RPA endo Flashcards
Diagnosis of diabetes in haemoglobinopathies
OGTT
what virus is proven to cause T1DM
congenital rubella unproven: coxackie, rotavirus, mumps, reovirus, herpes, cows’ milk
genetics of T1DM - what chromosome is involved
chromosome 6
what MHC is involved in beta cell destruction
MHC II - on antigen presenting cells
what HLA is protective of T1DM
DR2 is protective
what HLA is a risk factor of T1DM
DR3 and DR4 are expressed in 95% of white patients with Type 1 diabetes
does the mother or father confer higher risk for T1DM
father is 6.1% risk mother is 2.1% risk
what antibodies are implicated in T1DM
anti GAD anti IA2 zinc transporter 8 first 2 more clinically important
which autoantibody is most important for the development of T1DM
anti GAD
screening for T1DM - what tests to do
HLA DR3/DR4 nmeasure anti GAD and anti IA2 ab insulin secreting potential
pathogenesis of T2DM
insulin resistance but also relative insulin deficiency due to defect glucorecognition
does the mother or father confer higher risk for T2DM
mothers intrauterine environment is important for the development of type 2 DM
what type of genes are affected in T2DM
majority relate to beta cell function loss only a small inter related to insulin resistance
most important gene for T2DM
TCF7L2 - mechanism unknown
MODY genetics
autosomal dominant single gene defects MODY1-5 enzyme defect - HNF-4alpha, glucokinase (mild hyperglycaemia), HNF-1alpha (very sensitive to sulphonylureas), IPF-1
clinical features MODY
onset <25 for at least another family member correction of fasting hyperglycaemia for at least 2 years without insulin no ketotic events impaired insulin secretion
HNF-1alpha characteristics
MODY enzyme defect very sensitive to sulphonylureas
glucokinase clinical significance
MODY enzyme defect mild hyperglycaemia usually does not require treatment
impaired glucose tolerance prevention for diabetes
lifestyle - diet, exercise +/- weight loss effects seen without weight loss rosiglitazone reduced new DM by >60% small increase in heart failure however practically lifestyle
sulfonylurea MOA, adverse effects
stimulates release insulin from the beta cells may have weight gain hypoglycaemia is possible gliceride preferred as metabolites not active and lower risk of hypo CVS impact is neutral on latest study
what allergies should avoid for sulfonylureas
sulfur allergies
biguanides MOA and aderse effects
increases insulin action decrease hepatic gluconeogenesis does not cause hypos by itself but can potential hypos in combination with other things lactic acidosis - rare GI side effects start low and go slow
metformin eGFR cut off
<30
metformin contradindications
liver damage (pregnancy) nephropathy eGFR <30
acarbose MOA and adverse effects
decrease HbA1c by 0.5% at most (very weak agent) AE: flatuence and diarrhoea in 80%! malabsorption
TZD - thiazolidinediones
Activates PPAR_gamma nucleus receptor central to insulin action Tosiglitazone + pioglitazone AE: weight gain, fluid retention/CCF, ?cardiac disease (rose), fractures, ?bladder cancer (pio)
incretic mimetics
GIT hormones - GLP-1, GIP GLP-1 analog - exenatides, dulagutide (both weekly injections)
what does incretin and GLP1 do
increase insulin release and inhibit glucagon to lower blood glucose
what does DPP-4 do
inactivates GLP-1 (so DPP-4 inhibitors increase endogenous GLP-1)
GLP-1 analog advantages
potent weight loss ++ low risk of hypos dual/tripe therapy CV outcome studies
GLP1 A
expensive injection nausea ++
DPP-4 inhibitors
gliptins
DPP-4 advantages
tablet otherwise similar to GLP1
DPP-4 AE
depends on endogenous production of GLP-1 which is already decreased in T2DM not as potent as GLP-1 no weight loss (As weaker) neutral CV outcome studies
what has positive CVS outcome studies
SGLT-2 and GLP-1
SGLT-2 transported
transports 90% of glucose out of the tubular lumen
pros SGLT-2
relatively potent 0.5-1% HbA1c reduction weight loss lowers BP
cons SGLT-2
genital fungal infections euglycaemia DKA
SGLT2 eGFR cut off
<45
when does SGLT2 need to be stopped before surgery..procedure or fasting
2-3 days prior
lispro insulin, aspart, glulisine vs actrapid
absorbed faster than act rapid
what is the next step if someone has good BSL at bedtime but wakes up with high pre breakfast BSL
measure BSL at 3am to see whether it’s dawn phenomenon or somogyi effect to see whether it’s too little insulin (dawn) or too much (somogyi) causing rebound hyperglycaemia after 3am hypo
HbA1C aim T1DM
6.5-7
tighter control and weight in T2DM
tighter control = more weight gain
good glucose control and micro and macrovascular in T2DM
less micro vascular and maybe macrovascular EDIC showed reduced in major cardiovascular events in group that had initial good HbA1C control (2 groups of good and poor HbA1C but long term both groups had good glucose control but initial good control group early on) so macrovascular outcomes may only be apparent after many years
intense glucose control in T2DM
ACCORD study short term outcomes aimed for 6% and lower excessive mortality now we aim for 7% in cardiac disease
good glucose control and macrovascular outcomes
improves macrovascular but over long term and need initial good control
HBA1C aims T2DM no CV + metformin
<6%
glitazone in CVS
rosiglitazone worsen lipids pioglitazone possibly decreases cardiac outcomes however both should not be used oedema
gliptin (DPP4) on CVS
sitaglipin does not increase HF saxagliptin does increase hospitalisation for HF
empagliflozin/dapagliflozin none endo effects
3 point MACE heart failure reduced renal composite outcomes note empa has trend towards increased stroke
significance of dulagltide for CVS
other studies had populations w established CVS disease the rewind study of dulaglutide included 69% without baseline CV disease so it is showing the dulaglutide as PRIMARY prevention
BP lowering DM agents
SGLT2s and GLP1
insulinoma testing
prolonged fast when the person gets a hypo, simultaneous c peptide,, insulin insulinoma does not produce hypoglycaemia w OGTT
impaired glucose tolerance hypoglycaemia
high-isa C-peptide rapid reactive/postprandial hypoglycaemia
c peptide in sulfnoyureas hypoglycaemia
high c-peptide
diabetes and VGEF
vgef is the bad guy in pathogenesis in retinopathy
treatment of retinopathy
anti-VGEF intravitreal
type 2 DM vs type 1 DM - proteinuria and prevention of renal progression
Type 2 DM - ARB Type 1 DM - ACE I
bp targets in DM
accord study - no difference SBP 120-140 so aim now 140/80 if microalbuminuria; 140/90 no microalbuminuria
fenofibrate in DM
retinopathy add on to statin slow progression of retinopathy does not prevent retinopathy
production sites of T4 and T3
T4 soley from the thyroid gland
T3 mainy from the peripheral tissue
what happens to TFTs in first trimester of pregnancy, hyperemesis gravidarum, hydatidiform mole
TSH is suppressed
can present like a thyrotoxicosis picture
Glucocorticoids TSH
Low TSH
normal T4, low T3
TRAb
very high sensitivity and specificity but can occasionally be negative in Graves and occasionally positive in Hashimoto’s
effect of biotin on TFTs
low TSH
High T3 and T4
TSHRAb positive
(False positive Graves disease picture; normalising after biotin is ceased)
Graves disease
Multinodular goitre
most common cause of Hyperthyroidism
Graves disease
clinical dx of graves
symmetrically enlarged thyroid
Graves orbitopathy
mod to severe hyperthyroidism
when is scintigraphy contraindicated
pregnancy and lactation
what is more elevated (T3 vs T4) in Graves disease
T3 more elevated than T4
what BB can blocker T4 to T4 conversion
propanolol
what treatment if contraindication in bad graves eye disease
radioactive iodine because it causes an initial rise in TRAb
how long to treat with anti-thyroid medications in Graves disease
until TRAb becomes undetectable
what treatment for Graves disease has the highest rate of remission
anti-thyroid drugs
prevalence of eye disease in Graves’ disease
30-50%
5% will develop severe eye disease
what is the most common sign of eye disease in Graves?
what is the most specific sign
most common = eyelid retrction of both eyes
most specific - exophthalmos
what is the most common eye muscle affected in Graves disease
inferior rectus
management of Graves eye orbitopathy
Mild - selenium
Mod-severe - Pulse glucocorticoird
Surgery and orbital decompression
Teprotumumab (IGF-1 receptor inhibitory monoclonal antibody; SE - hyperglyaemia)
when to treat subclinical hyperthyroidism
Suppressed TSH <0.1
>65 treat
amiodarone induced tyroiditis pathophysioogy
37.3% iodine by weight
can induce both hypothyroidism and hyperthyroidism
Type I - Jod-Basedow phenomenon; treated with antithyroid medications
Type II - destructive thyroiditis 5-10% patients, need glucocorticoids
treatment of amiodarone induced hyperthyroidism
both carbimazole and prednisolone
who to treat for subclinical hypothyroidism
<70 years of age
AND TSH >10
between TSH 7-10, treat if there are other high risk factors
what’s the size cut off for FNA of thyroid nodule
>1cm
USS features of malignancy for thyroid nodule
microcalcification
nodule hypoechogenicity compared with surrounding thyroid/muscle
Irregular margins - infiltrative, microlobuated, spiculated
Taller than wide on a transverse view
cyst more likely to be benign
hyperthyroidism and warfarin
hyperthyroidism increases efficacy of warfarin through increasing catabolism of vitamin K dependent clotting factors
DIagnosis of diabetes insipidus
water deprivation test (DI patients will continue losing water)
Central DI has response to DDAVP
Peripheral DI does not have response to DDAVP
hypertonic saline insulin test is more sensitive and specific but might not be suitable for use in hypontraemia
Arginine-stimulation and measuring copeptin is aso sensitive/specific
gold standard for hypothalamic-pituitary adrenal axis
insulin tolerance test
what can insulin tolerance test be used to test
growth hormone and cortisol production
pituitary tumour classification
<1cm microadenoma
>1cm macroadenoma (has capaticy to compress on the pituitary)
acromegaly diagnosis
treatment of acromegaly
- Surgery
- Radiotherapy
- Somatostatin receptor ligand
- octreotide acting on SSTR2
- Pasireotide acts on 4 somatostatin receptors
- Hyperglycaemia and diabetes
- Growth hormone receptor antagonist
- Pegvisomant - most efficacious (>90%)
- Dopamine Agonist
screening test for Cushing’s syndrome
dexamethasone 1mg suppression test
cushing’s confirmatory testing
late night salivary cortisol (high sensitivity and specificity)
pituitary adenoma treatment
- Medical therapy first line
- Cabergoline
- Visual field
- Pregnancy
- Microadeoma - cease treatment during pregnancy
- Macroadenoma - cont treatment, switch to bromocriptine
- Visual fields testing once a trimester
which immunotherapy is most likely to cause hypophysitis
anti-CTLA4
diagnosis of congenital adrenal hyperplasia
basal 17-OHP
confirmation testing with 250mcg of synacthen test and seeing if 17-OHP increases
treatment is not indicated in classical non symptomatic
what’s the most common cause of primary hyperaldosteronism
bilateral adrenal hyperplasia
pathogenesis of obesity
leptin deficiency (long term appetite suppressant)
cholecystokinin (short term satiety factor that regulates meal size)
ghrelin: appetite trigger
Genetic factors:
- MC4R deficiency(causes reduction of appetite; most common monogeneic cause of paediatric obesity)
- FTO - found with GWAS; linked to IRX3 which is another gene which is shown to have an effect of browning white fat; small effect size
marker of brown fat
UCP1
browns fat burns energy rather than storing it
orlistat
blocks gastrointestinal lipase
causes fatty diarrhoea
-2.75kg over 52 weeks treatment
only works if there is fat consumption
phentermine + topiramate
does lead to ~10% weight loss
but note topiramate can cause depression in an already high risk group
mean weight loss following bariatric surgery
25% over 12months
physiological changes after gastric bypass
increase in GLP-1 and PYY (appetite regulator) (possibly explains sustained weight loss)
what outcome has not been demonstrate in bariatric surgery RCTs
mortality diet
(likely because there has not been a long enough follow up)
osteocyte - what does it secrete
see slides
what is the role of RANK ligand in bone remodelling
rank L are secreted by osteoblasts
they bind to the RANK receptor on the osteoclast
activated RANk causes the osteoclast to be activated and resorb bone
OPG is a decoy receptor that prevents RANK ligant to activate the osteoclast.
what happens to RANKL in aging
RANK L goes up
OPG goes down
remodlling of bone in aging
cortex thins
holes in the cortex (cortical porosity)
less trabecular bone and loss of connectivity
can lead to skeletal fragility and fracture risk
MOA of bisphosphonates and RANK- inhibiter
- gets uptaken by osteoclasts and kills them
- stops osteoclast activation
what is the z score good at identifying
not as clinically helpful as T scores
but they may be helpful to identify those with underlying accelerated causes of bone loss
who to treat for osteoporosis
- fragility fracture in post menopausal woman or man >50 years
- vertebral fractures (loss of weight 20% of front or middle vs back end)
- No existing fracture but on the basis of risk (but note larger NNT to prevent future fractures). E.g. 70 year olds with low bone density. 20% risk of fracture over 10 years
- Low BMD
- Age
- Previous fracture - HIGHEST RISK
- iatrogenic
- Prednisolone: >7.5mg for 3 months and T score < -1.5
- SERM: treat T<-2 or #
- Angrogenic dep: treat if T <2.5 or #
steroids and bone
dose dependent but any dose will cause bone loss.
short duration results in reversible bone loss.
occurs very quickly (6-12% in the first year)
inhaled and topical no significant effects
HRT in osteoporosis
only if they arehaving sx of menopause and know the risks (increased breast CA and CVS)
raloxifene and osteoporosis
useful in people with a persona concern of breast cancer
what should be avoided in AF and osteoporosis problem
zolendronic acid
what fractures are the most resistance to osteoporosis therapy
non vertebral non hip
(e.g. humerus, colles)
denosumab and discontinuation
rebound fractures due to intense trabeculae remodelling
alendronate discontinuation
slow decline in bone density
re-evaluate risk after a few years
SE of antiresorptive therapy
- osteonecrosis of the jaw (bisphosphonates, denosumab)
- atypical femoral fractures (presents with pain in thigh that occurs months before fracture occurs)
- Declines with drug holidays
- Subtrochanteria (no communication, transverse at the lateral cortex, medialslike, diffuse cortiacl thickening, local lateral cortical thickening)
- Increased by duration of therapy
4.
management of atypical fractures
Discontinue anti-resorptive therapy
Consider nail fixation
Consider teriparatide
Monitor the contralateral hip (imagine w XR +/- bone scan or MRI)
anabolic therapy
- PTH
- Once daily injection
- stimulate osteoblast and clast - which forms the anabolic window of ~18 months which is where osteoblast activity > osteoclast
- New targets - Romosozunab
- Sclerostin inihibiting mAb
- LRP5 - a receptor that is important for osteoblast function. LRP5 is inihibited by Sclerostin and DKK
- TGA but not PBS yet
- Potent anabolic therapy
Paget’s pathogenesis
osteoclasc activity is increased
- > increased bone turn over
- > weakening of the bone
- > deformity
- > fracture
on imaging - alternating areas of lucency
can affect 1 bone or multiple bones
Investigations: ALP, XR, Bone scan
paget’s treatment
indications fo treatment: high risk of fracture, critical area
zolendronic IV 5mg once every few years
hypergonadotropic primary ovarian failure sex hormones
high FSH, low E2
next step - karyotype
hypogonadotropic amenorrhoea causes
most commonly functional: weight loss, anorexia, exercise, debilitating disease, psychologic stress
or structural causes
amenorrhoea and elevated gonadotropin Ddx
turner syndrome
premature ovarian failure
what cardiac diseases to screen for in Turner’s
co-arctation and aortic dissection
definition of premature ovarian failure
<40 years amenorrhea
hypergonadotrophic amenorrhea
ancillary studies in PCOS
endometrial carcinoma
flucose intolerance
lipids
OSA
PCOS fertility tx
- Weight loss
- Letrozole
- Metformin (but not as effective as letrozole)
Clomiphene should be combined with metformin
tall, gynaecomastic male
high LH, FSH
features of hypogonadism
Consider kleinfeltter’s
XXR
MOA of iodine and carbimazole/PTU
iodine: decreases thyroidal iodide uptake, dcreases iodide oxidation and organification and blocks release of thyroid hormones
PTU./carbimazole: prevent synthesis of new thyroid hormone. PTU can also inhibit the conversion of T4 to T4 at high levels
waht happens to the thyroid after Iodine I-131
hypothyroidism depending on how much of the thyroid take up radioactive iodine
e.g. in Graves, the patients almost always be hypothyroidism but for a single nodule, the patient woudl be euthyroid
Wolff-Chaikoff effect
During the use of a high dose short duration of iodine (usually used as bridge to surgery or to control thyroid storm)
an autoregulatory phenomenon that inhibits organification in the thyroid gland, the formation of thyroid hormones inside the thyroid follicle, and the release of thyroid hormones into the bloodstream
Jod-Basedow effect
iodine exposure in uderlying thyroid disease may lead to hypersecretion of thyroid hormones
usually seen in pre-existent thyroid disease or subclinical thyroid disease
adrenal crisis w/ hypoNa hyperK+ b/g metastatic melanoma on pembrolizumab - cause?
adrenal metastasis
(adrenalitis is extremely rare)
C-RET
mutation of MEN2A
MEN 1
parathyroid
pacnreatic
pituitary
genetic MEN1
VHL - Von Hippel-Lindau syndrome
hemangioblastomas
renal cell carcinoma
phaeo
gene (VHL)
inheritance AD
cushing’s syndrome w normal ACTH
most likely cushing’s disease
cushing’s syndrome confirmed, next step
ACTH
pituitary apoplexy first management step
hydrocort
what might precipitate addisonian crisis on adrenal replacements
CYP3A4 inducers:henobarbital, phenytoin and rifampicin
menopause management
depends if they have the uterus
if no uterus, can give unopposed estrogen
if uterus, then need progesterone
initially estrogen then cyclical progesterone but after 1-2 years can do oral oestrogen and continuous progesterone
also depends if there are risk factors for thromboembolic diseases or if she has hypertriglyceridaemia - use transdermal if possible
also consider non hormonal treatments - 2nd or 3rd line
reason for low morning testosterone in obese male
decreased sex hormone inding globulin
High Ca2+ and high PTH next step
factional excretion of Ca2+
Familial hypocalciuric hypercalcemia vs primary hyperparathyroidism
dumping syndrome
rapid gastric emptying -> early vs late dumping
after bypass surgery
rapid correction of glucose levels adverse effect
retinopathy or neuropathy
amyotrophy diabetes
it’s a plexopathy
occurs in poorly controlled diabetes
T4 elevated and TSH normal
most likely cause
exogenous thyroxine intake
but can also be caused by pituitary thyrotorphy and thyroid homrone resistance and increased heterophile antibodies
