Endocrinology Flashcards
How reproducible is the OGTT
65%
How often to have HbA1Cs for
1) diagnosis
2) monitoring
MBS rebats:
1) every 12 months for diagnosis
2) 4 times/year for established diabetes
Factors that alter HbA1C
1) erythropoiesis: lower erythropoiesis = increased HbA1C and increased erythropoiesis (e.g. EPO administration) = decreased HbA1C
2) Altered Hb - haemoglobinopathies
3) Glycation - ETOH, CKD increased HbA1C, aspirin, vit C decreased HbA1C
4) Erythrocyte destruction - splenectomies increase HbA1C, things that decrease erythrocyte lifespans (splenomegaly) decrease HbA1C
5) Things that affect the assay: Bilirubin, triglycerides
What’s Whipple’s Triad
3 clinic criteria that suggests the non diabetic patient’s symptoms may result from an insulinoma.
1) Symptoms known or likely to be caused by hypoglycemia especially after fasting or heavy exercise
2) A low plasma glucose measured at the time of the symptoms
3) Relief of symptoms when the glucose level is raised
What investigations to do for hypoglycaemia in a non diabetic?
Insulin
C-peptide
What is C-peptide
A byproduct of insulin production. It is a good marker of insulin production.
When to avoid contrast in thyroid disease
Multinodular goitre, suppressed TSH, thyrotoxicosis history
What is C-peptide
A byproduct of insulin production. It is a good marker of insulin production.
When to avoid contrast in thyroid disease
Multinodular goitre, suppressed TSH, thyrotoxicosis history
1st investigation after finding a thyroid nodule clinically
TSH
Thyroid nodule and TSH not suppressed
Fine-needle aspiration biopsy
Are malignant thyroid nodules taller or wider
taller
Adrenal incidentoloma <10 HFU and <4cm
Check functional status – ARR – 24h Urinary Catecholamines – 1 mg Dexamethasone suppression test • Repeat adrenal CT scan in 6 months • Then annual CT scans for 1-2 years • Hormone re-evaluation annually for 5 years
Antihypertensives that do not affect ARR
verapamil, prazosin, hydralazine, moxonidine
Antihypertensives that do not affect ARR
verapamil, prazosin, hydralazine, moxonidine
What effects would ACE I have on renin?
Increase renin
What effects would ACE I have on renin?
Increase renin
How frequently to monitor for pituitary microadenomas (<1cm)
Re-scan in 12 months; annual scans for 3 years
Next investigation for androgen deficiency
LH/FSH
To work out if it’s a testicular (high LH/FSH) or hypothalamo-pituitary (low LH/FSH)
What does prolactinomas do to androgen levels?
It suppresses LH and FSH and hence suppresses androgen production
Criteria for striae that discriminates Cushings syndrome from the normal population
Reddish purple and 1cm wide
Screening test positive for Cushing’s Syndrome - what next
ACTH - to see if the hypercortisolism is ACTH dependent or not
ACTH independent suggests adrenal source
Cushing’s Syndrome + high ACTH - what next
High dose dexamethasone suppression tests - suppresses cortisol in Cushing’s Disease patients (temporarily) but not ectopic ACTH producing tumours
OR
Bilateral inferior petrosal sinus sampling - ratio of central to peripheral ACTH of more than 2 in the basal state or more than 3 after CRH stimulation is consistent with Cushing’s disease
DKA criteria
Hyperglycaemia (serum glucose >14)
Ketosis
pH <7.3 (bicarb <20 mmol/l)
HHS criteria
Hyperglycaemia (serum glucose >30 mmol/l)
Minimal ketosis
Serum osmol>320 mOsm/kg
What medication can result in euglycaemic DKA
SGLT2 inihibitor (gliflozin)
HHS mortality compared with DKA
3x higher
Most common precipitant of DKA
Infection
DKA fluid loss
3-6L
HHS fluid loss
8-10L
Insulin infusion rate for DKA
0.1units/kg/hr until BGL <11.1 then swap to IV dextrose and halve insulin infusion rate
Insulin infusion rate for HHS
0.5units/kg/hr until BGL <15 then half insulin infusion rate
Indication for bicarbonate in DKA
Low level evidence, may be used in severe DKA pH <7
How long should IV insulin infusion and SC insulin overlap for
2 hours
What is ketosis-prone diabetes
Also called flatbush diabetes. Common in African ethnicity. A clinical spectrum of patients who develop DKA but does not fit the phenotype of T1DM. They are thought to be diabetes autoantibody negative and have severe insulin resistance +/- reversible beta-cell dysfunction.
These patient can get recovery in their insulin production and do not necessarily remain insulin-dependent. However, they should still be discharged on insulin therapy to be monitored.
What OHG needs to be withheld before the day of surgery
SGLT2 inhibitors due to the risk of DKA (at least 2 days, and USA guidelines state 3 days prior surgery).
Metformin needs to be withheld for 24 hours before major surgery
Plan for insulin day prior to surgery
Give usual insulin dose day before surgery including nocte basal insulin
Where does SGLT2 inhibitors act
They decrease glucose reabsorption in the proximal tubule independent of insulin - leading to glycosuria
Pathophysiology of euglycaemic DKA
Reduction in plasma glucose leads to reduction in plasma insulin levels and risk in plasma glucagon.
The lower insulin:glucagon ratio stimulates lipolysis and enhanced lipid oxidation which results in mild ketogenesis. This becomes more pronounced in a lack of carbohydrate availability and the mild ketosis and evolve into ketoacidosis
Mechanism of action if DPPIV inhibitors (gliptins)
They inhibit the DPP4 enzyme which inactivates GLP1 and GIP. GLP1 increases glucose uptake by peripheral tissues and decrease hepatic glucose production.
DPPIV adverse effect compared with sulfonylurea
DPPIV have no hypoglycaemia because it only stimulates insulin during meals instead of all the time like sulfonylurea. It also causes weight loss instead of weight gain. However, there is no mortality benefit. It is non inferior to sulfonylurea
Mechanism of GLP-1 analogues
Insulin sparing agents (use in conjunction with insulin).
E.g. exenatide, dulaglutide, liraglutide
GLP1 increases glucose uptake by peripheral tissues and decrease hepatic glucose production. It also stimulates beta pancreatic cells to produce more insulin
Assoc w weight loss and risk of hypoglycaemia is low
HbA1C targets in pregnancy
<6.0
What is foundational therapy in T2DM
Metformin
What OHG to avoid in heart failure and T2DM
Thiazolidinediones “-glitazone”
Second line in T2DM without cardiovascular disease or weight loss or hypoglycaemia issues
sulfonyureas, thiazolidinediones
Polycystic ovary syndrome clinical features
hyperandrogenism (clinical, biochemical, or both), ovulatory dysfunction, and polycystic ovarian morphologic features.
FSH, LH, estrogen and testosterone findings in PCOS
High LH
Low FSH
Excessive androgen
Biochemical findings that suggest primary ovarian failure
Low or normal E2 that is associated with an elevated FSH indicates POI, while low or normal E2 associated with FSH that is normal or low suggests the possibility of secondary (pituitary or hypothalamic) hypogonadism, either structural or functional
What happens to prolactin secretion in pituitary stalk resection?
Increased prolactin production because the predominant central control mechanism is inhibitory (Via D2 receptors)
What hormones are produced by the anterior pituitary
Growth hormone Prolactin ACTH TSH Gonadotropins - FSH and LH
What are the actions of FSH and LH in women and men
In women, FSH regulates ovarian follicle development and stimulates ovarian estrogen production. LH mediates ovulation and maintenance of the corpus luteum. In men, LH induces Leydig cell testosterone synthesis and secretion, and FSH stimulates seminiferous tubule development and regulates spermatogenesis.
Amenorrhea/oligomenorrhea, normal uterus outflow tract and negative beta HCG and high FSH
Ovarian insufficiency
FSH is a better marker of ovarian failure because of loss of negative feedback effects of both estradiol and the inhibins and because its levels are less variable than those of LH.
Amenorrhea/oligomenorrhea, normal uterus outflow tract and negative beta HCG and low FSH
What to test next and what are the possibilities
Test Prolactin next
Ddx: neuroanatomic abnormalities or idiopathic hypogonadotropic hypogonadism
or hypothalamic amenorrhea
Treatment of symptomatic hyperthyroidism during pregnancy
Diagnosis within the first trimester should take PTU.
Diagnosis after the first trimester should take carbimazole.
Beta blockers can be used in the short term
What are the actions of FSH and LH in women and men
In women, FSH regulates ovarian follicle development and stimulates ovarian estrogen production. LH mediates ovulation and maintenance of the corpus luteum. In men, LH induces Leydig cell testosterone synthesis and secretion, and FSH stimulates seminiferous tubule development and regulates spermatogenesis.
Amenorrhea/oligomenorrhea, normal uterus outflow tract and negative beta HCG and high FSH
Ovarian insufficiency
Adverse effects of PTU and carbimazole
Minor AEs: pruritus, rash, urticaria, arthralgias, arthritis, fever, abnormal taste sensation, nausea, or vomiting in up to 13 percent of patients
Major AEs: Agranulocytosis, hepatotoxicity (PTU more), ANCA positive vasculitis
Treatment of symptomatic hyperthyroidism during pregnancy
Diagnosis within the first trimester should take PTU.
Diagnosis after the first trimester should take carbimazole.
Beta blockers can be used in the short term
What are the 2 most common causes of hyperthyroidism during pregnancy
Graves and hCG-mediated hyperthyroidism
Mechanism of action of PTU vs carbimazole
They are both thionamide compounds that PTU inhibits the 5’-monodeiodinase that converts thyroxine (T4) to triiodothyronine (T3) in extrathyroidal tissue. They are actively transported into the thyroid gland where they inhibit both the organification of iodine to tyrosine residues in thyroglobulin and the coupling of iodotyrosines
Carbimazole has longer half life, has higher intrathyroid concentrations
Treatment of primary adrenal insufficiency and acute illness
Increase their normal glucocorticoid dose 3 fold.
Do not require mineralcorticoid because high doses of glucocorticoid has mineralcorticoid receptor effects.
What type of medication is biguanides and what are the side effects
Metformin
MOA - inhibiting gluconeogenesis, increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver), particularly after meals, and has an antilipolytic effect that lowers serum free fatty acid concentrations, thereby reducing substrate availability for gluconeogenesis
Side effect profile: weight loss, maybe improved CVS profile GI effects (metallic taste in mouth, mild anorexia, nausea, diarrhoea), B12 deficiency (usually not severe), lactic acidosis
Difference in clinical manifestations of primary adrenal insufficiency (Addison’s) and secondary adrenal insufficiency
Addison’s - loss of both glucocorticoid and mineralocorticoid secretion
Secondary - only glucocorticoid deficiency is present, as the adrenal itself is intact and thus still amenable to regulation by the RAA system.
Adrenal androgen secretion is disrupted in both primary and secondary adrenal insufficiency
MOA of sulfonylureas and side effect profile
E.g. glicazide
Sulfonylureas bind to the sulfonylurea receptor on the K-ATP channel in the beta pancreatic cells and inhibits them, leading to calcium influx and release of insulin.
Good effects:
Glycemic efficacy — Sulfonylureas usually lower blood glucose concentrations by approximately 20 percent and glycated hemoglobin (A1C) by 1 to 2 percent
Side effects:
- Hypoglycaemia
- Weight gain
- ?negative cardiovascular effects
- CKD may increase risk of hypoglycaemia
Treatment of primary adrenal insufficiency and illness
Increase their normal glucocorticoid dose 3 fold.
Do not require mineralcorticoid because high doses of glucocorticoid has mineralcorticoid receptor effects.
What type of medication is biguanides and what are the side effects
Metformin
MOA - inhibiting gluconeogenesis, increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver), particularly after meals, and has an antilipolytic effect that lowers serum free fatty acid concentrations, thereby reducing substrate availability for gluconeogenesis
Side effect profile: weight loss, maybe improved CVS profile GI effects (metallic taste in mouth, mild anorexia, nausea, diarrhoea), B12 deficiency (usually not severe), lactic acidosis
What are anabolic (build up bone) drugs used in osteoporosis
full-length parathyroid hormone (PTH 1-84) or its N-terminal fragment, teriparatide (PTH 1-34)
MOA of sulfonylureas and side effect profile
E.g. glicazide
Sulfonylureas bind to the sulfonylurea receptor on the K-ATP channel in the beta pancreatic cells and inhibits them, leading to calcium influx and release of insulin.
Good effects:
Glycemic efficacy — Sulfonylureas usually lower blood glucose concentrations by approximately 20 percent and glycated hemoglobin (A1C) by 1 to 2 percent
Side effects:
- Hypoglycaemia
- Weight gain
- ?negative cardiovascular effects
- CKD may increase risk of hypoglycaemia
MOA of thiazolidinediones and side effect profile
e.g. glitazone
MOA: increase insulin sensitivity by acting on adipose, muscle, and liver to increase glucose utilization and decrease glucose production
Effects:
- Increased risk of heart failure, weight gain, fluid retention and fractures
- NOT likely to cause hypoglycaemia
- Cause weight gain
Other non glycaemic effects of SGLT2 inhibitors
Decrease BP and weight.
Do not cause hypoglycaemia as the glucose lowering effect is independent of insulin
denosumab MOA
Prevents RANKL binding to RANK and prevents osteoclast differentiation and activity
amiodarone induced thyrotoxicosis types and treatments
Type 1 - iodine induced hyperthyroidism
- normally has underlying predisposition: toxic nodules/Graves’ disease; treat with thionamide
Type 2 - inflammatory/destructive thyroiditis
- treat with glucocorticoids
What conditions does not respond to carbimazole
subacute viral thyroidisitis
type 2 inflammatory amiodarone inducd thyrotoxicosis
wolff chaikoff effect
protective mechanism
Iodine excess -> reduced expression of Na-iodide symporter and inhibition of H2O2 generation
-> escape to Jod-Basedow phenomenon
Amiodarone TFT pattern
early phase - mild TSH rise
prolonged therapy - TSH normalises, tend to low TSH, free T4 normal-high, normal T3
Amiodarone induced hypothyroidism treatment
levothyroxine and mostly does not need to cease amiodarone
differentiating between amiodarone induced thyroiditis type 1 vs type 1
thyroid U/S with colour flow doppler sonography: reduced/absent vascularity in type 2
AIT that develops quickly after commencement of amiodarone is more likely to be type 1
AIT that develops after drug cessation is more likely to be type 2
free T4 may be disproportionally higher in type 2 due to massive release of preformed thyroid hormone
Risk factor for developing graves’ opthalmopathy
smoking thyroid peroxidase antibodies have no bearing on the develpment of graves opthalmopathy pre-tibial myxedema duration of graves TSH receptor Ab titre Advancing age
what is thyroid bruit specific for
Graves (not multinodular goitre)
what are the specific signs for graves opthalmopathy
proptosis, periorbital oedema, conjunctival oedema, opthalmoplegia
where as lid retraction is due to increased sympathetic system
thyroiditis on thyroid uptake scan
no uptake
iodine induced thyrotoxicosis also has no uptake
what will give diffusely decreased technetium 99m pertechnetate uptake
hasimoto’s iodinated contrast, excess iodine, amiodarone, subacute thyroiditis, painless thyroiditis, tactitious thyrotoxicosis, struma ovarii, hyperfunctioning thyroid cancer mets
painful thyroiditis
subacute/de Quervain’s thyroiditis
- post viral (usually URTI)
infections/supprative thyroiditis
- systemically unwell
- TFTs usually normal
- USS +/- aspiration
painless thyroiditis
Hashimoto’s thyroiditis/lymphocytic thyroiditis
Postpartum thyroiditis
- normally within 3 months but up to 1 year
- increased risk with higher TPO Ab titre
Drugs
- Amiodarone, lithium, check point inhibitors, TKIs, IFN-alpha
when is pregnancy thyrotoxicosis
up to 16 weeks
what is associated with gestational thyrotoxicosis
hyperemesis gravidarum
heterophile antibodies in thyroid disease
assay interference in relation to antibodies
usually assos with TSH rise
clinically picture of TSHoma and TRH
mild sx of hyperthyroidism
goitres mostly present
normal TSH
high T4
what is the MOA of potassium iodide
prevents release of pre-formed thyroid effect
what kind of calcification in thyroid lesions are concerning
microcalcification
macrocalcification is not concerning
what HLA allele is most associated with T1DM
DR3 and DR4 (in combination)
Treatment target for T1DM - general population (HbA1C)
<7.0
Treatment target for T1DM pregnancy or planning pregnancy (HbA1C)
<7.0
Treatment target for T1DM recurrent severe hypoglycaemia or hypoglycaemia unawareness
<8.0
which OHG has shown efficacy in T1DM for glycaemic control
SGLT2
in what population does calcium and vitamin D have the greatest effect for primary prevention of fractures?
institutionalised elderly - no effect in free living individuals
what are the 3 main actions of the parathyroid hormone
- Increased bone resorption (osteoclast breakdown), which occurs within minutes after PTH secretion increases.
- Increased intestinal calcium absorption mediated by increased production of calcitriol, the most active form of vitamin D, which occurs days after PTH secretion increases.
- Decreased urinary calcium excretion due to stimulation of calcium reabsorption in the distal tubule, which occurs within minutes after PTH secretion increases
Where is bone density loss the greatest in primary hyperparathyroidism
vertebra > femoral > radius
Management of inoperable PHPT
- Oestrogens
- SERMs
- Alendronate
- Cinacalcet (calcimimetics) - only reduces serum Ca and PTH levels for up to 12 months, No effect on BMD
what antipsychotic gives a picture of hyperparathyroidism
lithium
hypercalcaemia with low urinary calcium diagnosis w family hx of same
Familial hypocalciuric hypercalcemia - mutation in the calcium sensing receptor; autosomal dominant inheritance
hypocalcaemia with high urinary calcium w family hx of same
autosomal dominant hypocalcaemia; treat with calcitriol
biochemical findings of osteomalacia
If due to vit D deficiency:
- high ALP (increased osteoblastic activity)
- low vit D
- low/normal calcium
- secondary hyperparathyroidism
- low phosphate
renal phosphate wasting and increased fibroblast growth factor 23
tumour induced osteomalasia and hypophosphataemia
benign mesenchymal tumour
which arcuate nucleus nerves make you hungry and suppresses hunger
NPY - want to eat
CART - suppresses hunger
What is P1NP in osteoporosis
a marker of bone formation
synthesised by osteoblasts
what is the most potent bisphosphonate available?
zoledronic acid
how long should bisphosphonates be
high risk (low hip T-score, hx fracture) - continuation of treatment for up to 10 years oral and 6 years IV non-high risk - 3-5 years and a drug holiday of 2-3 years can be considered
what population has the greatest incidence of osteonecrosis of the jaw?
oncology patients as the frequency of bisphosphonates is much higher
only 0.001% in the osteoporosis patient population
what is the PBS criteria for teriparatide?
BMD T score <3.0
2 or more fractures due to minimal trauma
At least 1 new symptomatic fracture after at least 1 months of continuous treatment with antiresorptive therapy at adequate doses
MOA denosumab
mAb to RANK-ligant - an osteoclast differentiating factor
the cessation of which anti-resorptive therapy would increase the risk of rebound fractures significantly?
denosumab - bisphosphantes shoudl be considered to prevent or reduce the rebound increase in bone turnover
BP target in diabetes
<140/90
at what age should statins be implemented for all diabetic patients?
> 40 yr
next step to lower LDL after statin
ezetimibe
the effect of intensive glycaemic control in type 2 diabetes on macrovascular, microvascular and mortality
- no significant effect on macrovascular
- decreases microvascular events
- increases mortality
what is the best marker/index of diabetic kidney disease progression
GFR
albuminemia is non specific
why is there an initial drop in eGFR when starting SGLT2 inihibitors
increased tone of afferent arteriole and decreased intragomerular pressure
screening of diabetic kidney disease in T2DM
Yearly from diagnosis (ACR + eGFR)
Diagnosis of acromegaly
- IGF-1
- OGTT for GH suppression if IGF-1 equivocal
- Pituitary MRI to differentiate between pituitary and extra-pituitary acromegaly
Acromegaly treatment
- Resection - selective trans-sphenoidal microadenomectomy vs total hypophysectomy +/- radiotherapy
- Medical - somatostatin analogue therapy (octreotide, pasireotide); possible role for adjunctive dopaminergic drug, GH receptor antagonist 3rd line (pegvisomant)
How does manifest ectopic ACTH present differently from Cushing’s disease?
Pigmentation
Hypokalaemia
Very high cortisol and ACTH
Severe myopathy
(Occult ectopic ACTH may closely resemble Cushing’s disease)
Treatment of Cushing’s disease
- Resection/irradiation of pituitary/bilateral adrenals
- Medical preparation pre-operatively: metyrapone, ketoconazole, mifepristone
- Medical treatment if failed other therapy - pasireotide
What is Carney complex?
Autosomal dominant condition with PRKAR1A mutations (tumour suppressor gene)
Presents with hyperpigmented skin and endocrine excess
Which test for Cushing’s syndrome is not accurate in woman on oral oestrogen
dexamethasone suppression test because of increased corticosteroid-binding globulin
How to classify micro vs macroprolactinoma
Macro = >1cm
Management of prolactinomas - micro and macro
- Micro = dopaminergic agent (bromocriptine, cabergolin)
2. Macro = medication +/- surgery with adjunctive radiotherapy
Pathology in central diabetes insipidus
Hypothalamic damage
Vasopressin/ADH deficiency
How to differentiate between central and nephrogenic diabetes insipidus
central responds to Pitressin or DDVAP
Management of hyperkalaemia in adrenal failure
IV calcium gluconate or bicarbonate. NOT insulin/glucose or resonium
Management of primary hyperaldosteronism and unilateral adrenal tumour on CT
<40 yr - adrenalectomy
>40 yr - adrenal vein sampling -> if lateralisation then medical prep with spironolactone and adrenalectomy
Management of Graves’ disease
Based on patient preference
Low risk can have antithyroid drugs (<40, small goitres, low titre TRABs, during pregnancy)
Older patients/high risk have a higher risk of relapse and should consider ablative therapy
I131 may exacerbate opthalmopathy
Surgery is good for obstructive goitre
Management of multinodular goitre/toxic adenoma
Both should get ablative therapy intead of thionamide therapy as remission is unlikely.
Toxic adenoma is particularly suited to I131
MNG can have either depending on seizure of goitre, obstructive symptoms or suspicion of malignancy
Indications for treatment of subclinical hyperthyroidism
TSH <0.1mL
Osteoporosis/heart disease
>65 years
MNG
Management of thyroid storm
HDU/ICU Propanolol PTU (lowers T3 levels quicker) Steroids Cholestyramine PLEX
When to treat subclinical hypothyroidism
TSH >10
Treat if pregnant or contemplating pregnancy
Goitre, hyperlipidaemia, depression
Treatment of subacute thyroiditis
NSAIDS +/- prednisolone
BBlocker for symptoms
Thionamides ineffective
Is hyperechoeic or hypoechoic worse prognosis for thyroid nodules?
Hypoechoic
Which thyroid nodules to FNA?
Non-hot nodules on Tc99m uptake scan
>2cm and not cyst
1-2 cm based on TI-RADS 3-5
<1cm repeat evaluation in 6-12 months
What thyroid cancers may be amendable to a partial thyroidectomy?
<4cm young patients with no adverse features
General management of thyroid cancer
- Total thyroidectomy
- Remnant ablation with I131
- Surveillance with thyroglobulin measurement
- Stimulated thyroglobulin
- Whole body iodine scans
Neck US - TKI therapy for non-iodine avid recurrent and progressive disease
What cancer is PCOS associated with?
Endometrial carcinoma
Treatment of infertility in PCOS
- Lifestyle modificaiton (weight loss)
- Letrozole (aromatase inhibitor)
- Clomiphene
- Metformin
- Gonadotrophin therapy
- IVF
What to exclude in patient with hyperandrogenism and virilization?
Androgen secreting tumour
Cutaneous manifestations of Turner syndrome
Small fingernails Brown spots (nevi)
Cardiac manifestations of Turner Syndrome
Coarctation of aorta Bicuspid aortic valve Mitral valve prolapse IHD Dissection ECHO every 3-5 years
What condition is FMR1 mutation implicated in?
Fragile X
Most likely cause of Cushing’s syndrome in ACTH dependent Cushing’s syndrome with normal MRI scan of the pituitary fossa
still pituitary tumour that’s small and not seen on MRI
What dietary intake is associated with hypokalaemia in primary hyperaldosteronism
high salt intake
