex (the inner layer) produce
androgens: oestrogen and testosterone
what does the adrenal medulla produce
catecholamines : noroadrenaline and Adrenaline
what is the process by which cortisol is released from the adrenal glands starting from the hypothalamus
hypothalamus releases CRH —> signals the anterior pituitary to release ACTH —> signals adrenals to release cortisol
what us cortisol bound to
albumin
when is the production of cortisol at its highest
30 minutes after waking
do levels of cortisol stay high through the day
no they decline throughout the day
what are the levels of cortisol regulated by
suprachiasmatic nucleas of the hypothalamus
which cells are cortisol(GC) receptors present on
almost all cells - affecting all body systems
during what times do we get an increase in cortisol production
during times of stress
are levels of cortisol essential for feotal devlelopmemnt? do levels increase during pregnancy?
yes cortisol levels are essential for foetal development and thereby levels increase by 2-4 fold during pregnancy
what are the actions of cortisol
- reduce inflammation
- increase glucose availibity to the brain
how does cortisol reduce inflammation
- surpesssses B cell antibody production
- apoptosis of T cells
- reduce neutrophil migration
how does cortisol increase glucose availability
- acts on the liver, pancreas, muscle and adipose tissue to increase gluconeogenesis, lipolysis and reduce glycogen synthesis
how does cortisol effect insulin and glucagon
reduces insulin production and increases glucagon synthesis
what are the actions of cortisol on the CV system
- circadian rhythm affects BP and HR
- Increased cardiovascular tone = can cause hypertension
what is circadian rhythm
the day and night rhythm
what are the actions of cortisol on the nervous system
GC receptors found throughout the CNS - part of fight or flight response
what is Addisons disease
adrenal insufficiency - lack of cortisol
does Addisons doses usually present by itself
no usually presents with another autoimmune disease e
what are the primary causes of Addisons disease
problem is with adrenal gland itself:
- chronic granulomatous disease
- autoimmune (producing antibodies against)
- malignancy
- haemorrhage
- infective
what are the secondary causes of Addisons disease
insufficient ACTH production:
- pituitary disease
- exogenous steroids
why is primary adrenal disease not as bad as secondary adrenal disease
because we have 2 adrenal glands - so if one affected still have another
what are the signs and symptoms of Addisons disease
- weakness and fatigue
- orthostatic hypotension (feel dizzy when stand)
- hypoglycaemia
- weight loss
- reduced body hair (due to reduced androgens)
- hyperpigmentation
- hyperkalaemia and hyponatraemia
is hyperpigmentation seen in primary or secondary Addisons disease
only primary
what is hyperkalaemia and hyponatraemia ? and why do we get it
hyperkalamia - is an increase potassium
hyponatraemia - is a decrease in sodium
due to lack of aldosterone
what are the gastrointestinal symptoms we get with Addisons disease
- nausea
- diarrhoea
- vomtting
- constipation
- abdominal pain
why do we get an Addisonian crisis
due to inability to produce cortisol in stressful situations (eg. infection, trauma, surgery, non-compliance with medications)
how serious is Addisonian crisis
very serious- life threatening
do we get an increase or decrease in BP in an Addison crisis
decrease in BP - low BP
also hyperkalamia and hyponatraemia
how might patients present in an Addisonian crisis
nausea
confusion
pyrexia (fever)
vomiting
how would we investigate for Addisons disease
- random cortisol level
- U&Es
- normocytic normochromic anaemia
- SST (short synathen test)
- ECG
what are we looking for in U&Es if someone has presented with Addisons disease
raised urea creatinine acidosis hyponatraemia hyperkalaemia
why would we perform an ECG on someone in an Addisonian crisis
because the hyperkalaemia and hyponatraemia can effect the heart rate and functioning of heart
what is a SST - short synacthen test
test for adrenaline insufficiency
would we do an SST in a critically ill patient
no if the patient is critically ill give steroids straight away
before you carry out a SST what medication would you need to stop
any form of hormone replacement therapy or oral contraceptive pill
how does the SST work
- take a basal cortisol level
- synthetic injection of ACTH
- take cortisol levels at each 30-60 minutes
- cortisol > 420 at 30 mins is adequate
what is the treatment for someone in an Addisonian crisis
must treat as ion life threatening
- IV steroids - cortisol
- IV fluids
why would we give IV fluids to someone in an Addisonian crisis
to support low BP
what is the long term treatment for Addisonian disease ? why do we give this ?
hydrocortisone
- replicate circadian rhythm
- increase
how would you administer hydrocortisone
need to replicate circadian rhythm so high dose in the morning and lower doses in the evening
* if body under less need to double the dose of hydrocortisone as would happen normally*
what is Cushings syndrome
when there is an excess amount of steroid
what are the causes of Cushings syndrome
prolonged exposure to excess steroid- glucocorticoid meds:
endogenous or exogenous
what age do we get the peak incidence of bushings syndrome
25-40 years
are cushings disease and syndrome the same thing ? why
no Cushings disease is only concerned with a pituitary tumour - ACTH dependent
Cushings syndrome is is due to excess cortisol from any other cause : ectopic ACTH production
what is the primary cause of cushings syndrome
excess iatrogenic - excess cortisol given
what are the signs and symptoms of cushings syndrome
tomato with matchstick arms and legs:
- weight gain
- proximal muscle weakness
- brusising
- striae
- hypertension
- osteoporosis
- diabetes
- impaired immune function
- personality changes
- moon face
- hyperglycaemia
- thin extremities
what are the extra symptoms off cushings syndrome in females
amenorrhea
hirsutism
what investigations would you do to diagnose cushings syndrome
- initial Ix:
ONDST
late night salivary cortisol
24 hour burniangy cortisol
how does ONDST work in diagnosing bushings syndrome
overnight dexomethozone suppression test - steroids given at night (11pm) given should suppress morning cortisol production
what imaging tests would you carry out to diagnose for cushings syndrome
- MRI pituitary (check brain)
- CT adrenal
- CT TAP
- PET-CT
what is the primary treatment given in cushings syndrome
primary treatment is surgery - removal of casual tumour : adrenal, adrenalectomy
surgery done from the back of the body
what is the secondary treatment for cushings syndrome
medication
radiotherapy
what medications are given to people with cushings syndrome
- steroidogenesis inhibitors
- somatostatin analogues
- adrenal steroid inhibitors
- anti-neoplastic drugs
how do steroidogenesis inhibitors work
inhibits the enzyme that catalyses the last step of cortisol synthesis in adrenal cortex
how do somatostatin analogues work
bind and activate human somatostatin receptors resulting in inhibition of ACTH secretion
how do adrenal steroid inhibitors work
inhibit steroid synthesis
how do anti-neoplastic drugs work
decrease steroid production - mitochondria destruction of cells
how do thyroid hormones function
control basal metabolic rate
what 2 hormones does the thyroid produce
T4 and T3
what is T4 called
thyroxine
what is T3 called
triiodothyronine
is T3 or T4 or both biologically active?
T3 is biologically active
out of T3 and T4 which one is mainly produced
T4 most abundant - but converted to T3 in the periphery
what are the 2 essential components for thyroxine production
tyrosine and iodine
how is thyroxine produced
- iodine is taken up from blood by thyroid epithelial cells
- tyrosine is produced from thyroglobulin
- thyroglobulin is synthesised from the thyroid epithelial cells and secreted into lumen follicle
- thyroid peroxidase on thyroid epithelial cells iodinasases tyrosine on thyroglobulin
- synthesis of T4/ T3 from 2 iodotyrosines
is hypothyroidism common?
yes very common endocrine disorder
what are the usual causes for hypothyroidism
usually primary failure of thyroid to produce thyroxine
rarely secondary or tertiary
what are the main causes for primary hypothyroidism
- iodine excess or defiancecy
- autoimmune disease
- iatrogenic
- thyroiditis
what are the symptoms of hypothyroidism
range from asymptomatic to myxoedema coma:
- thinning hair/ loss
- enlarged thyroid
- puffy face
- slow heartbeat
- dry and coarse skin
- poor appetite
- constipation
- infertility
- heavy menstration
- weight gain
- intolerance to cold
- feeling tired
- poor memory
in who is hypothyroidism most common
females and elderly
how do we treat hypothyroidism
improve symptoms:
- daily dose of levothyroxine (T4)
do we give both young healthy individuals and elderly the same dose of levothyroxine to treat hypothryoidism
no :
in young healthy adults start treatment in full dose but in elderly give it gradually
does treatment of hypothyroidism with levothyroxine have immediate effect
no can take up to 4-6 weeks to show
what are the primary causes for hyperthyroidism
- graves disease
- toxic goitre
- solitary goiture (only one nodule effected)
- thyroiditis
what are the secondary causes for hyperthyroidism
- pituitary tumour
- iatrogenic
what are the symptoms of hyperthyroidism
- excessive sweating
- heat intolerance
- increased bowel movements
- tremor
- nervousness , agitation
- rapid heart rate
- weight loss
- fatigue
- decreased concentration
are the presentation of symptoms in older and younger patients the same
no in younger patients there’s more symptoms of sympathetic activation and in older patents in mainly effects the CVS
how can graves disease effect the eye
- peri-orbital oedema
- diplopia- seeing 2 images instead of one
- proptosis = abnormal profusion of eye
what us hyperthyroidism also known as
thyrotoxicosis
how do we treat thyrotoxicosis
- anti-thyroid agents
- B blockers
- glucocorticoids
- radioactive iodine
- surgery
why is it risky to give radioactive iodine and in what patients should we really avoid giving this
there’s a risk of hypothyroidism and avoid in patients with eye dieseas
in what state do we need increased thyroxine requirements
during pregnancy - for foetal development
importnant to raise levothyroxine dose in hypothyroid patients
when does the foetal thyroid reach maturity
11 weeks
when does the foetal thyroid begin secreting thyroid
16 weeks
what kind fo development is the thyroid hormone essential for in a foetus
for the neurological development of the foetus
what are the 2 reasons we may get hypothyroidism in babies
due to lack of maternal thyroxine or thyroid ageeneis
what is growth hormone also known as
somatotropin
what is growth hormone importnant in maintaining
lean body mass and controls metabolism
when do we get the maximal release of GH
second half of the night
what is GH release stimulated by
GHRH Secreted from hypothalamus
what is GH release inhibited by
GHIH
somatostatin
what kind of things affect GH release
age gender puberty sleep exercise
how does GH effect protein metabolism
- anabolic effect
- stimulates transcription
- increased AA uptake and protein synthesis
how does GH effect fat metabolism
promotes lipolysis
increase fat utilisation
how does GH effect carbohydrate metabolism
antagonistic to insulin
promotes gluconeogensis
increases utilisation of glucose
inhibits glycolysis
how does growth hormone induce growth
- promotes linear growth in children
- transforms cartilage to bone (condrocyte stimulation production)
- increase bone mass
what are the autogenic effects of GH
- enhances milk production
- prolactin like effect
what can hyper secretion of Gh lead to in children
gigantism : tall, large hands and feet, loss of libido, impotence, hyperglycaemia, macrocephaly, prognathism
what can hyper secretion of Gh lead to in adults
acromegaly
what are the features of acromegaly
enlargement of hands and feet coarse facial features (ie. large bulging head) prognathism - bulging of lower jaw macroglossia - large tongue hyperhidrosis- excessive sweating
what can acromegaly lead to
hypertension
sleep apnoea
type 2 diabetes
cardiomyopathy
what investigations can be done for acromegaly and giantism
- IGF-1 levels (insulin-like growth factor-1 (IGF-1) test = indirect measure of the average amount of growth hormone)
- GH levels after glucose challenge
- prolactin levels (levels increase with increased levels of GH)
- MRI pituarty
- CT TAP (Computed Tomography of Thorax, Abdomen and Pelvis)
What is the treatment for acromegaly and giantism: hyper secretion of GH
- transsphenoidal surgery
- endoscopic neurosurgical procedure
- post op imaging to check for residual tumour
- check for hypopituarism post op
what is transsphenoidal surgery
remove tumors of the pituitary gland by inserting an endoscope into the brain by going through the nose and sphenoid bone
what is the second line fo treatment for hyper secretion of GH (acromegaly and giantism)
medical treatment
radiation
what medical treatment can we use for hyper secretion of GH (acromegaly or giantism)
- somatostatin analogue (man made version of somatostatin)
- dopamine receptor analogues - binds to dopamine type 2 receptors and decrease GH secretion
- GH receptor antagonists
how does somatostatin effect GH levels
slows down the production of GH
how can radiation help with hyper secretion of GH (acromegaly and giantism)
prevent growth of pituitary tumour in most patients
what are the risks of radiation in hyper secretion of GH levels
can lead to hypothyroidism
does radiation in order to treat hyper secretion of GH hormone have an immediate effect
no takes years to reduce levels of GH hormone
