Endocrinology Flashcards
1
Q
Criteria for surgery in adrenal incidentaloma
A
- Size >6cm or imaging suggestive of malignancy
- Increase in size from interval scan
- Functional tumour - pheochromocytoma, unilateral disease in primary hyperaldosteronism, autonomous cortisol secretion
2
Q
Test of choice for acromegaly
A
IGF-1 as a screening test
OGTT to check for GH suppression
3
Q
Describe the action of bisphosphonates.
How long should bisphosphonates be used for?
A
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
4
Q
5 causes of hypokalaemia WITHOUT hypertension
A
- Diuretics
- Bartters
- Gitelman
- GI loss (diarrhoea, vomiting)
- RTA 1 and 2
5
Q
What are the absolute risks/benefits of HRT?
A
Benefits: reduced hip fracture, colon cancer
Risks: Increased rates of breast cancer, PE, stroke, CAD
6
Q
5 causes of premature menopause?
A
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
7
Q
Causes of nephrogenic DI
A
- 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
8
Q
Lifetime risk of T1DM if following family members are affected:
- Identical twin
- Both parents
- Parent and sibling
- Father only
- Mother only
- Sibling
A
- 40%
- 25%
- 25%
- 5%
- 2%
- 7%
9
Q
How would you test for cure of acromegaly?
A
75g oral glucose load. Normally GH should be undetectable 2 hours after glucose loading.
10
Q
What cancers are associated with acromegaly?
A
Colon cancer (screen from age of 40 onwards)
Thyroid cancers - screening for this is currently uncertain area.
11
Q
Describe Wolf-Chaikoff phenomenon
A
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.
12
Q
Definition of central obesity on the basis of waist circumference
A
Male >102cm
Females >88cm
13
Q
What is the role of thyroperoxidase at the apical mebrane?
A
Involved in iodination of thyroglobulin and coupling to form DIT.
Regulated by iodide and H2O2 supply.
14
Q
Name 6 hormones from the anterior pituitary
A
FSH LH Prolactin GH ACTH TSH
15
Q
Compare and contrast aldosterone producing adenoma (APA) vs idiopathic hyperaldosteronism (IHA) ie bilateral hyperplasia
A
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.
16
Q
Contraindications to insulin stress test
A
epilepsy
ischaemic heart disease
adrenal insufficiency
17
Q
4 GH stimulation tests available in testing for GH deficiency
A
- 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
18
Q
Who should be screened for primary hyperaldosteronism?
A
- 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
19
Q
4 risk factors for hypocalcaemia in denosumab use?
A
- CKD
- Malabsorption
- Hypoparathyroidism
- Malignancy
20
Q
Describe 4 side effects of thionamides (CBZ, PTU)
A
- Rash
- LFT derangements
- Neutropenia
- pANCA vasculitis
21
Q
Describe follicular thyroid carcinoma
A
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
22
Q
BP target in diabetes and hypertension
A
<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.
23
Q
Describe short synacthen test
A
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
24
Q
How would you distinguish between type 1 and type 2 amiodarone induced thyrotoxicosis?
A
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.
25
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
26
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.
27
4 major endocrinological manifestations of Turner's disease
1. Autoimmune thyroid disease
2. Diabetes
3. Coeliac disease
4. Osteoporosis
28
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.
29
Common side effects of octreotide/lanreotide?
GI side effects including gall stones and abdominal pains
30
4 factors which decrease sex hormone binding globulin
1. Obesity
2. Nephrotic syndrome
3. Diabetes
4. Use of steroids, progestin and androgenic steroids
31
Name 3 factors which can increase/decrease HbA1c
Decrease - anything that shortens RBC lifespan
1. Sickle cell anaemia
2. G6PD deficiency
3. Hereditary spherocytosis
Increase - due to increased RBC lifespan
1. Vit B12/foalte deficiency
2. Iron deficiency anaemia
3. Splenectomy
32
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.
33
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.
34
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.
35
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:
1. PCOS
2. HAIR-AN (hyperandrogenism, insulin resistance, acanthosis nigricans)
3. Tumours - ovarian, adrenal tumour
4. Ovarian hyperthecosis - hyperplasia of the theca cells
5. Drugs - anabolic steroids
6. Late onset CAH (eg 21 hydroxylase deficiency)
36
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.
37
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
38
5 antihypertensive agents used to control BP prior to PAC/PRC measurements
Verapamil
Hydralazine
Prazosin, doxazosin, terazosin
39
Describe the action of denosumab
'Artifical OPG'
| Binds to RANK-L and prevents osteoclast differentiation.
40
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.
41
3 risk factors for Graves ophthalmopathy.
1. Smoking
2. Aggressive control leading to hypothyroidism
3. I131 therapy
42
6 causes of raised prolactin other than prolactinomas.
1. Pregnancy/lactation
2. Hypothyroidism - TRH stimulates PRL release
3. Craniopharyngioma
4. Metoclopramide
5. Neuroleptics - most commonly affecting dopamine such as 1st generation agents, haloperidol
6. Stress
43
3 factors associated with INCREASE in sex hormone binding globulin
1. Ageing
2. Hepatic cirrhosis and hepatitis
3. Use of anticonvulsants
44
What are the 5 evidences of fetal thyroid dysfunction on ultrasound in TRAb positive pregnancy?
1. Thyroid enlargement
2. IUGR
3. Hydrops
4. Advanced bone age
5. Fetal tachycardia
45
Diagnosis of Cushing's syndrome
Key principles:
1. 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
2. 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.
46
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.
47
Describe the effects of following medications on thyroid.
1. anti-CTLA/PD1 inhibitors
2. Anti-CD52 (alemtuzumab)
3. TKI
1. Causes central hypothyroidism and thyroiditis.
Central hypothyroidism is more common with CTLA4 inhibitors. Thyroiditis more common with PD1 inhibitors
2. Graves disease 15%
3. Hypothyroidism in 25%
48
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.
49
Retinopathy screening in Type 1 DM
At diagnosis then every 1-2 years
In children, start screening at puberty.
50
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)
51
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.
52
What risk is conferred by presence of anti-thyroid antibodies in pregnancy?
1. Miscarriage
| 2. Premature birth
53
HLA genes involved in Type 1 DM
HLA DR3/4
54
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.
55
What is a rare side effect of zolendronic acid?
Serious atrial fibrillation in 1.3%
56
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:
1. Pregnancy
2. Oestrogen administration (increased hepatic synthesis)
3. Hyperthyroidism or hypothyroidism
4. Inflammation or acute illness.
Given that serum cortisol assay measures TOTAL level, think about measuring urine and salivary free cortisol level.
57
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.
58
Physiological mechanisms in response to hypoglycaemia?
1. Decreased insulin first
2. Increase in glucagon leading to increased hepatic gluconeogenesis and glycogenolysis
3. 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.
59
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
60
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
61
4 causes of hypokalaemia AND hypertension
1. 11B hydroxylase deficiency
2. Cushings syndrome
3. Conns syndrome (primary hyperaldosteronism)
4. Liddles syndrome
62
Describe Jod Basedow phenomenon
Intake of iodine results in hyperthyroidism.
Usually in patients with ABNORMAL thyroid glands such as MND, toxic nodules, goitre.
63
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.
2. The urine osmolality is stable on two or three successive hourly measurements despite a rising plasma osmolality.
3. 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.
64
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
65
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.
66
How much would you increase the thyroxine dose by during pregnancy?
1.3x especially in the first 20 weeks
67
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.
68
Mechanism of licorice poisoning
Causes hypermineralocorticordism via inhibition of 11 beta hydroxysteroid dehydrogenase type 2 which usually metabolizes cortisol. As a result, cortisol excess occurs causing hypokalaemia, salt retention and metabolic alkalosis.
69
5 risk factors for ONJ?
1. Steroid use
2. High dose IV bisphosphonates with longer duration
3. Cancer
4. Poor dental hygiene and those who undergo a dental procedure such as dental extraction
5. Alcohol/tobacco use
Highest risk in oncology population on bisphosphonates (1-15%) especially if used regularly.
In the osteoporosis patient poulation, ONJ risk is only around 0.001%
70
What is the mechanism of hyponatremia in primary adrenal insufficiency?
Cortisol is a physiological tonic inhibitor of ADH secretion.
Lack of cortisol leads to unchecked CRH release
CRH release stimulates ADH release leading to hyponatremia via water conservation.
71
Describe the PTH paradox in teriparatide.
Continuous infusion causes bone loss but once daily injection is anabolic.
There is an anabolic window of 12-18 months where bone formation supercedes bone resorption.
Unlike other agents, teriparatide is an ANABOLIC agent, not inhibitory.
72
4 cancers with strongest association with obesity
1. Endometrial cancer (oestrogen mechanism)
2. Oesophagus cancer (reflux mechanism)
3. Renal
4. Gall bladder
73
What cell secretes RANK-L and what is its role?
Osteoblasts secrete RANK-L.
RANK-L then binds to osteoclast which promotes it to become multinucleated osteoclasts and goes onto cause bone resorption.
74
Define type 1 and type 2 thyrotoxicosis secondary to amiodarone
Type 1 - acute iodine load (carbimazole)
Type 2 - thyroiditis (prednsione)
Difficult to distinguish between the two - Tc99 scan will be cold in both.
fT4 will be disproportionately high usually.
Start treating both with steroids and carbimazole
75
Diabetic medications which does not cause hypoglycaemia
Exenatide, Sitagliptin, pioglitazone, metformin, acarbose
76
Explain TDD, insulin sensitivity factor, and the 500 rule in calculation of insulin requirement
First, calculate the total daily dose (TDD)
Insulin sensitivity factor = 100/TDD
Insulin sensitivity factor is used in calculation of correction bolus dose.
eg: TDD = 50 units.
ISF = 100/50 = 2
If target BSL is 6mmol/L and pre-meal BSL is 14, then BSL is high by 8 mmol/L.
Therefore insulin required to correct BSL from 14 to 6 is 8/2 = 4 units.
USING 500 Rule and TDD
500 rule: 500/TDD (450 for regular insulin)
If total daily insulin dose is 50 units,
500/50 = 10
Therefore 1 unit of Humalog insulin will cover 10g of carb.
77
4 clues which suggest craniopharyngioma over pituitary lesion?
1. Location - suprasellar and calcified
2. Diabetes insipidus (rarely seen with adenomas)
3. Hyperphagia due to hypothalamic involvement
4. Anterior pituitary insufficiency with raised prolactin
78
Who should be treated in osteoporosis? (4 indications)
1. Existing fracture in post-menopausal women or men in >50 age especially if the mechanism of the fracture indicates fragility (eg: colles fracture)
2. Any patients with diagnosed vertebral fracture
3. Patients with documented osteoporosis with T score <2.5 above age of 70
4. Iatrogenic osteoporosis caused by oral corticosteroids, aromatase inhibitors, androgen deprivation.
79
How do you measure renin?
Renin can be measured in terms of its enzymatic activity (PRA) or its mass (active renin concentration)
80
USS features which suggests a benign thyroid nodule?
Notable malignant features?
1. Spongiform/honeycomb appearance
2. Purely cystic nodule
3. Egg shell type calcification around the periphery of a nodule
Malignant features:
1. Taller than wide shape referring to AP >TR diameter when imaged in the axial plane
2. Egg shell type calcification around the nodule with broken calcified rim where there is extension beyond the calcified rims of a hypoechoic mass
3. Irregular margin, intranodular vascularity, absence of associated halo
81
When to start aspirin as a primary prevention in type 1/2 diabetes?
When CVD risk is >10% at 10 years.
This includes most men age >50 or women >60 with at least one additional major risk factors:
1. Family history of CVD
2. Hypertension
3. Smoking
4. Dyslipidaemia
5. Albuminuria
Aspirin is NOT a benign drug - NNT for total CVD event is 120, NNH for non-trivial bleed is 73!
82
What is the role of OPG?
OPG is a decoy receptor that binds to RANK-L and stops it from binding to osteoclast.
83
3 main bariatric surgery techniques
1. Laparoscopic sleeve gastrectomy - The stomach is tubularized by removing 80% of it; morbidity is 1.3%, and complications include staple-line leakage (0.25%), bleeding (0.61%), stricture, reflux, and vitamin deficiency
2. Laparoscopic Roux-en-Y gastric bypass - A small stomach pouch is created and attached to the small intestine, bypassing the duodenum and part of the jejunum; results in formation of gastrojejunostomy and jejunojejunostomy. Morbidity is 2.59%, and complications include anastomotic leakage (0.33%), bleeding (1.49%), internal hernia, small-bowel obstruction, stricture, and vitamin deficiency
3. Laparoscopic gastric banding - A band is placed around the stomach in such a way as to create a small pouch; morbidity is 0.21%, and complications include band slippage, band erosion, pseudoachalasia (esophageal dilation), and reflux
84
Name 8 secondary causes of bone loss.
```
Hypogonadism
Vitamin D deficiency
Hyperthyroidism
Hyperparathyroidism
Coeliac disease - above 3 are frequently unrecognized at 3% per condition
Multiple myeloma
Drugs
Chronic diseases such as CKD, RA
```
85
4 main causes of slow onset primary and secondary adrenal insufficiency
What about fast onset?
1. Autoimmune
2. Tumour infiltration
3. Infection - TB
4. Drugs - ketoconazole for primary, megestrol for secondary
Fast onset - infarction or haemorrhage
86
What should be considered when both PRA/PRC and PAC are elevated but the ratio is <10?
Secondary hyperaldosteronism (eg: renovascular disease). Indicates that aldosterone is high due to stimulation from high renin.
87
What is the gold standard test for growth hormone deficiency and addisons disease?
Insulin tolerance test.
| Only interpretable if symptomatic hypoglycaemia is induced (ie, BSL <2.5 mmol/L)
88
Diagnosis of acromegaly?
Age corrected IGF-1 level
| Failure of GH to suppress with glucose load
89
Most common cause of toxic nodule/MNG?
TSHr mutation.
90
What is necrobiosis lipoidica diabeticorum?
Chronic granulomatous dermatitis associated with DM
Yellow brown, telangiectatic plaques with central atrophy and raised violaceous borders.
Often occurs on the shins or the dorsa of the feet.
Often associated with diabetic nephropathy and/or retinopathy.
91
What are the BSL targets in pregnancy?
Usually measured before meals and 1-2 hours after meals.
Pre-meal BSL 4-5.5 mmol/L
1 hour post meal - <8mmol/L
2 hours post meal - <7mmol/L
92
What activating mutation is associated with high bone mass?
LRP5
93
Pseudo-pseudohypoparathyroidism
Due to paternally transmitted GNAS1 mutation.
Have the phenotype of AHO but with normal serum calcium concentrations and without renal tubular resistance to PTH; this pattern is termed "pseudo-pseudohypoparathyroidism". In these patients, the paternal transmission of a mutated GNAS1 gene results in AHO but the normal maternal allele results in the maintenance of renal responsiveness to PTH. As a result, these patients have normal calcium homeostasis with normal concentrations of calcium, phosphate, and PTH.
94
Describe 2 broad groups of osteomalacia (deficiency of mineralized bone)
1. Vitamin D deficiency - malabsorption, liver/renal disease, anti-epileptics
2. Hypophosphotaemia due to Fanconi, Tumour induced osteomalacia, renal wasting from anti-retrovirals such as tenofovir and iron polymaltose
95
What did the diabetes prevention program (DPP) study show?`
In those with impaired glucose tolerance and impaired fasting glucose, lifestyle modification including diet and exercise was more effective in weight loss and diabetes prevention.
Metformin was less effective but still more so than placebo.
96
How would you manage atypical femoral fracture in patients?
Discontinue anti-resorptive.
Monitor the contralateral hip (as AFF risk is still high at around 20% even if meds are discontinued)
Prophylactic nail fixation if incomplete fracture with pain and/or cortical lucency.
If incomplete fracture with NO pain, may manage with limited weight bearing until repeat MRI shows no oedema.
97
Describe Riedel's thyroiditis.
Rare condition, now part of IgG4 spectrum disease
Dense fibrosis of the thyroid associated with eu/hypothyroidism
Associated with horners, carotid stenosis, hypoparathyroidism
May be associated with fibrosis else where - eg retroperitoneum.
98
6 effects of glucagon.
Glucagon is mainly a catabolic hormone:
1. Increased hepatic glucose production
2. Increased lipolysis
3. Increased FA oxidation and ketogenesis
4. Increased satiety and decreased food intake
5. Increased thermogenesis and energy expenditure
6. Increased bile acid synthesis
99
Describe features of papillary thyroid carcinoma
80% of differentiated thyroid cancers
Spread to LN common, but spread beyond neck not common <10%
Metastasis to lungs, bones, liver, adrenals
Poor prognostic features include >40, tumour size >4cm, local extension or distant metastasis
100
What is the effect of SERM on osteoporosis?
Reduces vertebral fracture risk by 36% in post menopausal women with osteoprosis.
NO effect on non-vertebral fracture risks however.
101
What genetic mutation is associated with medullary thyroid cancer?
RET proto-oncogene.
102
Factors which suggest poor chance of remission with anti-thyroid drug therapy only and who may benefit more from front-line radioiodine therapy?
1. Male gender
2. Older patients
3. High TRAb titre
4. Large goitre
103
What is the central pathogenesis of Paget's disease?
Osteoclast activity is greatly increased leading to increased osteoblast activity as well.
Abnormal bone is formed however which causes bony deformities, bone pain, OA of adjacent joints, spinal stenosis.
104
Management of thyroid storm?
1. Non selective beta blockers such as propranolol
2. Rehydration, control of fever
3. PTU - preferred over carbimazole as it can reduce T3 level more quickly and has a theoretical advantage of reduced peripheral conversion from T4 to T3
4. Lugol's solution - iodine which will cause Wolff-Chaikoff phenomenon and transiently reduce T4/T3 production - should not be used for more than 4 days
5. Hydrocortisone - blocks thyroid output and T4->T3 conversion
6. Cholestyramine - increases T4 clearance by preventing reabsorption of free thyroid hormones from the gut
7. Plasmapheresis can be considered if life threatening thyrotoxicosis
105
Prognosis of lymphocytic/post partum thyroiditis?
Associated with aTPO and TG antibodies
Limited thyrotoxicosis initially followed by hypothyroidism
20-30% have persisting hypothyroidism
Those that recover have increased incidence of eventual hypothyroidism.
106
Causes of secondary amenorrhoea?
Think top-down approach from hypothalamus down to the uterus! Always exclude pregnancy.
Hypothalamus - stress, exercise, weight loss, medical illness
Pituitary - prolactinoma, other tumours, Sheehan's syndrome (post partum hypopituitarism)
Any thyroid disorders
Adrenals - CAH, tumours, Cushings/addisons
Ovarian - PCOS, causes of premature menopause
Uterine cause - Asherman's syndrome
107
6 indications for parathyroidectomy
1. Serum calcium concentration of 0.25 mmol/L or more above the upper limit of normal.
2. Estimated glomerular filtration rate (eGFR) <60 mL/min.
3. Osteoporosis via DEXA scan
4. Renal calcium excretion 400 mg/day (>10 mmol/day).
5. Nephrolithiasis or nephrocalcinosis by radiograph, ultrasound, or CT.
6. Age less than 50 years
108
How useful is MRI pituitary scan in diagnosis of Cushings disease?
Not reliable without bilateral inferior petrosal sinus sampling.
10% of normal populations have adenoma
Upto 50% with Cushings disease have no visible adenoma.
BIPPS is often necessary unless MRI shows >6mm adenoma AND demonstrable suppression of cortisol with high dose overnight dexamethasone suppression test or CRH stimulation test.
109
3 screening tests used for Cushings syndrome and their caveats
1. 24 hour urinary free cortisol x2
2. Midnight salivary cortisol x2 - however not a good test for a shift worker
3. Overnight 1mg dexamethasone test
- DSTs are not a good choice for patients in whom CBG levels may be abnormal or in those taking medications that may alter the metabolism of the drug [65]. Estrogen-containing drugs, such as oral contraceptives, raise CBG and may result in a false-positive DST. Oral contraceptives should be stopped for six weeks before performing a DST, or an alternate test should be used. Overnight DSTs are also not a reliable test in pregnancy.
110
Function of leptin
Peptide hormone synthesized in adipocytes in proportion to cell size. Crosses the BBB then acts on the leptin receptors found in the choroid plexus
1. Inhibits food intake and increases energy expenditure
2. Reduces the expression of neurotransmitters that increases food intake (NPY, AgRP)
111
Which diabetic medications have been shownt o reduce cardiovascular event?
1. Metformin
2. Empagliflozin (EMPA-REG study) - reduced hospitalization for heart failure, CV death and all cause mortality reduced by 30+%. did not improve incidence of no-fatal MI or non-fatal stroke.
3. Liraglutide (LEADER study) - reduction in CV death, but no effect on heart failure, heart failure or non fatal MI)
112
Describe the action of PTH.
PTH binds to PTHR1 on osteoblast causing cortical bone loss.
Primary hyperparathyroidism can cause low BMD, fracture, osteitis fibrosa cystica.
113
Describe the pathologies of pituitary adenoma from most common to least common.
Most common - prolactinomas
Followed by: non functioning adenoma (frequently stains for FSH), GH secreting, ACTH secreting.
Thyrotroph are the least common.
114
Causes of falsely positive 24 hour urinary free cortisol measurement
Patients with equivocally raised values (above normal but less than three times the upper reference value) may have physiologic hypercortisolism (pseudo-Cushing's). For example, up to 40 percent of patients with severe depression or polycystic ovary syndrome (PCOS) have slightly high 24-hour urinary cortisol excretion
115
How does pegvisomant work?
GH receptor antagonist. Used in acromegaly and is effective.
116
Most common cause of ectopic ACTH secretion
Bronchial carcinoid and small cell lung cancer.
117
What is the chance of long term remission in Graves disease after 12-18 months of thionamide therapy?
50%
Most relapses occur in first 6 months of drug cessation
Remission is highest in mild hyperthyroidism with small goitre or goitre which shrinks with therapy
118
Action of GLP1
Upon ingestion of food, GLP1 is released from L cells of the jejunum and ileum.
This in turn:
1. Stimulates glucose dependent insulin secretion (exenatide does not overshoot like insulin injection causing hypoglycaemia)
2. Suppresses glucagon synthesis preventing hyperglycaemia
3. Slows gastric emptying
4. Improves insulin sensitivity
5. Reduces food intake
Exenatide mimics GLP1 action as above
119
What is the advantage of PTU over carbimazole?
And vice versa?
PTU has the advantage of being safer in 1st trimester and useful in T3 toxicosis as it blocks T4-T3 conversion.
Carbimazole has longer half life so can be dosed daily,. Not associated with fulminant inflammatory hepatitis like PTU.
120
Side effects of SGLT-2 inhibitors (eg dapagliflozin)
1. Genitourinary infections such as UTIs, candidiasis
2. Hypotension
3. Euglycaemic DKA
4. AKI
121
Management of thyroid storm
● A beta blocker to control the symptoms and signs induced by increased adrenergic tone
●A thionamide to block new hormone synthesis (PTU has advantage over carbimazole/methimazole in that it also prevents peripheral conversion of T4 to T3)
●An iodine solution to block the release of thyroid hormone
●Glucocorticoids to reduce T4-to-T3 conversion, promote vasomotor stability, and possibly treat an associated relative adrenal insufficiency
●Bile acid sequestrants to decrease enterohepatic recycling of thyroid hormones
122
What is the mechanism of oestrogen hormone replacement on increased risk of VTE and hypertriglyceridaemia?
How would you minimize these risks?
Stimulates the liver to produce more clotting factors and TGLs. Also increases production of TBG, Corticosteroid binding globulin, SHBG, HDL.
Transdermal administration is more physiological in terms of delivery and has minimal hepatic impact of above.
Also as effective as oral oestrogen in preserving bone density and preserving menopausal symptoms.
123
6 diseases associated with thyroid autoimmunity
1. Diabetes
2. Addisons
3. Pernicious anaemia
4. Vitiligo
5. Myasthenia gravis
6. Pituitary autoimmunity
124
Features of hypokalaemic periodic paralysis
Presents between 5-20 years
Attacks may be precipitated by carbohydrate rich meal
Autosomal dominant inheritance
Mutation in sodium/calcium channel.
Presence of myotonia is impmortant in distinguishing between hyperkaleamic from hypokalaemic periodic paralysis (75% vs 0%)
125
What is the most reliable test to distinguish between Cushings disease and ectopic ACTH secretion?
CRH stimulation test. ACTH/cortisol increases by >30% in Cushings disease but not in ectopic. SnSp >90%.
Can also do high dose dexamethasone suppression test which will show >70% suppression in cortisol but overlap exist... (90% in Cushings disease, 10% in ectopic ACTH disease)
126
What are the 6 risk factors for glucocorticoid induced osteoporosis?
1. Age
2. Underlying inflammatory disease
3. Dose and duration of GC
- There is NO safe dose. RR >4 for spine fracture at dose above 7.5mg/day
4. Low baseline BMD
5. Low BMI
6. Previous fracture
127
What are the consequences of hip fracture in terms of:
1. 1 year mortality
2. Assistances with mobility/ADLs
3. Requirement of full time nursing cares?
1. 1 year mortality of 20%
2. 50% require long term help with routine activities and cannot walk unaided
3. 25% will require full time nursing home cares
128
Summary of benefits of testosterone treatment of older men
1. No change in lean mass or muscle strength
2. Decreased fat mass
3. Increased BMD
4. Increased libido
5. Increased cognition
However overall effects are modest at best.
129
Treatment of acromegaly?
If small tumour - elective trans-sphenoidal microadenomectomy
If large tumour - total hypophysectomy +/- radiotherapy and/or somatostatin analogue therapy with octreotide or lanreotide.
130
Name 2 hormones from posterior pituitary.
ADH
| Oxytocin
131
Key management principles in hypothyroidism
1. Rule out coexisting adrenal insufficiency
2. Start replacement therapy slow especially if concurrent IHD
3. Increase by 50% in pregnancy
132
6 causes of thyroiditis
1. Sub acute (DeQuervain)'s thyroiditis
2. Autoimmune thyroiditis - ie, lymphocytic, post partum
3. Riedel's thyroiditis
4. Radiation/drug induced
5. Sarcoid/amyloid infiltration
6. Infection
133
Effects of following on ARR:
```
Diuretics and spironolactone
Beta blockers
ACEI/ARB
Low salt intake/hypokalaemia
Renal impairment
```
Diuretics and spironolactone - increases renin secretion and decreases ARR. Should avoid before measuring ARR.
ACEI/ARB - stimulates renin release leading to decrease in ARR. Thus, in a patient treated with one of these drugs, a detectable PRA level or a low PAC/PRA ratio does not exclude the diagnosis of primary aldosteronism. On the other hand, a strong predictor for primary aldosteronism is an undetectable PRA or PRC in a patient taking one of these drugs.
Beta blockers - decrease renin secretion leading to increase in ARR. However this effect is considered to be minimal as aldosterone level should be low/normal in most patients without primary hyperaldosteronism.
Renal impairment - fluid retention leading to suppressed renin and increased ARR
If HTN needs to be controlled for ARR testing, use hydralazine, verapamil or alpha blockers such as prazosin/doxazosin
134
When is genetic testing warranted in pheochromocytoma?
>50% of all pheochromocytomas are due to genetic causes, despite absence of family history.
Genetic testing is warranted if:
1. Young patient <40
2. Multiple phaeochromocytomas
3. Extrarenal location
4. Positive family history.
Testing needs to be prioritized according to syndromic features (VHL, MEN type 2, NF1, paraganglioma syndromes), location of tumour, and biochemical profile.
Extrarenal location - SDHB
Adrenal - RET, VHL
Multiple - SDHD, VHL
Malignant - SDHB
135
What is the risk associated with high dose Vit D?
Risks of falls and fractures increased in the vitamin D group.
136
Treatment of subacute thyroiditis?
1. NSAIDs
2. Prednisone - tapering, usually effective
3. Propranolol or metoprolol for symptomatic control
4. Thyroxine replacement for hypothyroid stage
PTU/Carbimazole not effective as there are no ongoing synthesis of T4/T3
137
Indications for DEXA scan
1. Any men >70 age, women >65
2. Any adult with fragility fracture - vertebral fractures, fractures of the neck of the femur, and Colles fracture of the wrist.
3. Disease or medications associated with osteoporosis
4. Follow up of treatment effect for osteoporosis
138
4 characteristics of ectopic ACTH cushing's syndrome?
1. Severe myopathy
2. Pigmentation
3. Hypokalaemia
4. Very high cortisol and ACTH
139
What does TSH receptor stimulate?
Sodium iodide symporter which facilitates the diffusion of sodium and iodine down the sodium concentration gradient maintained by Na? ATPase.
140
What are the stimulators and inhibitors of 1,25 Vit D?
Stimulators: PTH, low phosphate level
Inhibitors: FGF-23
FGF-23 works via FGF receptor -1 and its membrane bound protein clotho as a co factor.
FGF23 is secreted by osteocytes in response to elevated calcitriol. FGF23 acts on the kidneys, where it decreases the expression of NPT2, a sodium-phosphate cotransporter in the proximal tubule.
Thus, FGF23 decreases the reabsorption and increases excretion of phosphate. FGF23 may also suppress 1-alpha-hydroxylase, reducing its ability to activate vitamin D and subsequently impairing calcium absorption
141
Causes affecting renin level in aldosterone-renin ratio
1. Renin increased by - ACEI, diuretics,ambulancy
2. Renin decreased by - beta blockers, CCB, dietary sodium
Therefore should be taken as a mid morning ambulant sampling
Repeat values for confirmation
If plasma aldosterone is <400 with normokalaemia then PHA rare even if ARR is raised.
142
Medical management of hypercortisolism (cushing's syndrome)
Indicated when surgery is contraindicated, or bridging is required, or recurrence despite surgery occurs.
2 strategies exist depending on variability of hypercortisolism from day to day by measuring urinary cortisol level:
1. Block and replace - if wide variations in cortisol secretion
2. Normalisation -if invariable cortisol secretion
Agents used:
1. Steroidogenesis inhibitors - ketoconazole, metyrapone
2. Mitotane - adrenocorticolytic agent also used in adrenocortical carcinoma
143
Describe how technetium-99m bone scan works.
Uses technetium-99m-labelled bisphosphonates which bind to hydroxyapatite at sites of active bone formation.
Useful in:
1. Diagnosis and follow up of metastatic cancer
2. To differentiate between soft tissue infection and OM
3. Occult/stress fractures
4. Evaluation of prosthetic joints for infection, loosening or fracture
5. Evaluation of bone pain in normal XR
Not useful for tumours confined to the marrow such as myeloma and predominantly osteolytic metastasis such as RCCs.
144
How would you differentiate between aldosterone producing adenoma and idiopathic hyperaldosteronism?
Imaging which confirms unilateral tumour especially in age <40 is useful and should proceed to adrenalectomy.
If unilateral tumour above age of 40 or no unilateral tumour, then for adrenal vein sampling for aldosterone to confirm lateralization.
If no lateralization, then treat medically with spironolacton/amiloride.
145
What do you need to exclude in pituitary mass causing mass effect before considering surgery?
Prolactinomas!!!
Very responsive to bromocriptine and will shrink the tumour quite rapidly.
146
PTH action in the kidneys
Main roles are to increase renal calcium resorption and phosphate excretion in the tubules and activate vitamin D.
1. Proximal tubule: blocks reabsorption of phosphate
2. Calcium reabsorption in the ascending loop of Henle, distal tubule, and collecting tubule.
3. Conversion of 25-hydroxyvitamin D to its most active metabolite, 1,25-dihydroxyvitamin D-3 [1,25-(OH)2 D3], by activation of the enzyme 1-hydroxylase in the proximal tubules of the kidney.
147
How do you diagnose primary hyperaldosteronism?
You need both HIGH PAC as well as HIGH PAC/PRC or PRA ratio!
This is because PAC/PRC ratio is denominator dependent and depends on the sensitivity of the assay to detect lower level of renin activity/concentration.
If PAC as well as PAC/PRC ratio is high, then need to do saline suppression test while patient is seated. Potassium needs to be replaced vigorously as hypokalaemia suppresses aldosterone secretion. Diagnostic of primary hyperaldosteronism if aldosterone level is not suppressed.
Once diagnosis of primary hyperaldosteronism is established, unilateral aldosterone producing adenoma needs to be distinguished from bilateral hyperplasia (also called idiopathic hyperaldosteronism). Adrenal CT is the imaging of choice first.
148
Results of EMPA-REG study
Empagliflozin lowered 3 point MACE of CV death, non fatal MI, non fatal strokes, with decrease in all cause mortality.
Subanalysis of the MACE showed that decrease in mortality was mainly due to reduction in heart failure hospitalizations. No significant decline in MI/strokes.
149
Pathogenesis of sick euthyroidism
Local concentration of T3 is controlled by deiodinases.
Starvation and illness causes a rapid inhibition of type 1 deiodinase in the liver and results in reduced serum and tissue T3 level, with increase in rT3.
Therefore typical pattern in sick euthyroidism is decreased T3 more than T4, more severe illnesses in ICU may lead to fall in T4 and TSH as well.
150
Which of the following cross-reacts with the serum cortisol assay?
Prednisone
Prednisolone
Hydrocortisone
Dexamethasone
All except dexamethasone.
151
Main side effects of exenatide
Increased risk of pancreatitis and possibly thyroid cancer
152
When would you consider post operative TSH stimulated remnant ablation with I 131 therapy in papillary or follicular cancers?
If the cancer is >1cm and had local invasion or metastasis at time of the thyroidectomy.
This confers a survival benefit.
Lifelong TSH suppression is mandatory for high risk pateints.
Ablation of remnants virtually removes all source of Tg and hence can be used as a follow up cancer marker.
153
IMPROVE-IT study
Showed that ezetimibe and statin had 2% absolute risk reduction in composite end point of CV death, MI, unstable angina, coronary revascularisation or stroke when added to patient post MI.
No differences in all cause mortality.
Overall a modest effect only.
154
Surgery cures Cushing's disease in 70% of patients. However in 30% which is not cured, how would you manage this medically?
1. Pituitary radiotherapy
2. Bilateral adrenalectomy with pituitary radiotherapy
3. Medical therapy with ketoconazole or metyrapone which inhibits steroidogenesis.
155
Pseudohypoparathyroidism 1a
Characterized by triad of:
1. Hypocalcaemia
2. Hyperphosphotaemia
3. High PTH
Due to MATERNAL TRANSMISSION of mutation of GNAS1, gene encoding the alpha subunit of the G protein coupled with PTH receptor resulting in PTH unresponsiveness in end organ (parathyroid gland, kidneys).
Paternal transmission results in pseudo-pseudohypoparathyroidis
Patients with PHP type 1a have a constellation of findings known as Albright hereditary osteodystrophy (AHO), which includes round facies, short stature, short fourth metacarpal bones, obesity, subcutaneous calcifications, and developmental delay.
In addition, the PTH resistance of the renal tubule leads to hyperphosphatemia and hypocalcemia, and secondary hyperparathyroidism and hyperparathyroid bone disease (osteitis fibrosa).
156
4 thyroid related changes in pregnancy?
1. Raised thyroxine binding globulin secondary to oestrogen induced synthesis and decreased hepatic clearance
2. Decreased body iodide store secondary to increased renal clearance and transplacental transfer to fetus
3. Rise in thyroglobulin reflecting larger thyroid size
4. Decrease in TSH receptor antibody titre
157
Describe the role of insulin tolerance test.
Used in testing for corticotroph or somatotroph deficiency.
Induce hypoglycaemia with insulin.
With hypoglycaemia, would expect rise in ACTH and GH which are measured.
158
How do you calculate serum osmolality?
2x sodium + glucose + urea
This does not take into account of undetected osmotic molecules such as mannitol and IVIG.
159
Calculation of corrected sodium on the basis of hyperglycaemia
Decrease sodium by 2mmol/L for every 5.5 mmol/L increase in BGL...
But practically, divide BGL by 3 and then add to sodium.
ie: Sodium 120, BGL 30
Corrected sodium = 130
160
How does central pontine demyelination present?
What is the most sensitive test for diagnosis?
Confusion, seizures, drowsiness, pseudobulbar palsy, tetraparesis
MRI is the most sensitive test for diagnosis.
161
How do you confirm cure post hypophysectomy for Cushing's disease?
Measure 0800 plasma cortisol level 24 hours after last dose of hydrocortisone, at least 3-7 days after the surgery.
Both ACTH and cortisol should be undetectable.
Persistently detectable cortisol even if it is within the 'normal' range indicates incomplete resection and almost certain recurrence.
162
Difference between SDHD and SDHB
SDHB - presents as paraganglioma
| SDHB - head and neck tumours
163
How does corticosteroids induce osteoporosis?
Increased apoptosis of osteoblasts is the main mechanism.
Other mechanisms include:
1. Decreased gut calcium absorption and increased urinary calcium excretion leading to increased PTH and bone resorption
2. Decreased testosterone and oestrogen
164
Which factor has the greatest impact upon bone density?
Genetic factors.
165
Which factor has the greatest impact upon bone density?
Genetic factors.
166
Other autoimmune diseases associated with type 1 DM
1. Thyroid disease 5%
2. Coeliac disease 5%
3. Addisons 1%
167
Difference between P1NP and CTX (cross linked telopeptides of type 1 collagen)
P1NP is synthesized by osteoblasts.
CTX is released during bone resorption as fragments of type 1 collagen enters the circulation.
Both are markers of bone turnover.
168
Diagnosis of premature ovarian failure
Women <40 with FSH in the post menopausal range
Presence of amenorrhoea is not required to make the diagnosis, as women can have spontaneous intermittent ovarian function years after the diagnosis.
169
Which hormones have nuclear receptors?
Androgen, Oestrogen, Progesterone, Glucocorticoid, Thyroid Hormone
