Dunedin- Endocrine Flashcards
What antibodies are associated with LADA or slowly evolving immune mediates diabetes of adults?
GAD (glutamic acid decarboxylase)
note- insulin not required at diagnosis
often >35 years
What is fulminant Type 1 diabetes
20% of acute onset T1DM in Japan
abrupt onset <7 days
frequent flulike and gastrointestinal symptoms
ketoacidosis at diagnosis
no c-peptide secretion
negative for islet autoantibodies
increased levels of pancreatic enzymes
What is ketosis prone type 2 diabetes?
diabetes that typically presents with ketosis and evidence of severe insulin deficiency
goes into remission and doesnt need insulin treatment
What Is the mode of inheritance of monogenic diabetes?
autosomal dominant
What type of monogenic diabetes is most common? and what is the gene related?
Type 3, gene HNF1a
How can you treat MODY3?
sulfonylurea
How do you treat MODY 2 (GCK)?
dont need to
How do you treat MODY MODY5, MODY6, MODY7, MODY8?
Insulin
List some strongly diabetogenic drugs
glucocorticoids, immunosuppressives, antipsychotics
List some weakly diabetogenic drugs
Thiazides, B-blockers, statins
Post-transplant diabetes/NODAT (new onset diabetes after transplantation)
Is it more common with solid or non-solid Organs?
Solid organs
What drugs are linked to NODAT (new onset diabetes after transplant)? is there any viruses linked to it?
Glucocorticoids
calcineurin inhibitors (tacrolimus >cyclosporin)
HCV or CMV virus
Why do immune checkpoint inhibitors cause diabetes?
Beta cells have PDL-1 receptors
often presents with DKA
does not reverse! life-long insulin
When to think about MODY?
if they act like T1DM but antibodies negative
often young and well
What is the lifetime risk of T1DM depending on family members affected?
Sibling 8%
Father 5%
Mother 3%
Mono Twin:
* 150-fold increased risk
* 50% concordance (greater the younger age that 1st twin affected)
What are common haplotype of T1DM?
1st chromosome - DR3
2nd chromosome DR4-DQ8
List some Genes related to T1DM?
Insulin VNTR (variable number tandem repeats)
PTPN22 (protein tyrosine phosphate)
CTLA4
IL2RA (interleukin-2 receptor-alpha)
List some viral precipitants for T1DM
enteroviruses esp coxackie viruses
congenital rubella infection
Briefly describe the pathogenesis of T1DM?
B cell destruction, further excaberated by the release of pro inflammatory cytokines
Describe what islet cells look like in T1DM?
Marked heterogeneity of islet lesions:
– Normal (no inflammation and normal beta cells)
Intense insulitis (marked infiltration of inflammatory cells)
* CD8 + T cells main inflammatory cell
* Only 10-30% show insulitis at any time.
* Can persist for many years (>10yr) after diagnosis
– Pseudoatrophic (lack of beta cells and no inflammatory cells)
Describe autoantibodies to T1DM
note, these are not actually relevant to the pathogenesis
and they also go away over time
– Insulin autoantibodies (IAA)
– Glutamic Acid Decarboxylase antibodies (GAD)
– Islet cell tyrosine phosphatase-2 (IA-2)
– Tetraspanin-7
– Zinc Transporter-8 (ZnT8)
What is teplizumab?
anti-CD3 monoclonal antibody
in stage 2 diabetes, and delays Type 1 diabetes by 2years.
Describe some stage 3 studies/drugs for T1DM
verapamil, teplizumab, baricitinib
What are some benefits of short acting insulin analogues?
- better control of postprandial hyperglycaemia
- reduced late hypoglycaemia and nocturnal hypoglycaemia
- decreased severe hypoglycaemia by 30%
- no evidence of reduced complication and only very small reduction in HBA1c
How long does Glargine (Lantus) last for?
24 hours, begins to wane at 15 hours
How to reduce risk of nocturnal hypoglycaemia with glargine (Lantus)?
give with breakfast
Should you split Glargine?
similar results with splitting however splitting causes weight gain.
How long does insulin detemir work?
20 hours
given twice daily
reduces hypoglycaemia compared with isoprene
less weight gain
binds to albumin
How long does Insulin degludec work?
40 hours
less nocturnal hypoglycaemia than evening glargine
How long does insulin isodec work?
half life of 8 days. given once a week
What is 500/100 rule in diabetes?
carbohydrates ratio: 500/total daily unit of insulin
insulin sensitivity factor: 100/total daily unit of insulin
What is the daily insulin requirement?
0.5unit/kg- 50% as basal and 50% as prandial
Describe glycaemia targets for T1DM, and in the case of continuous glucose monitoring.
pre-prandial: 4.4-7.2 mmol/L
post-prandial: <10mmol/ml
Time in range 4-10mmol/L: >70%
Time below range <5%
What is the “dawn phenomenon”
Rise in blood glucose levels in the morning “dawn” as we have higher GH and cortisol.
when you are giving insulin in the morning it cant respond to that but pumps were good in overcoming dawn phenomenon.
What is the somogy effect?
high BSL in the morning due to hypoglycaemic event in the night.
How much does closed-loop pump improve time in range compared to non-closed loop pump?
10%
What are methods of cell replacement therapy in T1DM?
Whole pancreas transplant
Islet cell transplantation
Stem cell therapy
What are the different levels of hypoglycaemia?
Level 1: glucose 3-3.9
Level 2: glucose <3mmol/L
Level 3: hypoglycaemia with altered mental status and/or physical status
What is the normal response to hypoglycaemia?
reduce insulin secretion
increased glucagon secretion
increased adrenaline secretion
increased GH and cortisol secretion
behavioural secondary to SNS activation
What are symptoms of hypoglycaemia?
Autonomic
- adrenergic: palpitations, tremor, anxiety
- cholinergic: sweating, hunger, parasthesia
Neuroglycopenic
- brain glucose deprivation: confusion, fatigue, weakness, visual changes, seizure, loss of consciousness
Describe the pathophysiology of T2DM
Characterised by both insulin resistance and initial hyperinsulinaemia followed by progressive beta cell dysfunction
What is the action of insulin?
suppression of lipolysis
stimulation of glucose uptake
When you gain weight, what occurs to adipose tissue?
hypertrophy more prominent than hyperplasia
creates hypoxic conditions and adipocyte death
macrophages are recruited to clear the dead adipocytes
dysfunctional adipocytes and macrophages release FFA’s and cytokines e.g. TNFalpha, IL-6
FFAs and these cytokines are toxic to Beta cells
What are some methods of prevention of T2DM?
lifestyle intervention
Metformin
pioglitazone
liraglutide
Describe the different diabetic drugs in terms of mechanism, cardiovascular effects, adverse effects
What are the diabetic drugs proven to be cardioprotective?
SGLT2, GLP-1 agonist
+/- metformin
What is the MOA of SGLT2 inhibitor?
Inhibiting glucose reuptake in
proximal tubule
What is the MOA of sulphonylurea? main risk?
SU receptor on beta cells stimulating insulin secretion
hypoglycaemia risk, some have increased CV risks
What is the MOA of metformin? S/E?
insulin sensitiser
AMP kinase activation
S/E GI symptoms, vit B12 deficiency
What is the MOA of GLP1 agonist
Stimulating insulin
inhibiting glucagon secretion
Induces satiety
Delays gastric emptying
better stroke reduction
risk of pancreatitis and medullary thyroid cancer
What are some of the new incretins?
orforglipron, cagrilinitide+semalgutide, retratrutide
What are the risk of complications in diabetes in order?
Retinopathy >nephropathy > neuropathy > microalbuminuria
Other factors that can affect HBA1c
Increased A1c: iron deficiency, B12, deficiency, decreased eryhtopoiesis
Decreased A1c: use of erythropoietin, iron or B12, reticulocytosis, chronic liver disease
What can occur to retinopathy if sudden improvement in BSL?
worsening retinopathy if advanced baseline retinopathy and higher HbA1c
Describe screening for diabetic retinopathy
screening with retinal photography
- from diagnosis of T2
- within 5y diagnosis for T1DM
What is the treatment for diabetic retinopathy treatment?
treat HTN
lower lipids (fenofibrate)
pan retinal photocoagulation (in severe PDR or vision threatening)
anti-VEGF in macular oedema eg ranibizumab
Describe the pathology of diabetic kidney disease
thickened GBM
mesangial expansion
podocyte injury
glomerulosclerosis
tubulointerstital fibrosis
Describe natural history of diabetic nephropathy
1) increase GFR (kidney hypertrophy)
2) microalbuminuria, hypertension (mesangial matrix expansion, glomerular basement membrane thickening, arteriolar hyallinosis)
3) proteinuria, nephrotic syndrome, decreased GFR (mesangial nodules- kimmesltiel-wilson, tubulo-interstital fibrosis)
How to treat diabetic kidney disease
Glycemic control
BP control
RAS inhibition
SGLT2
How do SGLT2s act in diabetic kidney disease?
when you use SGLT2 you get an increase of sodium which gets to the macula dense which causes vasoconstriction of afferent arterioles and dilation of efferent which reduces perfusion of glomerulus
What are the common fibres affected in diabetic neuropathy?
large fiber neuropathy and small fibre neuropathy common
can also get proximal motor neuropathy, acute mono-neuropathy, compression palsies
Does tight glycemic control in diabetes reduce CV outcomes?
NOPE
What is the management of metabolic associated fatty liver disease?
lifestyle intervention
metformin may reduce risk of HCC
pioglitazone –> has side effects but good
Liraglutide
SGLT2
What is the effect of gestational diabetes on childhood?
more likely to have impaired glucose tolerance in childhood
What is the effect of inadequate glycemic control in the first trimester?
Increased risk of diabetic embryopathy:
– anencephaly, microcephaly, congenital heart disease,
renal anomalies, and caudal regression
– Risk directly proportional to HbA1c
What are the glucose targets in pregnancy?
fasting plasma glucose < 5.3 mmol/L and
1-h postprandial glucose 7.8 mmol/L or 2-h postprandial 6.7 mmol/L)
Can we use HBA1c in pregnancy?
No- HbA1c levels are reduced during pregnancy due to increased rbc turnover
How to prevent risk of pre-eclampsia in patients with type 1 or type 2 diabetes?
low-dose aspirin 100–150 mg/day starting at 12 to 16 weeks of gestation
What are the major categories of lipoproteins and their specific apoproteins?
chylomicrons - Apo B48
VLDL, IDL, LDL- Apo B100
HDL- Apo-A
What is the mode of inheritance of familial chylomicronaemia syndrome?
autosomal recessive disorder
LPL deficiency in 80% of cases
get extreme hypertriglyercaemia
Why is the inheritance of familial hypercholesterolaemia?
autosomal dominant
usually see heterozygous, homozygous rare
lack of LDL receptor and APOB , can get gain of function of PCSK9
What is the management of treatment of familial hypercholesterolaemia?
Statins
if LDL-C >2.6 still, add in ezetimibe
Describe the diagnosis if familial hypercholesterolaeia
Simon Broome Criteria
Definite
* Total cholesterol >7.5mmol/L or LDL> 4.9mmol/L
PLUS one of the following:
* Tenon xanthomas in the patient or 1st or 2nd degree relative
* DNA based mutation of LDLR, apoB or PCSK9
Possible
* Total cholesterol >7.5mmol/L or LDL> 4.9mmol/L
PLUS one of the following:
* MI in 1st degree relative <60 years or 2nd degree relative <50 years
* Raised total cholesterol >7.5mmol/L in a 1st degree relative
What is the MOA of thiazolidenione (e.g. pioglitazone)?
PPARgamma receptor activation
S/E Increased risk of heart failure, weight gain, fluid retention and fractures
What is the MOA of alpha glucosidase inhibitor (e.g. Acarbose)
Reduce CHO absorption from intestine
What is the mechanism of familial hypertriglyceridaemia?
Increased VLDL particle
get increased triglycerides
What is the genetic mutation in familial lipoprotein lipase deficiency?
Lipoprotein lipase mutation, APO C-II deficiency
get increased triglycerides and decreased HDL
What conditions can cause secondary hyperlipidaemia?
Diabetes mellitus
obesity
hypothyroidism
chronic kidney disease
alcohol excess
cholestasis
List the types of hyperlipidaemia:
Type 1:
Type 2: Familial hypercholesterolaemia (IIa)
- this is what we usually refer to.
Familial combined hypercholesterolaemia (IIb)
- overproduction of VLDL by the liver –> raised liver and triglycerides
Type 3: dysbetalipoproteinaemia
- homozygous carrier status (autosomal recessive)
- usually have a precipitating events
- total cholesterol >10, triglyceride >10, xanthomas in 50%
Type 4: Primary hypertriglyceridaemia
- autosomal dominant, polygenic
- reduced lipolysis of triglycerides + hepatic overproduction of VLDL
- Note Chylomicrons NOT PRESENT
Type 5: Mixed hypertriglyceridaemia
- polygenic
- presence of chylomicrons after 12-14 hours of fasting
- elevated levels of VLDL
Describe pituitary anatomy
How big is a pituitary microadenoma?
<1cm in diameter
majority non-functioning
hypodense after gadolinium due to reduced blood supply
What is the size of a pituitary macroademoma? How to tell if it is function
> 1cm in diameter
if change in
- prolactin
- TSH, FT4
- UFC (urianry free cortisol)
- IG-1
Note, even in non-functioning prolactin can be raised
What are causes of pituitary mass lesions other than pituitary tumours?
Rathke’s cyst
Chordomas
craniopharyngioma
Meningioma
option gliomas
hypothalamic masses
metastases
carotid artery aneurym
infiltrative disease (sarcoidosis, histiocytosis, tuberculosis, lymphoma)
lymphocytic hypohpysitis
What is an easy way to distinguish between craniopharyngioma and other pituitary masses?
BRAFV600E mutation exists in most cases
Describe the pituitary development
Lactotroph, somatotroph, and thyrotroph are classified as PIT1 lineage
Corticotroph as TPIT lineage
Gonadotroph as SF1 lineage
How to manage pituitary apoplexy?
Often presents as subarachnoid haemorrhage, severe headache, and can get visual changes
manage with steroids
What are causes of hypophysitis?
Primary
1) Lymphocytic 70% (often in pregnancy or postpartum)
2) Granulomatous 20$
3) IgG4 related
4) Xanthomatous
Secondary
1) immune checkpoint inhibitor induced
2) Anti-PIT1 antibody syndrome
3) Inflammatory or infectious disorders (sarcoidosis, tuberculosis, histiocytosis)
What is a common cause of inflammatory/infiltrative changes in the infundibulum (pituitary)
sarcoidosis
What immune medications are most likely to cause hypophysitis?
Anti CTLA-4 + antiPD1/PDL-1 > Anti-CTLA-4 > Anti PD1 > Anti-PDL1
What is the pathophysiology of ICPi- induced hypophysitis?
Describe the difference in pituitary hormone deficiencies depending on which immune therapy is used
CTLA-4 inhibitor-induced IH –> total anterior pituitary hypofunction
PD-1/PD-L1 inhibitor –> isolated ACTH deficiency
What hormones are released by the pituitary gland?
Testing for Acromegaly
Acromegaly is a GH producing pituitary tumour.
Screening test: IGF-1
Oral glucose tolerance test (in a normal person, GH reduces in glucose tolerance test, this is a test of exclusion)
What subtype of acromegaly is more aggressive?
Sparsely granulated subtypes are aggressive and occur in younger patients
Densely granulated somatotropin is more insidious
What are some somatostatin receptor ligands that can be used in pituitary adenoma/acromegaly?
Ocreotide and lanreotide
Pasiroetide
S/E
cholelithiasis, bradycardia, alopecia
Pasireotide –> reduces insulin and incretin levels so can cause hyperglycaemia. GLP agonists work well
In general these are better in densely granulated, women, SSR2 expression
Reduces response in younger patients, T2 hypersensitivity, sparsely granulated, ALP expression, High Ki-67 index
What are treatments for acromegaly?
Surgery
Somatostatin receptor ligants
Pegvisomant (modified growth hormone molecule)
- note, normally growth hormones binds to two receptors to work. pegvistomant is targeted in peripheries, so GH is still high but IGF-1 can be normal
- also good in diabetes
Cabergoline
- GH secreting tumours hae D2 receptors, 30% normalise IGF1 levels
Radiotherapy
What are clinical features of adult GH deficiency
*Altered body composition (increased abdominal adiposity, decreased lean body mass, decreased bone mineral density)
*abnormal lipid profile: elevated total and LDL cholesterol
- decreased muscle strength and aerobic capacity
- poor quality of life: low energy, reduced functional capacity, social isolation
How to diagnose GH deficiency?
Glucagon response <3Ug/L diagnostic
If BMI >30 use lower cut off
How does growth hormone replacement therapy affect other hormones?
*increases conversion of cortisol to cortisone (therefore inactivates it)
* increases metabolism of T4 to T3
*women taking oral oestrogen’s are relatively resistant to growth hormone
What is macroprolactinaemia ?
this is prolactin that is bound together by immunoglobulin. occurs in some people and increases half life of prolactin in circulation.
you can check this by doing PEG precipitation which takes out any anticoagulation
What are causes of hyperprolactinaemia?
Spurious: macroprolactinaemia
Physiological: sleep, stress, pregnancy, breast-feeding
Pharmacological
- DA receptor blockers
- Metaclopramide, domperadone
- opioids
- H2 antagonists
- SSRI- fluoxetine
- oestrogen
Pathologic:
- hypothalamic/pituitary stalk lesions- craniopharyngioma, infiltrative disease, stalk section
- pituitary disease- prolactinoma’s, mixed tumours, non-functioning tumours , primary hypothyroidism
What is the pathophysiology of hyperprolactinaemia?
Inhibits kisspeptin production in the hypothalamus which in turn inhibits GnRH secretion
Increased hypothalamic dopaminergic tone –> suppresses GnRH pulsatility, blocks the oestrogen induced LH surge
Gonadal steroid production inhibition
Galactorrhoea (not all women get this because of oestrogen deficiency)
What prolactin levels indicate a macroprolactinoma vs a non-functioning tumour?
> 2000 is macro
<2000 is non-functioning
Management of hyperprolactinaemia?
Dopamine agonists
Cabergoline (fever side effects because more specific to D2 receptor)
note with cabergoline, some people dont have recurrence even after stopping
Indications for neurosurgery in patients with prolactinomas
What electrolyte derrangmenets can result in a similar picture to diabetes insipidus?
Hypercalcaemia and hypokalaemia as they can down regulate aquaporin-2 channels
What is copeptin?
derived from the cleavage of pre-pro-vasopressin
strong correlation between copeptin and AVP levels
When is growth hormone high?
second half of the night
What factors inhibit growth hormone?
FFAs
Glucose
Obesity
What is the pathogenesis of Graves disease?
T cells present antigen to B cells
CD40-CD154 interaction
note, iscalimab is an anti CD40 MAB
inhibits autoreactive B activation
What are risks of antithyroid drugs?
Agranulocytosis
Rash and Arthralgia
Hepatotoxicity with PTU
lupus-like vasculitis
Pancreatitis
When is PTU preferred over carbimazole?
1st trimester of pregnancy
Thyroid storm (PTU more valuable in preventing conversion of T3 –> T4 in periphery)
When to avoid giving radiotherapy in Graves disease?
active Graves orbitopathy
pregnancy
breastfeeding
Graves orbitopathy may run an independent course to the thyrotoxicosis. True or false?
True
What is the pathophysiology of Graves orbitopathy?
TSH receptors on retro-orbital fibroblasts –> TSH receptor antibodies stimulate fibroblasts to secrete glycosaminoglycans –> swelling of retroorbital tissue (muscles and adipose tissue) –> pushes the eye forward (exophthalmos) –> impairs extraocular muscle relaxation (diplopia) –> impairs venous drainage of eyelids (peri orbital oedema) and conjunctiva (chemises) –> optic nerve compression may cause dysthyroid optic neuropathy (DON) and visual loss
Treatment of Graves Orbitopathy?
Stop smoking
maintain euthyroidism
Avoid radio iodine
Eye specific measures:
-lubricants
- selenium 100ug BD
Mod-Severe
- IV methylprednisone +/- cyclosporin, rituximab or orbital radiotherapy
- Tociluzimab
- teprotumamab (anti-IGF1 receptor)
DON (dysthyroid optic neuropathy) and visual loss –> high dose IV methylpred and if unresponsive urgent surgical decompression
Describe the pathogenesis of toxic multinodular goitre and toxic adenoma
iodine deficiency leading to hyperplasia –> mutagenesis leading to cell clones containing somatic mutations –> ultimately nodular transformation
Describe the treatment of toxic nodular goitre or toxic adenoma
Radioactive iodine
surgery
Describe how different things present on thyroid scintiscans
*Graves –> diffuse uptake
*Multinodular goitre –> patchy uptake
*Toxic nodule –> single area of uptake
* No uptake –> thyroiditis, exogenous thyroid hormones, iodine exposure
How to manage thyroiditis
Treat symptoms
Describe what subacute (De Quervain) thyroiditis is
*Post viral infection: granulomatous thyroiditis on pathology
*painful thyroid on palpation
* Biochemical thyrotoxicosis, raised inflammatory markers
* Absent uptake on thyroid scintiscan
Describe what silent painless thyroiditis and postpartum thyroiditis is
Autoimmune aetiology- thyroid antibodies present
non-painful and inflammatory markers not raised
Describe what wolff-chaikoff effect and the Jod-Basedow phenomenon is
These phenomenon relate to iodine and the thyroid
wolff-chaikoff effect: large amount of iodine reduces thyroid hormones. return to euthyroid in 24 to 48 hours
Jod-basedow phenomenon: iodine increases thyroid levels. usually have a background of autoimmune disease or nodular goitre. thyrotoxicosis
What are the underlying mechanisms that cause iodine induced thyrotoxicosis?
Iodine containing agents: kelp tablets, iodinated contrast agents, drugs (Lugols iodine, amiodarone)
1) underlying thyroid disease –> Jod-Basedow phenomenon (transient, managed with anti-thyroid drugs)
2) Underlying normal thyroid –> cytotoxic effect of iodine causing thyroiditis
Why does amiodarone induce thyrotoxicosis? What are the types
Amiodarone has a lot of iodine in it
it is also stored in fat tissues so can persist for ages
Type 1 AIT –> due to Jod-basedow phenomenon. treat with antithyroid drugs, stop amiodarone.
Type 2 AIT –> destructive thyroiditis, treat with prednisone and beta blockers. self-limited. amiodarone can be continued.
What drugs can cause thyroid impairment?
*Lithium (hypothyroidism but also graves thyroiditis)
*HAART
*Alemtuzumab- can cause immune reconstitution syndrome
*Immune checkpoint inhibitors
*TKIs (sunitinib, sorafenib)
What antibodies are involved in Hashimoto’s thyroiditis?
1) Anti-TPO (microsomal) antibodies
2) TSH receptor blocking antibodies
When to treat subclinical hypothyroidism?
pregnancy
age <70 years and TSH >10mIU/L
When to treat subclinical hyperthyroidism?
TSH <0.1 mIU/L
TSH 0.1- 0.4 and >65 years
known cardiac disease
Which factors are worse for thyroid nodules on US?
Composition: Solid
Echogenicity: very hypoechoic
Shape: Taller than wide
Margin: extra-thyroidal extension
Echogenic foci: punctate echogenic foci
micro calcifications are suspicious for papillary cancer
What is the most common type of thyroid cancer?
Papillary –> excellent prognosis
Other types include
- follicular thyroid cancer: excellent prognosis
- anaplastic thyroid cancer: very aggressive
- medullary thyroid cancer
When to use calcitonin to monitor cancer?
For medullary thyroid cancer
What is the management of thyroid cancer
1) surgery- either lobectomy (low risk) or total thyroidectomy
2) radioactive iodine ablative treatment
3) Monitoring- US neck, thyroglobulin (in those who have had a total thyroidectomy)
4) TSH suppression
5) recurrence –> treat by surgery if possible or radioactive iodine
if radioactive iodine resistant –> TKI therapy (lenvatinib)
How to treat gestational transient thyrotoxicosis?
resolved by 16 weeks when hCG levels have fallen
treatment not required
What happens to Graves disease and pregnancy?
Often goes into remission during pregnancy but usually relapses postpartum
Treat with PTU in first trimester
If you have had radio iodine treatment, how long do you have to wait before conception?
6 months
How to with hypothyroidism in pregnancy?
at time of conception, increase dose of thyroxine by 30% (increased requirements are due to increased TBG levels)
What is myxoedema coma and what is the leading cause of death?
mortality mainly due to resp failure
hypothermia and reduced level of consciousness
usually precipitating event
obtunded, bradycardic, hypotension, hypoventilation, hypothermia, cool and dry skin
treatment: mechanical ventilation, glucocorticoid therapy, parenteral T4 or T3 treatment
What is the treatment of thyroid storm?
PTU or carbimazole
beta blockage
potassium iodide- wait at least 1 hour after ATD
glucocorticoids
treat underlying cause
What is a TSH receptor?
Located on the cell membrane of follicular thyroid cells and is a G protein coupled receptor
In circulation, what is thyroid hormone bound to?
TBG (75%), transthyretin (10%), and albumin (15%)
What is active, T3 or T4?
T3 is active
What are some physiological effects of thyroid hormone?
*Thermogenesis- regulated basal metabolic rate
*activates Na/K/ATPase in cell membrane
*regulates Ca-ATPase in the sarcoplasmic reticulum of muscle cells
*increases the expression of uncoupling protein in BAT
What is the most common cause of adrenal insufficiency?
Tuberculosis in developing world
Autoimmune adrenalitis in developed world
Describe the pathogenesis of autoimmune adrenalitis
cytotoxic CD8 T cells and helper CD4 T cells with reactivities against 21-hydroxylase
What is autoimmune polyendocrine syndrome
A form of adrenal insufficiency
15% are APS-1: adrenal insufficiency, hypoparathyroisim and chronic mucocutaneous candidiasis. AIRE gene mutation
85% APS-2: adrenal insufficiency + autoimmune thyroid disease (Schmidt’s syndrome) + Type 1 diabetes (Carpenter’s syndrome)
Both can get primary ovarian infufficiency
What is adrenoleukodystrophy? mode of inheritance?
a cause of adrenal insufficiency
X-linked
ALD gene mutation
very long chain fatty acid accumulation
What are investigations in adrenal insufficiency?
*Synacthen test abnormal (<400nmol/L)
*ACTH measurement- high
*aldosterone low
*renin raised
* DHEAS low
* 21 hydroxylase antibodies +ve
In antibody negative cases –> measure VLCFAs, image the adrenals for TB, metastases, lymphoma, and test for antiphospholipid syndrome
How much is a physiological requirement of glucocorticoid?
15-25mg hydrocortisone a day
common regimen: 10mg mane, 5mg midday, 5mg 4pm
increased requirements in 3rd trimester of pregnancy
What are the steroid conversions?
4 dexamethasone, 25mg pred, 100mg hydrocortisone
When is cortisol the highest?
in the morning
What is a normal mineralocorticoid replacement?
start with fludrocortisone 100ug/day
adjust according to plasma renin level
hydrocortisone has some mineralocorticoid activity, but prednisone has minimal and dexamethasone has none
Why does fludrocortisone dose need to be increased in pregnancy?
Progesterone has an anti-minerolcorticoid effect, and fludrocortisone dose usually needs to increase in the 3rd trimester
What is Critical Illness- related corticosteroid insufficiency (CIRCI)?
Sustained high levels of cortisol resulting in suppression of ACTH due to negative feedback
no single diagnostic test
treatment: hydrocortisone 40mg IV in the AM, 20mg IV in evening
What deficiency is involved in congenital adrenal hyperplasia?
autosomal recessive, low cortisol
mutations of the gene CYP21A2 causes steroids 21-hydroxylase deficiency
therefore you get 17a hydroxy progesterone build up
diagnosis: synacthin test and 17OHP levels go higher
What is the difference between classical and non-class forms of congenital adrenal hyperplasia?
Classic form –> diagnosed at birth, high 17OHP, cortisol lowly. Treatment: glucocorticoids +/- mineralocorticoids
Non-Classic form –> can have normal cortisol production, usually have hirsuitism, irregular periods, acne, infertility. 17OHP 30-300. Antiandrogen therapy
How does Crinecefont work in congenital adrenal hyperplasia?
A corticotrophic releasing factor type 1 receptor antagonist
reduces ACTH levels and in turn androgen levels
allows for physiologic glucocorticoid replacement
How to treat primary aldosteronism?
adrenalectomy for unilateral hyperaldosteronism
MRA therapy for bilateral forms of primary aldosteronism
How to screen for primary aldosteronism? What drugs to sto
Aldosterone: renin ratio
stop B-blockers, ACE-inhibitors/ARB, diuretics, DHP CCB
stop diuretics and Spiro for 6 weeks
all others 2-4 weeks
What are some confirmatory tests for primary aldosteronism?
Adrenal vein sampling
IV saline test
Captopril test
What are familial causes of primary aldosteronism?
Type 1: due to chimeric gene CYP11B1 (11B hydroxylase) + CYP11B2 (aldosterone synthase) expressed in zone fasiculata –> treat with steroids
When can you bypass adrenal vein sampling in aldosteronism?
If Adenoma >10mm + hypokalaemia + <35 years of age
What is the management of a aldosterone secreting adenoma?
Unilateral aldosterone secreting adenoma
- surgery > MRA
Bilateral adrenal hyperplasia
- MRA treatment: spironolactone or eplerenone
- aim for normal BP and K+ and normal plasma renin
- ENaC blockage: amiloride
- trials of aldosterone synthase inhibitors underway
What is the role of hounsfield units in adrenal incidentaloma?
hounsfield <10 likely non-functioning
suspicious lesions
>4cm in size
>10 HU density on non-contrast CT
<60% washout on delayed (15min) contrast scan
MRI- lack of signal drop out on chemical shift imaging
FDR-PET; SUVmax >5
What is the triad of pheochromocytoma?
Palpitations, headaches and sweating + Hypertension
How to investigate pheochromocytoma?
Plasma or urinary metanephrines
>3x ULN
if elevated but <3 xULN then try again or clonidine suppression test. if doesnt get suppressed likely pheo
Management of pheochromocytoma?
Alpha blockage, then Beta blockage
minimally invasive adrenalectomy
Describe approach to suspected Cushing’s syndrome
Describe screening test for Cushing syndrome
How to investigate ACTH dependent Cushing’s syndrome
MRI pituitary (tumour>10mm)
- CRH test, desmopression test, 8mg dexamethasone test
MRI normal or pituitary tumour <10mm
- bilateral inferior petrosal sinus sampling
What are some imaging options for suspected Cushing’s disease?
*MRI pituitary
*fine cut whole body CT
*Ga-Dotatate: modified (Tyr3)-octreotide molecule covalently linked to 1,4,7,10-tetraazacyclododecane-1,4,7,10tetraacetic acid (DOTA) combined with the radioactive 68Ga isotope
Diagnostic approach to amenorrhoea
What is that pathophysiology of PCOS?
What is Rotterdam criteria for PCOS?
Need 2 of 3
1) oligo or anovulation
2) clinical and/or biochemical hyperandrogenism
3) Polcystic ovaries on US (20 or more follicles measuring 2-9 diameter), increased ovarian volume >10ml, not recommended for diagnosis <8 years post menarche
What are typical lab findings of PCOS?
- elevated testosterone, low SHBG, elevated DHEAS
- elevated LH/FSH ratio, elevated AMH 2-3x
How to treat hirsuitism in PCOS?
anti-androgen- cyproterone, spironolactone (with contraception)
Describe fertility treatment in PCOS
ovulation induction:
*letrozole (aromatase inhibitor)
*clomiphene citrate- oestrogen receptor antagonist
*metformin (not superior to clomiphene)
IVF
Laparoscopic ovarial drilling/diathermy
What are investigation findings in functional hypothalamic amenorrhoea?
increase cortisol, decrease TSH, Decease T3, decrease IGF-1, decrease leptin
decrease FSH, decrease LH, decrease oestrogen
reduced bone density
What is the SRY gene on the Y chromosome?
This determines whether you will produce testes or not
What is 46XY complete gonadal dysgenesis?
Phenotypic female with normal external genitalia including uterus and fallopian tubes (normal mullerian structures)
increase FSH and LH, decrease oestradiol, normal testosterone, 46XY
underdeveloped streak gonads with increased risk dysgermimoma
treatment: HRT, remove streak gonads, fertility
What is complete androgen insensitivity syndrome (AIS)
- female external genitalia at birth, but absent mullerian structures (no uterus, fallopian tubes or upper vagina due to MIF produced by fetal testes)
- present with primary amenorrhoea
- pubic and axillary hair absent or sparse
- karyotype 46XY, testosterone N or increased, normal conversion to DHT, LH increased
- removal of testis to prevent malignant transformation but low risk and necessity/timing of surgery unclear
Turner syndrome, genetics + height?
45X
short stature
ovarian failure (streak gonads, elevated FSH/LH)
congenital bicuspid aortic valve, coarctation of the aorta
How long do you need to have amenorrhoea before you call it menopause?
12 months
What is Kallmans syndrome?
Anosmia + hypogonadotrophic hypogonadism
genes: ANOS1 (or Kal1) X linked recessive Xp22.3
midline defects (cleft lip and palate)
renal agenesis
sensorineural hearing loss
abnormal eye movements
synkinesia
What is Klinefelter syndrome?
*increase FSH and LH, decrease or low normal testosterone
*semen analysis- azospermia
*DEXA- reduced bone mineral density
Describe the calcium handling in the kidney
Majority is passively reabsorbed in the proximal tubule and thick ascending limb
Approximately 10% is actively reabsorbed in DCT
There is the calcium sensing receptor in the kidney
What is the pathophysiology for Familial hypocalciuric hypercalcaemia?
Autosomal dominant
often have hypermagnesaemia
PTH dependent
Inactivating mutation of CaSR
3 variants: CaSR gene, Ga11 gee, AP2S1 gene
correct Mx- do nothing
What is the effect of PTH in the kidney?
1) calcium reabsorption in the DCT
2) phosphate excretion in the PT
3) stimulates 1 alpha hydroxylase promoting 1, 25 Vit D synthesis
What is FGF23 made from?
Osteocytes
What is the action of FGF23?
What regulates PTH?
1) serum calcium via extracellular calcium sensing receptor –> inhibits release of preformed PTH
2) chronić hypomagnesaemia inhibits PTH release
3) FGF23 inhibits PTH secretion
4) 1,24 vitamin D inhibits PTH secretion
5) Hyperphosphataemia stimulates secretion directly
What does PTH act on?
Intestine –> increases renal 1,25OH2 Bit D
Kidney –> stimulates Ca reabsorption in distal tubule, stimulates 1alpha hydroxylase, inhibits phosphate reabsorption and bicarbonate reabsorption
Bone –> stimulate bone resorption or formation
Management of hyperparathyroidism?
Surgery
bisposphonates
cinacalcet –> stimulates calcium sensing receptor
Describe the structure of osteoblast
Express PTH and Vit D receptors and Alk Phos on cell surface
Produce type 1 collagen, osteocalcin, osteopontin
lay down bone matrix (osteoid) which is then mineralised by deposition of hydroxyapatite
What are osteocytes? and their relationship to sclerostin
Osteocytes are osteoblasts that remain within corticol bone
act as sensors of mechanical loading
secrete sclerostin tonically that inhibit bone formation
respond to mechanical forces by stopped sclerostin production triggering bone remodelling
What are osteoclasts and what do they arise from?
Multinucleated Giant cell specialised for bone resorption
arise from monocyte precursors
formation and activation is stimulated by osteoblasts
osteoclasts pump protons, generated by carbonic anhydrase II, into the resorbing compartment to dissolve the bone mineral
Then the collagen-rich bone matrix is degraded by proteases such as cathepsin K and matrix metalloproteinases
Discuss what produces Rank ligand?
osteocytes and osteoblasts
What is RANK and what is OPG?
RANK is a receptor for RANKL on osteoclast precursors
OPG is osteoprotegerin - a soluble “decoy” receptor for RANKL
When to treat osteoporosis?
*T score of -2.5 or less at the femoral neck, total hip, lumbar spine, 33% radius
*fracture of the hip or vertebra regardless of BMD or DXA
* osteopenia at the femoral neck or total hip by DKA with 10-year hip fracture risk >3%
*osteopenia with fracture of proximal humerus, pelvis, or distal forearm
How to treat high risk vs very high risk of osteoporosis?
High risk –> bisphosphonates
very high risk –> teriparatide or abaloparatide; romosuzumab if not at high CV risk
What bone turnover markers to monitor when you start someone on bisphosphonates:
CTX at 3 months
P1NP at 6 months
can monitor this in patients on bisphosphonates to establish treatment adherence and response
What is the max recommended daily dose of vitamin D?
4000 IU
What is the role of SERM drugs in fractures?
only have benefit in vertebral fractures
What is the MOA of bisphosphonates?
Bind to hydroxyapatite crystals at sites of active bone remodelling
inhibit bone resorption by inducing osteoclast apoptosis
Where is the greatest benefit of bisphosphonates?
Greatest effect in sites rich in trabecular bone where baseline turnover is high such as the lumbar spine
Describe features of atypical femoral fractures
Location: subtrochanteric, femoral shaft or diaphysis
*Usually bilateral
*Atraumatic or minimal trauma
*often a prodome of thigh pain
*biopsy: marked suppression of bone turnover
association with glucocorticoids, RA, PPIs, low vit D
Risk reduces rapidly after stopping bisphosphonate
Examples of bisphosphonates vs RankL antibody
bisphosphonates: alendronate, risedronate, zoledronic acid
RANKL monoclonal antibody: denosumab
What is the MOA of denosumab?
RANK L inhibitor
inhibits osteoclastogenesis
causes significant drop in BTO markers (CTX, P1NP)
can get osteonecrosis of the jaww and atypical fractures
What is a risk with suddenly stopping denosumab?
Rapid loss of BMD on stopping with clusters of vertebral fractures
* Mechanism unclear but may be due to dormant osteoclast precursors that then
undergo synchronous activation on stopping denosmab
What is the MOA of teriparatide?
Agonist of the PTH type 1 receptor
intermittent PTH preferential stimulates formation
Promotes differentiation of preosteoblasts and inhibits osteoblast apoptosis
Greater effect in trabecular than cortical bone i.e. lumbar spine compared to the hip
What is abaloparatide?
Analogue of human parathyroid hormone-related peptide
similar to teriparatide
What is canonical Wnt pathway?
stimulates bone formation
receptor: LRP5/6
co-receptor: frizzled
What are sclerostin inhibitors?
Sclerostin is produced by osteocytes
sclerostin reduces bone formation. SCLEROSTIN BAD
sclerostin inhibitors inhibit bone resorption by stimulating osteoprotegerin formation
eg romosuzumab
Is Denosumab followed by teriparatide good?
NO, leads to significant bone LOSS and should be avoided
What is the main mechanism of glucocorticoid induced osteoporosis?
stop osteoblast formation and cause osteoblast apoptosis
What type of fractures are most associated with glucocorticoids?
vertebral fractures
the risk of fractures rapidly decreases with glucocorticoids are discontinued
When to treat patients for osteoporosis when taking glucocorticoids?
1) treat if previous fracture or age >70 years OR prednisone dose >7.5mg/day
2) if no previous fracture and age <70 years and prednisone dose <7.5mg per day. Treat if: DEXA T score <-2.5 OR FRAX MOF >20% or hip fracture >3%
Which gene confers the greatest contribution to polygenic obesity from GWAS?
FTO gene
What is the action of leptin?
Secreted by white adipose tissue
low leptin levels are a strong stimulus of food intake (starvation response) but high leptin levels do not induce satiety.
What hormones make you full (satiety)? hungry?
Satiety: GLP1, PYY3 peptide, cholecystokinin (CKK), Pancreatic polypeptide
Hungry: Ghrelin, neuropeptide Y (NPY), agouti-related peptide, orexin, endocannabinoids, galanin
What is a classic MRI finding in charcot arthropathy?
MRI- bone marrow oedema, soft tissue oedema, subc
Summarise the different insulin and duration of action
Insulin isodec- half life of 8 days
insulin degludec- 40 hours (bind to albumin)
Insulin glargine- 24 hours
Insulin detamir- 20 hours (binds to albumin)
How to calculate cholesterol levels?
HDL + LDL + 20% triglycerides = total cholesterol
How to diagnose familial hypercholesterolaemia?
