Endocrinology Flashcards
Criteria for surgery in adrenal incidentaloma
- Size >6cm or imaging suggestive of malignancy
- Increase in size from interval scan
- Functional tumour - pheochromocytoma, unilateral disease in primary hyperaldosteronism, autonomous cortisol secretion
Test of choice for acromegaly
IGF-1 as a screening test
OGTT to check for GH suppression
Describe the action of bisphosphonates.
How long should bisphosphonates be used for?
Binds to hydroxyapatite crystals and acts as a toxin to osteoclasts causing accelerated apoptosis.
Little evidence to guide recommendation however…
- High risk osteoporosis (severe osteoporosis with previous fracture) - continuation of treatment for 10 years of oral or 6 years of IV with periodic evaluation
- Not at high risk after 3-5 years of therapy - consider drug holiday of 2-3 years
5 causes of hypokalaemia WITHOUT hypertension
- Diuretics
- Bartters
- Gitelman
- GI loss (diarrhoea, vomiting)
- RTA 1 and 2
What are the absolute risks/benefits of HRT?
Benefits: reduced hip fracture, colon cancer
Risks: Increased rates of breast cancer, PE, stroke, CAD
5 causes of premature menopause?
Premature if <40 age (occurs in 1%)
1. Idiopathic/autoimmune (>50%) Associated with autoimmune thyroid disease, T1DM and addisons disease 2. Turner's syndrome (23%) 3. Chemotherapy 23%) 4. Familial (4%) 5. Surgery, radiation
Causes of nephrogenic DI
- genetic: the more common form affects the vasopression (ADH) receptor, the less common form results from a mutation in the gene that encodes the aquaporin 2 channel
- electrolytes: hypercalcaemia, hypokalaemia
- drugs: demeclocycline, lithium
- tubulo-interstitial disease: obstruction, sickle-cell, pyelonephritis
Lifetime risk of T1DM if following family members are affected:
- Identical twin
- Both parents
- Parent and sibling
- Father only
- Mother only
- Sibling
- 40%
- 25%
- 25%
- 5%
- 2%
- 7%
How would you test for cure of acromegaly?
75g oral glucose load. Normally GH should be undetectable 2 hours after glucose loading.
What cancers are associated with acromegaly?
Colon cancer (screen from age of 40 onwards)
Thyroid cancers - screening for this is currently uncertain area.
Describe Wolf-Chaikoff phenomenon
Ingestion of large amount of iodine results in transient inhibition of organification of iodine, resulting in low thyroid hormone level.
Autoimmune thyroid diseases are more sensitive to this effect than normal gland.
Eventually an ‘escape’ phenomenon occurs via downregulation of sodium iodide symporter at the basolateral membrane and normal thyroid organification by thyroid perodixidase resumes.
Definition of central obesity on the basis of waist circumference
Male >102cm
Females >88cm
What is the role of thyroperoxidase at the apical mebrane?
Involved in iodination of thyroglobulin and coupling to form DIT.
Regulated by iodide and H2O2 supply.
Name 6 hormones from the anterior pituitary
FSH LH Prolactin GH ACTH TSH
Compare and contrast aldosterone producing adenoma (APA) vs idiopathic hyperaldosteronism (IHA) ie bilateral hyperplasia
In general, APA patients have higher aldosterone secretion rates, resulting in more severe hypertension, more profound hypokalemia (<3.2 mEq/L), and higher plasma (>25 ng/dL) and urinary (>30 mcg/24 hour) levels of aldosterone; these patients are also younger (<50 years) than those with IHA.
Bilateral adrenal hyperplasia, which accounts for approximately 60 percent of cases, is generally a milder disease with less hypersecretion of aldosterone and less hypokalemia; it should be treated with a mineralocorticoid receptor antagonist.
Contraindications to insulin stress test
epilepsy
ischaemic heart disease
adrenal insufficiency
4 GH stimulation tests available in testing for GH deficiency
- Insulin stimulation test
- Glucagon test - Administration of glucagon causes transient hyperglycemia, which in turn stimulates endogenous insulin secretion followed by controlled hypoglycemia, and consequent GH secretion. Less risky than insulin stimulation test and more suitable for children
- Clonidine test - induce GH stimulation via several mechanism including GHRH secretion. Need to watch out for hypotension and hypoglycaemia
- Arginine test
Who should be screened for primary hyperaldosteronism?
- Hypertension with hypokalaemia easily induced by low dose diuretics
- Drug-resistant hypertension (defined as suboptimally controlled hypertension on a three-drug program that includes an adrenergic inhibitor, vasodilator, and diuretic
- Adrenal incidentaloma
- Hypertension with family history of early onset HTN age <40
- All hypertensive first degree relatives with primary hyperaldosteronism
- Hypertension with sleep apnoea
4 risk factors for hypocalcaemia in denosumab use?
- CKD
- Malabsorption
- Hypoparathyroidism
- Malignancy
Describe 4 side effects of thionamides (CBZ, PTU)
- Rash
- LFT derangements
- Neutropenia
- pANCA vasculitis
Describe follicular thyroid carcinoma
10% of differentiated thyroid cancers.
Can be distinguished from follicular adenoma by capsular and vascular invasion
Spreads haematogenously to lungs, bone, brain, liver and skin
BP target in diabetes and hypertension
<140/90, or lower target at <130/80 if younger patient.
Lifestyle advice if >120/80
If above 140/90, advise lifestyle therapy and prompt initiation and uptitration of BP meds
ACCORD study investigated intensive vs standard BP therapy in diabetes. Intensive therapy did not translate to improved MI/stroke death. Therefore it is unclear at this stage how aggressively BP should be treated, however therapy should be individualized.
Describe short synacthen test
To test for adrenal insufficiency.
Cortisol level is measured at 30 and 60min post synacthen.
Level above >550 excludes primary adrenal insufficiency, however it cannot exclude RECENT secondary adrenal insufficiency (eg due to pituitary haemorrhage, surgery)
If <550, 3 possibilities
- Primary adrenal insufficiency
- Secondary adrenal insufficiency WITH adrenal atrophy (ie, not recent but chronic)
- Chronic steroid use with secondary adrenal atrophy
How would you distinguish between type 1 and type 2 amiodarone induced thyrotoxicosis?
When treated for both with prednisolone and carbimazole, if T4 falls by 50% in 2 weeks, likely type 2 (ie, thyrocyte cytotoxicity). Continue to treat with prednisolone and stop carbimazole.
WHO definition of osteoporosis
Definition of severe osteoporosis?
Bone mineral density <2.5 or more standard deviations below normal peak bone mass
Severe osteoporosis is above plus >1 fractures
What is the significance of anti-GAD positivity?
10% of adults who develop diabetes over the age of 25 are islet antibody positive. Majority of the asymptomatic GAD positive patient will progress to insulin treatment within 6 years of diagnosis.
4 major endocrinological manifestations of Turner’s disease
- Autoimmune thyroid disease
- Diabetes
- Coeliac disease
- Osteoporosis
Describe the usual insulin secretion pattern.
What is lost in type 1/2?
Rapid first phase insulin response within 2-4 min, followed by delayed second phase insulin response which plateaus at 2-3 hours.
Loss of first phase insulin response is characteristic in type 1/2 diabetes, resulting in post glucose challenge or post prandial hyperglycaemia.
Common side effects of octreotide/lanreotide?
GI side effects including gall stones and abdominal pains
4 factors which decrease sex hormone binding globulin
- Obesity
- Nephrotic syndrome
- Diabetes
- Use of steroids, progestin and androgenic steroids
Name 3 factors which can increase/decrease HbA1c
Decrease - anything that shortens RBC lifespan
- Sickle cell anaemia
- G6PD deficiency
- Hereditary spherocytosis
Increase - due to increased RBC lifespan
- Vit B12/foalte deficiency
- Iron deficiency anaemia
- Splenectomy
How do you distinguish between raised prolactin due to stalk effect vs prolactinoma?
Prolactin <5x ULN = stalk effect or macroprolactin (prolactin bound to IgG)
Prolactin >10x ULN = almost always due to prolactinoma.
How does testosterone circulate in the body?
44% tightly bound to sex hormone binding globulin
54% weakly bound to albumin, 2% are free testosterone.
Albumin bound and free testosterones are the bioavailable testosterones.
What confers the survival benefit in acromegalic patients who has persistently elevated IGF1 level after resection of the GH secreting tumour?
Normalization of the IGF-1 level with medical therapy.
Dopamine agonist often fails.
Second line are octreotide or lanreotide.
Definition of hirsutism
6 causes?
Excess of facial and body hair (terminal hairs which are pigmented and coarse compared to vellus hair which are fine, short and only lightly pigmented) in females in the male distribution.
Causes:
- PCOS
- HAIR-AN (hyperandrogenism, insulin resistance, acanthosis nigricans)
- Tumours - ovarian, adrenal tumour
- Ovarian hyperthecosis - hyperplasia of the theca cells
- Drugs - anabolic steroids
- Late onset CAH (eg 21 hydroxylase deficiency)
Characteristics of adrenal incidentalomas?
How would you manage them?
Functional tumour in 15%
9% - subclinical cushings
4% - phaeochromocytoma
2% - aldosteronoma
Rarely carcinoma
Usually removed if >6cm based on size.
If non functional and <4-6cm, then repeat scan in 6/12 months. If growing - remove. If stable - observe.
Diagnosis of Diabetes Mellitus
Fasting BSL >7 or random BSL >11.1 or HbA1c >48 mmol/mol
If symptomatic + above - diagnosis established
If asymptomatic - needs 2x measurements
2 hour OGTT:
At 0 hour - if fasting BSL 6.1 - 7 = impaired fasting glucose
If fasting BSL >7 mmol/L = DIABETES
At 2 hours -
If BSL 7.8 - 11.1 mmol/L = impaired glucose tolerance
If BSL >11.1 mmol/L = DIABETES
5 antihypertensive agents used to control BP prior to PAC/PRC measurements
Verapamil
Hydralazine
Prazosin, doxazosin, terazosin
Describe the action of denosumab
‘Artifical OPG’
Binds to RANK-L and prevents osteoclast differentiation.
What are the limitations of adrenal CTs in localizing the subtype of primary hyperaldosteronism?
Aldosteronin secreting adenomas can be small and can be missed from CT.
Bilateral lesions are not diagnostic of hyperplasia (because some patients with an aldosteronoma in one adrenal gland have a nonfunctioning adrenal nodule in the other).
This highlights the importance of adrenal vein sampling.
3 risk factors for Graves ophthalmopathy.
- Smoking
- Aggressive control leading to hypothyroidism
- I131 therapy
6 causes of raised prolactin other than prolactinomas.
- Pregnancy/lactation
- Hypothyroidism - TRH stimulates PRL release
- Craniopharyngioma
- Metoclopramide
- Neuroleptics - most commonly affecting dopamine such as 1st generation agents, haloperidol
- Stress
3 factors associated with INCREASE in sex hormone binding globulin
- Ageing
- Hepatic cirrhosis and hepatitis
- Use of anticonvulsants
What are the 5 evidences of fetal thyroid dysfunction on ultrasound in TRAb positive pregnancy?
- Thyroid enlargement
- IUGR
- Hydrops
- Advanced bone age
- Fetal tachycardia
Diagnosis of Cushing’s syndrome
Key principles:
- Demonstrate hypercortisolism
- 3x 24 hour urine free cortisol to demonstrate 3x fold elevation (1/3 collection will be normal)
- Late night salivary cortisol at 11pm-12am - Demonstrate pathophysiological dynamics of control of cortisol secretion, ie lack of suppressibility
- Overnight low dose dexamethasone suppression test
ACTH should only be done once these tests confirm Cushing’s syndrome.
What is the impact of hormone replacement therapy on breast cancer risk?
Small increase in risk of breast cancer in combination E+P therapy. Estrogen by itself is protective.
Risk increases with greater length of its use.
Risk is greater in thinner women than overweight and obese women.
Describe the effects of following medications on thyroid.
- anti-CTLA/PD1 inhibitors
- Anti-CD52 (alemtuzumab)
- TKI
- Causes central hypothyroidism and thyroiditis.
Central hypothyroidism is more common with CTLA4 inhibitors. Thyroiditis more common with PD1 inhibitors - Graves disease 15%
- Hypothyroidism in 25%
How would you distinguish between Cushing’s disease and ectopic ACTH secretion?
High dose DEX suppression test.
In cushing’s disease, suppression with high dose dexamethasone should be seen.
Retinopathy screening in Type 1 DM
At diagnosis then every 1-2 years
In children, start screening at puberty.
What hormones need to be replaced in pituitary insufficiency?
Thyroxine (follow fT4, not TSH)
HRT or testosterone unless history of prostate or breast cancer
Glucocorticoids
Prolactin does not need to be replaced unless Pt is pregnant and wants to breast feed.
Since adrenal glands are intact and most glucocorticoids have some mineralocorticoid effect, addition of fludrocortisone is not required.
GH replacement in children, but in adults it can increase sense of wellbeing (but currently not funded)
What is the agent of choice in cystic fibrosis related diabetes?
Insulin. Start with short acting insulin first.
Given pancreatic dysfunction leading to insulin and glucagon deficiency, Pt are very sensitive to insulin therapy but not for metformin and sulphonylurea.
Acarbose is also inappropriate - causes GI side effects in a patient already with pancreatic insufficiency.
What risk is conferred by presence of anti-thyroid antibodies in pregnancy?
- Miscarriage
2. Premature birth
HLA genes involved in Type 1 DM
HLA DR3/4
How would you manage a recurrent follicular/papillary cancer after thyroidectomy and I 131 ablation?
Can consider systemic therapy to re-differentiate the thyroid cancer using pioglitazone or rosiglitazone (if PPAR gamma expression by the tumour), or using multitargeted TKIs such as sorafenib.
Once redifferentiated, can use further course of I 131.
What is a rare side effect of zolendronic acid?
Serious atrial fibrillation in 1.3%
5 factors which increase plasma cortisol binding globulin production
Remember - 95% of cortisol is protein bound, and 80% of these are bound to CBG (rest are bound to albumin)
Therefore CBG can affect serum cortisol level.
Factors which increase CBG level:
- Pregnancy
- Oestrogen administration (increased hepatic synthesis)
- Hyperthyroidism or hypothyroidism
- Inflammation or acute illness.
Given that serum cortisol assay measures TOTAL level, think about measuring urine and salivary free cortisol level.
What is P1NP and how is it used?
Serum marker of bone turnover.
Can be used to monitor compliance to therapy.
Bisphosphonates - would expect the P1NP to fall by 40% over initial 3 months by further slow reduction over 12 months.
Teriparatide - stimulates bone formation therefore would expect the P1NP level to rise.
Physiological mechanisms in response to hypoglycaemia?
- Decreased insulin first
- Increase in glucagon leading to increased hepatic gluconeogenesis and glycogenolysis
- Increase in epinephrine secretion which increases the hepatic production of glucose via beta 2 receptor, and impairs peripheral uptake of glucose via alpha 2 receptor.
GH and cortisol rises if hypoglycaemia persist for hours.
When would you biopsy a thyroid nodule?
> 2cm and not a cyst or spongiform appearance
If <1cm - repeat USS 6-12 months
Lesions that increasee by 30% in volume or 10% in diameter should be biopsied
If hot nodule - do not biopsy
Lesions 1-2cm - selected based on high risk features
Mechanism of action and side effects of metyrapone
11 beta hydroxylase inhibitor.
Blocks metabolism of 11-deoxycortisol to cortisol.
Used in medical therapy for Cushings syndrome
Subsequent decrease in cortisol production leads to increased ACTH production and increased androgen synthesis with hirsutism in women
Also increased production of deoxycorticosterone leading to salt retention and hypertension
4 causes of hypokalaemia AND hypertension
- 11B hydroxylase deficiency
- Cushings syndrome
- Conns syndrome (primary hyperaldosteronism)
- Liddles syndrome
Describe Jod Basedow phenomenon
Intake of iodine results in hyperthyroidism.
Usually in patients with ABNORMAL thyroid glands such as MND, toxic nodules, goitre.
Water deprivation test
Once the plasma osmolality reaches 295 to 300 mosmol/kg (normal 275 to 290 mosmol/kg) or the plasma sodium is 145 meq/L or higher, the effect of endogenous ADH on the kidney is maximal.
Continued until following end points are met:
1. Urine osmolality reaches a clearly normal value (above 600 mosmol/kg), indicating that both ADH release and effect are intact. Patients with partial DI may have a substantial rise in urine osmolality, but not to this extent.
- The urine osmolality is stable on two or three successive hourly measurements despite a rising plasma osmolality.
- The plasma osmolality exceeds 295 to 300 mosmol/kg or the plasma sodium is 145 meq/L or higher.
In the last 2 situations, DDAVP is administered to check for rise in urine osmolality.
How does lithium affect thyroid gland?
Can cause both hyper and hypothyroidism.
Hypothyroidism - lithium inhibits T4 production and secretion. Usually normalizes upon drug cessation.
Hyperthyroidism - thyroiditis
Bone pain, muscle ache and weakness 3 weeks after iron infusion… what would you think about?
Renal phosphate wasting due to increased FGF23 from bone. Unclear as to why this happens.
How much would you increase the thyroxine dose by during pregnancy?
1.3x especially in the first 20 weeks
Describe Bilateral simultaneous inferior petrosal sinus sampling.
Simultaneous sampling for ACTH from both petrosal sinuses and peripheral blood, with measurement of basa and after CRH injection.
ACTH is deemed to be produced from pituitary source if there is an increase in gradient post-CRH.