Endocrinology 1 - Thyroid and Pituitary Flashcards
1
Q
What hormones stimulate the TSHR?
A
TSH and b-HCG
2
Q
Where is iodine taken up in the thyroid cell?
A
Via the NIS transporter (also transports Tc99)
3
Q
What inhibits TPO?
A
PTU, carbimazole, goitrogens, iodine - prevents trafficking of Tg+T4/3 into the colliod.
4
Q
What markers are increased in thyrotoxicosis?
A
Osteocalcin Urine pyridinium collagen cross links ALP Atrial natriuretic hormone SHBG Ferritin vWF
5
Q
What markers are decreased in thyrotoxicosis?
A
LDL cholesterol
Lp(a)
6
Q
What markers are increased in hypothyroidism?
A
CK (MM) LDL Prolactin Lp(a) Norepinephrine
7
Q
What markers are decreased in hypothyroidism?
A
Vasopressin
8
Q
What receptor antibodies are elevated in Grave’s disease?
A
TSHR-Ab 80-95%
hTgAb 50-70%
hTPOAb 50-80%
9
Q
What receptor antibodies are elevated in autoimmune thyroiditis?
A
TSHR-Ab 10-20%
hTgAb 80-90%
hTOPAb 90-100%
10
Q
What is the lifetime risk of grave’s disease?
A
2.5% in women, 0.25% in men
11
Q
What is the aetiology of grave’s disease?
A
T-cell autoimmune process in thyroid - leads to TSHrAb production.
Associated with FHx of AI thyroid disease
Recent iodine exposure (e.g. contrast)
Post partum
12
Q
What are clinical feat of grave’s disease?
A
Thyrotoxicosis
Diffuse goitre
eye signs
pretibial myxedema
13
Q
How is the Dx of grave’s disease made?
A
confirm with TSHrAb or Tc99 scan
14
Q
What is the management of Grave’s?
A
Control symptoms with b-blockade
Control hyperthyroidism with either carbimazole or PTU.
SEs include rash, altered LFTs, neutropenia, pANCA vasculitis.
I-131 usually safe, but caution in younger women or those with significant eye disease - successful Tx = hypothyroidism.
Surgery carries a risk of parathyroid injury, and may recur in remnant.
15
Q
What are features of PTU?
A
Short half life (bd or tds dosing) Blocks conversion from T4 to T4 (preferred in T3 toxicosis) Fulminant inflammatory hepatitis rarely Safer than carbimazole in T1 of preg. enters breast milk but safe if
16
Q
What are features of Carbimazole?
A
Daily dosing no effect on peripheral deiodinase can cause non-threatening cholestasis increased risk of aplasia cutis, omphalocoele and other birth defects enters breast milk, but safe if
17
Q
What is the rationale of thionamide therapy of Graves?
A
Can titrate or block/replace.
12-18 months of treatment, with 50% remission rate.
Most relapses occur within 6 months of therapy
18
Q
What are factors which favour long-term remission following anti-thyroid therapy?
A
T3 toxicosis Small goiter Decrease in goiter size during therapy Normal thyroid function tests and normal TSH Negative test for TSHr antibodiy
19
Q
What are features of grave’s ophthalmopathy?
A
Can be independent of thyrotoxicosis
Can by asymmetrical
Smoking, iatrogenic hypothyroidism and I131 therapy are established risk factors for progression.
20
Q
What are treatment options for grave’s ophthalmopathy?
A
may require referral to ophthalmolgist - pulse Iv steroid and radiotherapy in acute phase, surgical debulking in chronic phase.
21
Q
What is the mechanism of grave’s ophthalmopathy?
A
TSH binds g-protein coupled TSH receptor.
increased cAMP and mTOR, also via IGF-1 receptor.
Leads to adipogenesis and hyaluronic acid synthesis - expanded orbital muscles and adipose tissue.
22
Q
What medication is shown to improve orbitopathy in grave’s disease?
A
Selenium 100mcg bd improves orbitopathy in these patients. large proportion have selenium deficiency.
23
Q
What is the cause of periodic paralysis in grave’s disease?
A
caused by transient severe hypokalemia, often following high CHO meal or exercise.
Usually only in asian people
only during thyrotoxic phase of illness
24
Q
What are features of toxic nodule/MNG?
A
Usual presentation is of thyrotoxicosis, often isolated T3 toxicosis.
Often due to activating mutation (somatic) of TSHr
Treat with I131 or PTU/CBZ
Rarely malignant
Dx requires Tc99 scan.
25
What are features of thyroiditis?
Decreased Tc99 uptake with neck tenderness and thyrotoxicosis.
```
Causes:
Idiopathic - viral or dequervain's
Post pregnancy
Hashimoto (early stages)
Amiodarone
```
Rx: propranolol if necessary, NSAIDS/pred for pain.
PTU/CBZ not effective.
26
What effect does amiodarone have on thyroid function?
May cause hypothyroidism or thyrotoxicosis.
Hypothyroidism due to interference with T4 synthesis and action - treat by withdrawing the drug and thyroxine.
```
Thyrotoxicosis by either iodine load (type 1) and/or thyroiditis (type II)
any time after starting drug.
Tc99 often not helpful
FT4>>FT3.
Rx - stop amiodarone, PTU/CBZ and steroid (antiinflam and blocks T4-T3 conversion)
Surgery if no response
Colestyramine if desperate
I131 not useful.
```
Tc99 scan is cold in both type I and II disease.
27
What effect does iodine therapy have on the thryoid?
From diet or fro contrast loads, can cause
'Wolff-Chaikoff effect' - stunning of the gland via TPO
'Jod-Basedow effect' - iodine induced hyperthyroidism via NIS
May reflect underlying thyroid autonomy - so consider Ix for MNG/Grave's disease
28
What is the effect of lithium on thyroid function?
induces hypothyroidism mostly, via inhibition of T4 production and secretion.
May resolve on cessation.
Treated with T4 to normalise TSH
Lithium may also cause thyrotoxicosis
29
What is the effect of interferon alpha on thyroid disease?
Can cause hypothyroidism in 5%, or grave's in others due to immune modulation in conjunction with primary disease.
Anti-TPO and -Tg seen in 15% of patients with Hep C.
Can persist for years after cessation of interferon.
30
What are features of subclinical hypothyroidism?
Abnormal TSH with normal free T3 and free T4.
DDx = sick euthyroidism, non-steady state.
31
What are indications for treatment of subclinical hypothyroidism?
TSH >10 or symptoms of hypothyroidism.
| Age
32
When should one treat subclinical hyperthyroidism?
TSH
33
What are the types of thyroid cancer?
Follicular cell derived:
Follicular or papillary carcinoma
Poorly differentiated -> anaplastic carcinoma
Medullary (from c-cells) - RET oncogene
34
What is the W/U of thyroid nodules >1cm?
Determine if TSH is normal or abnormal.
If abnormal, proceed to SCAN - if hot, stop. if cold- to FNAB
If TSH is normal, proceed to FNAB.
If malignant or suspicious - surgery
If benign - T4 and observation - if growth, reevaluate, if nil growth, stop.
35
What are clinical features that increase the risk of thyroid follicular cell carcinoma?
```
Previous neck radiation
FHx of thyroid cancer
Rapid growth
Very firm or hard nodule
Fixation of nodule to adjacent structures
Paralysis of vocal cords
Regional lymphadenopathy
Distant mets
PET incidentaloma (14-40% chance of malignancy)
```
36
What are USS features concerning for malignancy in thyroid nodules?
microcalcifications
irregular borders
extrathyroid extension
very hypoechoic
37
What is the rationale of management based upon FNAB in thyroid nodules?
IF benign - observe or levothyroxine
Follicular neoplasm - If I123 scan is hyperfunctioning, evaluate for hyperthyroidism if cold or eufunctional, surgery or levothyroxine.
If malignant, surgery
if insufficient for Dx, repeat FNAB
38
What are the features of genetic mutations in papillary thyroid cancer?
BRAF - 40-45%
tall-cell, classical papillary cancer, extrathyroidal extension, higher stage at presentation, higher rate of recurrence and propensity to dedifferentiate
RET/PTC - 10-20%
classic papillary cancer, younger age at presentation, associated with rad exposure, frequent LN mets, lower stage at presentation.
RAS - 10-20%
Follicular variant of papillary cancer, more frequent encapsulation, less frequent LN mets, more frequent distant mets.
39
What oncogenes are associated w follicular carcinoma of the thyroid?
RAS 40-50%
PAX8/PPAR-gamma 30-35%
PIK3Ca
40
What oncogenes are associated with poorly differentiated carcinoma?
RAS 20-40%
TP53 20-30%
BRAF 10-20%
41
What onogenes are associated with anaplastic carcinoma?
TP53 50-80%
CTNNB1 5-60%
RAS 20-40%
BRAF 20-40%
42
What oncogenes are associated with medullary carcinoma?
RET >95
43
What is the treatment of thyroid carcinoma?
Post thyroidectomy +/- LN dissection
For papillary Ca >1cm or follicular Ca
- TSH stimulated remnant ablation w I131
- enables follow-up with TSH stimulated I131 scan with serum thyroglobulin (as long as anti-thyroglobulin negative)
- survival benefit only seen in pts with local invascion or mets at time of thyroidectomy
- TSH suppression lifelong indicated in high risk pts.
- clinical review w I131 scan and serum thyroglobulin to screen for locoregional recurrence.
- if recurrence - for high dose I131 and consider VEGF inhibitor (bevacizumab, sunitnib, sorafenib)
44
What is the singificance of rosiglitazone/pioglitazone in thyroid cancer?
Can use to redifferentiate prior to I131 therapy, if follicular and expressing PPARgamma
45
What is the function of recombinant TSH in thyroid ca?
more pleasant in TSH stimulation than T4 withdrawal, esp in patients with psychiatric comorbidities.
Is effective in ablating thyroid remnants - with lower doses of RAI
46
What is the treatment of medullary thyroid cancer?
Total thyroidectomy
RET oncogene testing and family screening
Strongly consider MEN2
- 2a = phaeochromocytoma, parathyroid adenoma
- 2b = phaeochromocytoma, cutaneous neuromas, ganglioneuromas, marfanoid habitus
Caclitonin = good marker of recurrence
Prophylactic thyroidectomy pre 20 years recommended for RET carriers
47
what are oral manifestations of MEN 2B?
thickened lips
| oral mucosal neuromas
48
What is the feature of B-HCG in the context of thyroid disease?
shares same alpha subunit of TSH and both can activate the TSHr on the thyroid.
TSH is hence often suppressed in the 1st trimester, FT3 and FT4 levels do not have reference ranges.
49
What must one do to thyroxine levels in pregnancy?
increase T4 supplementation by 1.3x in 1st 20 weeks especially.
50
What is associated with hyperemesis in T1 of pregnancy?
High bHCG and suppressed TSH and elevated T3, T4. Elevated bHCG is the cause of vomiting, not T3, T4.
51
What is the significance of anti-thyroid antibodies in pregnancy?
Risk factors for miscarriage and premature birth - women with Ab and subclinical hypothyroidism should receive thyroxine in T1.
52
What is the signficance of grave's disease in pregnancy?
not common - thyrotoxic women are relateively infertile. Dx by TSHr-Ab as Tc99 is C/I.
Use PTU preconception and switch to CBZ. Risk of passive graves in foetus 1%.
53
What are features of prolactin excess?
galactorrhoea or breast tenderness
54
What are dynamic tests for corticotrophs?
Deficiency suspected: insulin tolerance test, or short synacthen test (not useful in acute pituitary failure)
Overactivity suspected:
24hr free urine cortisol, midnight salivary cortisol or oral dexamethasone suppression:
low dose - 1mg at 11pm - 8am cortisol should be
55
What are dynamic tests for somatotrophs?
GH deficiency suspected - insulin tolerance test or glucagon or arginine/GHRH stimulation test
Assessment for cure of acromegaly: 75g oral glucose load, normall GH undetectable 2h after oral glucose
56
What are dynamic tests for posterior pit function?
ADH deficiency suspected - water deprivation test to induce plasma Osm >300 to assess if uOSM >500-600.
57
What are features of craniopharyngioma?
Most common hypothalamic lesion
Can be diagnosed only on Bx
Clues:
On MRI is suprasellar and calcified.
Diabetes insipitus - rarely seen with adenomas
Anterior pituitary insufficiency - with raised prolactin
Hyperphagia - hypothalamic involvement
treatment is difficult - often unresectable and high morbidity, esp due to obesity related complications.
58
What are the frequency of pituitary adenomas?
40% are non functional, however often stain for FSH
30% are prolactinomas
15% secrete GH and 10% secrete ACTCH
~5% are FSH/LH secreting tumours
59
What are the tumour factors associated with pituitary adenomas?
```
Lactotrophs - PIT1
Gonadotroph STF1, GATA2
Somatotroph PIT1
Corticotroph TBX19 (TPIT)
Thyrotroph PIT1
```
60
What are 4 genes that cause familial pituitary tumours?
MEN1 - parathyroid, pancreas and pituitary
P27 - MEN4 cyclin dependent kinase, parathyroid and pituitary
AIP - young onset tumours, particularly GH secreting
PPKAR1A - carney syndrome - spotty skin pigmentation, myxomas, testicular, adrenal and or pituitary adenomas or hyperplasia.
61
What are features of non-functioning pituitary tumours?
most stain for FSH on immunohistochemical analysis
may cause mass effect or anterior pit failure
prolactin can be 10x elevated due to stalk pressure
surgery usually necessary for Dx and debulking.
62
What must be checked prior to operative management of a pituitary lesion with mass effect?
prolactin! bromocriptine therapy can obviate need for surgery.
63
How are prolactinomas diagnosed?
High serum prolactin, hypogonadism (infertility), breast tenderness and discharge
64
What is the approach to Mx of prolactinomas?
must exclude hypothyroidism as TSH stimulates prolactin release and drugs that cause prolactin release.
MRI pituitary, then start bromocriptine or cabergoline.
Aim to normalise prolactin.
Can cease in 2-4y if prolactin normal, >50% reduction in mass size and >5mm from vital structures.
60% will not recur in 5 years. require life long surveillance with serum prolactin +/- MRI.
Normalisation of prolactin not mandatory in postmenopausal women.
Macroadenomas have highest rate of recurrence.
65
What are other causes of high PRL?
```
Pregnancy/lactation
Hypothyroidism
Metoclopramide
neuroleptics
stress
pituitary stalk pressure
```
66
What is the approach to diagnosis of cushing's disease?
Cushing's disease = ACTH secreting pituitary adenoma.
Expect hyperpigmentation.
Diagnose hypercortisolism by 24hr urinary free cortisol, or 11pm cortisol.
Demonstrate that ACTH is inappropriately normal or high - (ACTH dependent cushing's disease) - perform dexamethasone suppression test - 2mg QID for 2 days - if suppressed - Cushing's disease, not ectopic ACTH
MRI to determine if pituitary mass
Petrosal sinus sampling is needed to confirm dx and determine the side of the tumour prior to surgery.
67
What are options if surgery fails to cure cushing's disease?
Pituitary radiotherapy
Bilateral adrenalectomy (w pituitary radiotherapy)
medical therapy
68
What are medical therapy options for cushing's disease?
ketoconazole is the best tolerated - inhibits several steps of steroidogenesis - 70-80% effective. GI upset, hepatotoxicity, rash, gynaecomastia.
metyrapone - inhibits 11b hydroxylase - GI Sx, dizziness, rash, histuitism HTN, oedema, most common in pregnancy.
mitotane - inhibits several steroidogenic steps, adrenolytic, nausea, diarrheoea, dizziness, neurological Sx, dyslipideamie - should be avoided in women planning pregnancy in the next 5 years.
69
What are causes of endogenous cushing's syndrome?
```
Cushing disease 70%
Ectopic ACTH 10%
Adrenal adenoma 10%
Adrenal Carcinoma 5%
Adrenal other 4%
Ectopic CRH
```
70
How is the Dx of acromegaly made?
elevated IGF-1 in setting of acral enlargement and other clinical features (DM, OA, OSA, Vascular disease)
May have elevated PRL due to cosecretion of GH and PRL by tumour
71
How is Acromegaly treated?
Surgery, then aim to normalise it with survival benefit - dopamine agonist (often fails), then octreotide or lanreotide
- can cause gallstones abdo pain
Radiotherapy can achieve delayed biochemical control, with risk of damage to surrounding structures.
Colonoscopy from age 40 to screen for bowel cancer.
72
What is the most common cancer associated with acromegaly?
thyroid cancer
73
What is the MoA of pegvisomant?
GH receptor antagonist, highly effective in acromegaly.
Not covered by PBS at present
Theoretical risk of pituitary adenoma enlargement
74
What are features of TSHomas?
very rare
thyrotoxicosis with high T4/T3 and non-suppressed TSH.
TSH secreting pit tumour
DDx - resistance to thyroid hormone due to TSHr mut
Surgery 1st line, recurrence common
TSHomas may respond to somatostatin analogues
75
What is the frequency of pituitary adenomas?
20% in the population have
76
What should be replaced in pituitary insufficiency?
Glucocorticoids can just be glucocorticoid as adrenal cortex is intact
thyroxine
consider testosterone or OCP unless Hx of breast or prostate ca
GH replacement only funded in children
Prolactin deficiency not treatable, and not necessary to treat.
Pituitary insufficiency is associated with increased incidence of heart disease and stroke - assess and treat CV risk.
77
What are features of adult growth hormone deficiency?
High risk of GH def if deficiecny of one other pit hormone.
Requires stimulation test as IGF1 can be normal - insulin tolerance for example/glucagon stim
Treatment not funded.
Leads to higher well being, mental health, strength, increased muscle mass and lipid profile
CI if previous cancer.
78
What is pituitary apoplexy?
sudden haemorrhage into pituitary - often following complicated childbirth.
Frontal headache, +/- neuropraxias are features
emergency as it causes hypocortisolism and unstable mass effect.
Mx - bloods for cortisol and other hormones.
Steroid replacement - hydrocortisone 50mg qid or hi dose dex if neuropraxia
Imaging
Surgery for debulking and Dx
79
How is Diabetes insipidus Dx?
failure of urine to concentrate (>600) when serum osmolality rises to >300. Central cause if concentration occurs (>600) with administration of DDVAP.
80
What are causes of DI?
```
Central:
Head injury, surgical injury to post pit
idiopathic
infiltration - craniopharyngioma, germinoma, histiocytosis, Tb or sarcoid
Famillial
```
Nephrogenic: lithium, famililal
81
What is the MoA of the vaptan class of medications?
Block V2 vasopressin receptor. Used in SIADH but not recommended.
82
What is the principle of Mx of prolactinoma in pregnancy?
pit size increases during pregnancy due to lactotroph hyperplasia.
If microadenoma - discontinue dopamine agonist and periodic visual field testing and postpartum MRI after 6 weeks.
If macroadenoma >1cm - consider surgery pre pregnancy, ensure bromocriptine sn pre pregnancy - follow visual fields frequently - admin bromocriptine if there is visual field compromise - or consider bromocriptine all prengnacy if previous visual field impingement - consider hi dose steroids or surgery during pregnancy if vision threatened or adenoma haemorrhage. post partum MRI after 6 weeks.
83
What is the order of loss of ant pit deficiencies?
FSH/LH first, then GH, TSH, ACTH
84
What are features of isolated acquired ACTH deficiency?
rare, difficult dx, likely auto immune
rare, presents with non-specific symptoms - confusion and fever, no hyperpigmentation, salt craving or hypotension seen in addison's disease. hypercalcaemia often seen, leading to Dx.
85
What is the role of leptin in hypothalamic amenorrhoea?
suitable therapy
