ENDOCRONOLOGY WK 2 Flashcards
1
Q
what cells in the thyroid produce what
A
Follicles produce thyroxine
C-cells produce calcitonin
2
Q
how is thyroid hormone made
A
- Trap iodide ions into the epithelial cell through the apical membrane
- Converted to iodine inside
- Iodine molecules added onto protein skelenton (thyroglobulin) to create diff. types of thyroid hormone
o Catalysed by enzyme thyroid peroxidase
o And hydrogen peroxide
Different amounts of iodine added onto thyroglobulin skelenton - Add 1 = monolodotyrosine
- Add 2 = dilodotyrosine
- Add 3 = trilodotyrosine (T3)
- Add 4 = tetralodotyrosine (T4)
3
Q
T3 and T4 - “active” status and relationship to each other
A
- T4 is an inactive prohormone
- Is converted to T3 by removal of one iodine
- By deiodinase enzymes
- T3 is the active hormone
T4 is bound to albumin so exists in a bound state as inactive, only the free hormone is active
4
Q
thyroid hormone - where is T3 produced and what is it’s mechanism of action
A
- 20% T3 produced from thyroid gland
- The thyroid produces T4:T3 in a 14:1 ratio
- 80% T3 produced from peripheral conversion of T4 in liver, kidney and muscle
- Thyroid hormone acts on nuclear receptors – transported into the cell and binds to receptors in the nucleus
5
Q
what would you expect to happen to TSH levels if T4 levels are low - why is this important clinically
A
If someone has low T4 you’d expect them to be producing more than normal TSH
- If TSH is in normal reference range this would actually be inapropriate in this context
6
Q
actions of thyroid hormone
A
- Growth development
- Basal metabolic rate
- Activate mental processes
- Thermogenesis in brown adipose tissue
7
Q
Graves - hyperthryoidism
A
Graves (~75%)
- Autoimmune disease
- Antibodies attack thyroid to make it overactive
- Can be associated with eye disease
8
Q
toxic multinodular Goitre (MNG) - hyperthyroidism
A
- Mulitple lumps (nodules) or enlarged thyroid (goitre)
- Often one or more lumps will be overeactive
- Can get lid lag or lid retraction (starey look to their eyes), but no other features of thyroid eye disease
o Caused by thyrpoid hormones over activating SNS
9
Q
what is seen in scan if a patient has MNG
A
- Discrete areas of the gland light up (the nodules)
- Nodules over produce thyroid hormone which will feedback on the pituitary and switch off production of TSH
- Normal bits of gland between nodules will switch off because there’s no TSH information
10
Q
singular toxic nodule - hyperthyroidism
A
- Single overactive lump
- Only one part lights up as rest of the gland is producing no hormones
11
Q
thyroiditis - hyperthyroidism
A
- Temp. overeactivity of thyroid (isn’t technically overeactive)
- Gland is damaged which releases all the stored preformed hormones
- Can be followed by period of underactivity
- Truggered by pregnancy, infection or some drugs (eg amiodarone)
12
Q
symptoms of primary hyperthyroidism
A
- Weight loss
- Tiredness
- Tremor
- Hot,sweaty
- Palpitations
- Diarrhoea
- Light/absent menses
- Mood – irritabel, anxiety
- Eyes (change in appearance, red, gritty, painful, double vision)
- Muscle weakness
13
Q
what can be seen in an examination for primary hyperthyroidism
A
- agitated, talk fast
- warm, sweaty
- tremor
- inc. HR, atrial fibrillation
- smooh giotre (Graves) vs MNG vs single nodules vs no goitre (thyroiditis)
- bruit heard over goitre almost diagnostic of Graves
- Eye
o Lid retraction and lid lag in any casue of overactive thyroid
o Any other eye signs indicates Graves disease
14
Q
eye symptoms in hyperthyroidism
A
lid retraction and lid lag - Associated with any cause of thyrotoxicosis. All other eye signs are specific to Graves Graves… - Redness - Gritty sensation - Dry or watery eyes - Pain on eye movement - Swelling around the eyes - Proprosis (pushed forward appearance of eyes) - Double vision - Loss of colour vision
15
Q
diagnosis of P. hyperthyroidism
A
- TRAbs (TSH Receptor Antibodies) significantly positive indicates Graves
- TPO (thyroid peroxidase) antibodies less specific
- If TRAbs are neg, so scintigraphy (often technetium rather than radio-iodine uptake because lower dose of radioactivity)
16
Q
what would you expect to see in a technetium scan for the different causes of hyperthyroidism
A
thyroiditis - thyroid hardly seen at all
Graves disease - whole thyroid lights up more than usual
Toxic MNG - multiple areas light up more than normal and rest of the thyroid is barely seen
toxic adenoma - one area lights up more than normal with other areas not lighting up
17
Q
what’s the time course for destructive thyroiditis in terms of TSH, T3 and T4 levels
A
0-2 months (thyrotoxic
- TSH decreases due to massive increase in T3 and T4 as thyroid gland is destroyed releasing stores of these molecules
2-2.5 months (euthyroid)
- TSH rapidly inc. and T3 and T4 rapidly dec. but are within reference ranges
- 5-5 months (hypothyroid)
- TSH is very high due to drop in T3 and T4 as thyroid is damaged and can’t produce these hormones
> 5 months - recovery
18
Q
management of primary hyperthyroidism
A
Antithyroid drugs (ATDs):
- Carbimazole and propylthiouracil (PTU)
- Decrease production of thyroid hormone (block TPO)
- Not thyroiditis (high T4 levels are due to release of hormone stores from damaged gland, but gland is not actually overactive)
- Rare side effect of agranulocytosis (<1/500)
o Signs of this are high fever, bad sore throat, bad mouth ulcers = stop meds
Propranolol good for tremor and inc. HR
- Not used in asthmatics
Radioactive Iodine (I ^131)
- Taken up by bits of gland that are overreactive
- Risk of longterm hypothyroidism
- Avoid pregnancy for 6 months
- Restrict contact with children under age 12 and pregnant womedon’t share bed with partner for 4 days
Surgery
- Risk of longterm hypothyroidism or damager to recurrent laryngeal nerve and parathyroid glands (control calcium)
19
Q
treatment for Grave’s specifically
A
- Treated with ATDs first time around
o 12-18 month course of tablets
o 60-70% chance of relapse (since autoimmune) - I^131 fro recurrent Graves
o Once it returns it will keep coming back
20
Q
using Iodine^131 as treatment for MNG or singular toxic nodule
A
- I^131 for TMNG or toxic nodule
o No chance of long term remission with a course of tablets - Risk of hypothyroidism after I^131
o Lower with TMNG and toxic nodule than Graves - Risk of thyroid eye disease flaring up after I^131 so av oid in thyroid eye disease
21
Q
mechanism of thyroid eye disease
A
TRab Antibodies also bind to receptors in connective tissue in and behind the orbit
Effecting…
Adipocytes
- Adipogenesis – creation of new fat cells
- More tissue behind the eyes pushes them forward
Fibroblasts
- Increased amount of glycosaminoglycans
- These retain fluid leads to increase bulkiness of ECM
- Swelling behind the eyes – increase in pressur ebehind the eyes
22
Q
how to take a history of thyroid eye disease
A
- Change in appearance of eyes or periorbital tissues
- Corneal symptoms (grittiness, photophobia, watering)
- Extra-ocular muscle (EOM) restirction (eg diplopia/ double vision)
- Symptoms of EOM inflammation (pain at extreme gaze)
- Orbital ache unrelated to gaze
- Synptoms of optic neuropathy (Dec. colour vision, blurred vision)
- “popping” of eye – inability to close lids (globe subluxation)
23
Q
examination of thyroid eye disease
A
- Redness
- Eyelids
o Thickening/ oedema
o Lid retration - Chemosis
- Proptosis
- Test eye movements (H)
- Lagophthalmos (inability to close eyelids without forcing)
- Optic nerve
o Visual acuity (snellen chart)
o Fundoscopy or slot lamp to visualise head of optic nerve
24
Q
management of Graves eye disease
A
- Unless mild, should be managed in joint thyroid eye clinic
- Achieve euthyroidism
o Both hyper and hypothyroidism are bad
o Can have active eye disease without throid being overactive
o Thyroid eye disease can even present many months nefore thyroid disease develops
25
conservative measures for management of graves eye disease
- Smoking cessation (smokers have 9x inc. risk of developing severer and respond less well to treatment)
- Topical lubricants
- Selenium 200mcg daily (antioxidant)
- Steroids (oral or iv if active eye disease)
- Other immunosuppresion (eg cyclosporine)
26
what is seen an an xray of graves eye disease
- 50% of eyes should sit behind the red line so you can see they are vv swollen
- Extraocular muscles (medial and inferior rectus muscles) are swollen
- Optic nerve very compressed by swollen muscles – concern for sight
27
primary hypothyroidism, hormone levels, prevelance and symptoms
TSH increased, FT4 decreased, TT3 decreased/normal
```
- Prevelance depends on age and gender
o 0.3-2% women and <0.15% men
- Symptoms
o Tired (slowed down, lethargic)
o Weight gain, puffy eyes and skin
o Feeling cold
o Slow hr
o Constipation
o Dry hair and skin
o Heavy periods (menorrhagia)
o Hyperlipidaemia
o (enlarged thyroid = goitre)
- No evidence to support giving thyroxine to people with symptoms but normal TFTs
o A lot of people can present with these symptoms and no physiological changes
```
28
causes of primary hypothyroidism
Hashimoto’s thyroiditis
- Antibodies attack thyroid and make it undereactive
- Permanent
- Tendency can run in families
Iatrogenic (post surgery or radioactive iodine)
Spontaneous atrophic
Temporary thyroiditis
- Eg viral thyroiditis, postpartum thyroiditis
Other (congenital (screening programme), iodine deficiency (not UK), drug-induced (eg lithium)
- Babies screened after birth for TSH levels
- Because it’s key for growth and cognitive developm ent
29
treatment of primary hypothyroidism
Thyroid hormone replacement
Ideal replacemnet
- Need to know normal fluctuations of thyroid an dpituitary hormones are
- Free T4
o stable throughout day, drifts down inmorning then rises slowly
- TSH and free T3
o dips down in afternoon and rises in evening so it’s highest overnight and dips down in the morning again
30
thyroid replacement therapy - levothyroxine - aim of treatment and general info
- up to 3% of the UK population are on thyroid hormone replacement
- the vast majority of patients are treated with (and feel fine on) once daily levothyroxine (T4)
- a small proportion of patients feel considerably less well on levothyroxine than when they had a normally functioning thyroid
- half life lvothyroxine approx. 7 days
- once daily dosing results in stable fT4 and fT3 levles
- commonly around 100mcg thyroxine (1.6mcg/kg/day)
- aim to normalise TSH
- usually managed by GPs
- no further Inx needed for hypothyroidism if inc. TSH (scans do not change Mx)
31
levothyroxine - timing of dose, monitoring and what medications to avoid
```
LEVOTHYROXINE – TIMING OF DOSE
- aim of treatment is to normalise TSH
- taking on an empty stomach before breakfast is preferable to with breakfast or before bed
Monitorung therapy
- annual TFTs once stable
- if dose change, wait at leadt 6 wks before rpt TFTs
Some OTC meds impair T4 absorption
- PPIs eg omeprazole/iansoprazole
- H2 antagonists eg ranitidine
- Iron, calcium, aluminium
- Don’t take T4 <4h after these
Increased T4 requirement if start oestrogen (OCP, HRT) or anticonvulsants
```
32
T4 and T3 combination therapy
- Levothyroxine is not the perfect thyroid hormone replacement but current alt. do not have strong evidence of greater effectiveness (eg combinaton T3/T4, dessicated thyroid extract)
- T3 (liothyronine) peaks at 2-4 hrs and has a half-life of 1 day
- At least 3x daily dosing is required to achieve stable levels
- Concerns around effects of rapid peaks of highly active thyroid hormone
- What dose? What ratio of T3:T4?
- Difficult to achieve ‘blinding’ in studies
- No clear benefit of combination on quality of life
33
desiccated thyroid extract (DTE)
- Names > DTE, “natural thyroid”, armour thyroid
- Contains T3 and T4
- Human thyroid T4:T3 is 14:1 (unusual ratio for humans as it’s in 4:1 ratio instead)
- Contains pig thyroid extract with T3, T4 and a bunch of other thyroid products that are unecessary
- One grain (60mg) contains 38ug T4 and 9ug T3
34
in what case may levothyroxine not be adequate treatment
- Hypothyroid patients with less active deiodinase 2 had slightly better response to combination of T3 and T4 than T4 alone
- In the future, genetic markers may help guide therapy
35
subclinical hypothyroidism - hormone levels and why TSH is important
TT3 and FT4 normal, TSH elevated
- TSH more sensitive marker of thyroid hormone status than T4
- If T4 normally sits in upper end of normal range then drops to the lower end of the range it’s technically still normal but for them specifically thyroid is becoming underactive
Before T4 drops down below the normal reference range TSH detects this and pushes up the TSH
- For this reason TSH is most valuable bc/ it’s the earliest indicator of something going wrong
- So if TSH is above normal this is known as compensated hypothyroidism/ sub-clinical hypothyroidism
Same with hyperthyroidism
- As T4 rises to high in the normal range
- The TSH becomes supressed and is an ear;y sign of hyperthyroidism
36
subclinical hypothyroidism - prevalence, cause, adverse effects
- Prevelance 4-10%
- Main cause is autoimmune chronic thyroiditis
- Some (weak) evidence of adverse effects
o Lipids
o BP
o Other CV risks eg CRP, arterial stiffness
o No hard end-points evidence (ie no evidence that it increases heart attacks or strokes)
- No convincing evidence that it causes symtpoms
- However, TFTs often checked because of symptoms that MAY relate to thyroid so patients often convinced that the 2 are linked
37
conclusions of study into if subclinical thyroidism is likely to progress to hypothyroidism
- Having a raised TSH >2mU/l increases risk of hypothyroidism (independent of age)
- People with TPO antibodies increases risk also
- Treat if TSH> 10 on 2 occasions and/or if TPO strongly positive
38
secondary hypothyroidism - hormone levels, a clinical example of if it were misdiagnosed as P. hypothyroidism
TSH is low or nomal, low FT4 and low/normal TT3
- patient presents with low T4 and normal TSH
- diagnosed as hypothyroidism and patient given T4 replacement
- in follow up TSH is suppressed and so patient is given lower dose of T4
- emergency admission with bitemporal hamaenopia as has adenoma of pituitary gland
39
what is an important rule to remember when diagnosing hypothyroidism
IN ORDER TO DIAGNOSE PRIMARY HYPOTHYROIDISM YOU MUST HAVE A HIGH TSH
IF TSH IS INNAPROPRIATELY NORMAL/LOW THINK ABOUT PITUITARY DISEASE
40
non-thyroidal illness effect on thyroid hormones
- TSH – can be supressed acutely then rise on recovery
o can be misinterpreted as primary hyperthyroidism
- tT3 falls (imparied hepatic uptake and T4 to T3 conversion dec.)
- illnesses affects thyroid binding proteins, which reduces total hormone and raises free hormone fraction
- fT4 usually stays within references range or is modestly raised
- severity and duration of illness often correlated with the degree of abnormality observed in TFTs
- low T3 found in NTI may be an adaptive response (diminish basal rate, conserve essential body protein stores)
41
mechanisms of non-thyroidal illness
- TSH – can be supressed in acute phase of severe illness by range of mechanisms then ruse on recovery until normal thyroid hormone concentrations are restored
- Substances produced in illness that supress TSH
o IL-1
o Glucocorticoids
o Dopamine
o Low TRH
o TETRAC
o TRIAC
o Somatostatin
o TNFa
TRH release supressed by cytokine and glucorticoids
42
hypothyroidism in pregnancy
- Fetus need T4 from 4-5 weeks to ensure NS develops properly
- Uses maternal T4 exclusively up to 20 weeks and partially thereafter
- T4 requirements can increase by 50% by 20 wks then plateau
- Inc. T4 dose when pregnancy confirmed
- TFTs each trimester
- Can also be linked to inc. of oestrogen increasing levels of thyroid binding globulin so more thyroid hormone bound to protein and less available for use
- Untreated overt hypothyroidism associated with
o Infertility, miscarriage
o Pre-eclampsia, premature delivery
o Inc. foetal mortality, impaired neurological development
- Mild (subclincal hypothyroidism) associated with
o Neurodevelopmental delays, placental abruption
43
what are the 5 main modalities used for thyroid imaging
- Plain radiography (x-rays)
- US
- Computed tomography (CT)
- Magnetic resonance imaging (MRI)
- Radionuclide imaging (RNU including PET/CT)
44
firstline investigation - why is this?
- Ultrasound
- Neck is superficial
- No radiating ionising radiation
- Thyroid galnd susceptible to x-rays leading to inc. risk of cancer
good for differentiating benign from malignant
45
ultrasound - pros and cons
- High frequenct linear array rpobe
- Excellent soft tissue resolution
- Real time assessmnet
- Does not use ionosing radiation
Cons
- Operartor dependant
- Nto all patients are suitable eg obese
46
what are the 3 modes we can assess using ultrasound
```
- B mode assessment (black/white image)
o Structure, border, size, placement
- Colour flow doppler
o Vascularity
- Elastography
o Stiffness
```
47
what scale is used for classification of thyroid nodules
```
BTA (2014) classification of thyroid nodules
Ultrasound ‘U’ grade 1-5
- 1 = normal
- 2 = benign
- 3 = indeterminate
- 4 = suspicious
- 5 = malignant
```
48
what does a U2 thyroid grade mean
- Halo, hyper-/ iso-echoic
- Cystic change +/- ring down sign (colloid)
- Micro-cystic / spongiform
- Peripheral egg shell calcification
- Peripheral vascularity
doppler colour flow will show a lit up outline with no colour in the middle
elastography will be reddish to show softness
49
what does a U3 thyroid grade mean
a- Homogenous, isochoic/ hyperechoic, solid halo (follicular lesion)
b- Hypo-echois, equivocal echogenic foci, cystic change
c- Mixed/ central vascularity
X-ray shows dark outline at top left but becomes irregular outline as you move to bottom left lower margin
- Cystic spaces – hyperplastic nodule?
- Papillary carcinoma
50
what does a U4 thyroid grade mean
- Solid, hypoechoic (cf thyroid)
- Solid hypo-echoic (cf strap muscle)
- Disrupted peripheral calcification, hypo-echoic
- Lobulated outline
doppler will show some internal vascularity but mostly peripheral
51
what does a U5 thyroid grade mean
- Solid, hypo-echoic, lobulated/irregular outline, micro-calcification (papillary ca)
- Solid, hypo-echoic, lobulated/irregular outline, globular calcification (medullary ca)
- Intra-nodular vascularit
- Shape (taller>wide) as it’s invading through normal structures
- Characteristic lymphadenopathy
52
fine needle aspiration (FNA) - indications, procedure, risks
Indicated for U3. U4, U5
- Can be done under US guidance
Ultrasound-guided FSA
- 25g spinal needle
- Non suction capillary technique to reduce risk bleeding
- 3 passes
o 2 fixed, 2 air dried + needle rinse in cytoly solution for one of the air dried
Risks
- Bleeding
- Infection
- Iatrogenic injury to structures
- Inadequate sampling requiring repeat or biopsy
53
types of radionuclide imaging (RNI)
```
- (99mTc) technicium pertechnetate
o Good half life, not radioactive for days like they are with iodine
- (I-123) iodine (imaging)
- (I-131) Iodine (treatment)
o Higher strength
```
54
Radionuclide imaging - indications, interpretation of results
Typically used to assess the functionality of a thyroid nodule (context of hyperthyroidsim)
- Assesment of the casue of hyperthyroidism when aetiology is not clear
RNI FOR SOLITARY THYROID NODULE
- 99mTc pertechnetate scan
- Inc. uptake/ functionality – ‘hot’ nodule
- No uptake/ non-functioning – ‘cold’ nodule
Malignancy is extremely rare in ‘hot’ nodules on RNI imaging in this setting
However, 16% of ‘cold’ nodules are malignant
55
the 2 type of radioactive iodine and their uses
I-123 – imaging active thyroid tissue
- Harmless to thyoid
- Determine activity of thyroid
- Ectopic throid tissue
I-131 – treatment of thyroid disorders
- Destroys thyroid cells
- Hyperthyroidism
- Thyroid cancer
o Look for micro metastases
o 10 body planar imaging 10 days post treatment for thyroid cancer
o Uptake of radioiodine in lymph nodes and distant metastases is associated with a favourable prognosis
o Demonstration of disease is essential to ensure optimum follow up and management
56
cross-sectional imaging to assess the thyroid
- Role of CT/MRI
- Used for staging patients with suspected metastatic thyroid cancer
- Assessment for patients following treatment or on surveillance
- Assessment of patients with suspected recurrence when us is negative
57
F-18 FDG PET/CT
- Positron emission tomography
- FDG – fludeoxyglucose
- Glucose metabolsim scan
o Anything that takes up lots of glucose – hot (ie cancer)
- Used in staging of cancers (looking for involved lymoh nodes and distant disease)
58
describe what histology is
- Samples of solid tissues – either biopsy or resection
- Fixed in formalin, then embedded in parafin blocks
- Cut thinly and stained with Haemotoxylin and eosin
- Tissue architecture and cytological features well preserved
59
describe what cytology is
- Amterial is sucked out of a lesion (aspirated) using a needle
- The material is then smeared straight onto a slide (direct preparation)
- Or centrifuged down and filtered before being applied to a slide (liquid based cytology)
- Can make a cell block for ancillary testing
60
what are types of benign thyroid lesions
- Mulitnodular goitre
o Large mass in neck, nodules can benign or malignant in thyroid so must be investigated
- Graves disease
o Autoimmune overactivity
- Hashimotos thyroiditis
o Autoimmune disruption of thyroid parenchyma leading to hypothyroidism
- Follilucular adenoma
o No evidence of invasion of surrounding tissue/ blood vessels
61
what does multinodular goitre look like microscopically
- Big follicles containing macrophages with cholesterol clefts
- Variably sized follicles
- Cystically dilated follicles
- Foamy macrophages
- Fibrosis between follicles
This is due to multiple episodes of thyroid gland trying to produce more of its products
lots of. colloid
62
what does graves disease look like under the microscope
- Instead of follicles there’s papillary architecture
- Thyroid follicular epithelial cells become columnar cells
o Have basily located nuclei
- bubbles sitting above the the thyroid cells – called scolloping of the colloid
63
what does hashmotos thyroiditis look like under the microscope
- lymphoid aggregates with germinal centre formation
- follicles small and appear atrophic
- fibrosis
- thyroid gland destruction
- oncocytic change - eosinophils in cytoplasm
- oncocytic appearance = cytoplasm looks pink
64
what does follicular adenoma look like under the microscope
- thick fibrous capsule
| - lesion made up of small follicles
65
describe a follicular adenoma
- completely encapsulated lesion
o thick ring of fibrotic tissue surrounding lesion
- made up of thyroid follicles
- clonal population but benign
- if capsular or vascular invasion then becomes follicular carcinoma
66
what are the main types of malignant thyroid disease
- Follicular carcinoma
- Papillary carcinoma
- Medullary carcinoma
o Rare – sometimes assoc. with genetic conditions
- Anaplastic carcinoma
o Rare – 2nd top cancer you don’t want to get
67
follicular carcinoma
- Resembles benign thyroid gland parenchyma
o Produces follicles
- Tumour invades through fibrous capsule surrounding the lesion
- Can invade vascularly also
68
papillary carcinoma
- Have paillae – long finger-like projections
- Can be encapsulated
Nuclear features (chracteristic)
- Intranuclear inclusions
- Nuclear clearing
o Nucleus appears clearer than usual
- Nuclear irregularity
o Look like raisins
- Nuclear grooves
Sometimes have Psammoma bodies
- Calcified bodies
- Laminated appearance
Also has a follicular variant
- Must look at nuclear features to diagnose
69
medullary carcinoma
- Multiple endocrine neoplasias (MEN)
- Strange
o Looks like anything – vv wide range appearances
o Cells can be spindley
o Cells can have nucleur inclusions and nuclear grooves mimicking papillary carcinomas
- Unique as associated with pink stuff
o Amyloid
70
anaplastic carcinoma
```
- High grade malignancy
o Rabdoid variant – big malignant cells and prominent nuclei
o Spindle cell variant
- Death sentence
o Treated radiotherapy
o Not very good prognosis
```
71
thyroid cytology - uses, colloid importance
- Screening test only
- Most important features is colloid
- Cell to colloid ratio is a good indicator of malignancy
- Colloid is a reassuring feature – suggests benign
- For adequacy must have 6 groups of at least 10 cells
72
what is fine needle aspirate diagnoses (Bethesda classification)
- unsatisfactory, (not enough cells) (Thy1)
- Cyst fluid (not enough epithelium identify histogenesis of cyst) (Thy1c)
- non-neoplastic thyroid lesion (Thy2)
- cyst in non-neoplastic lesion (Thy2c)
- possible neoplasm thyroid (Thy3a)
- probable or certain follicular neoplasm (Thy3f)
- suspicion of malignant neoplasm (Thy4)
- malignant neoplasm (Thy5)
73
key cytological features of thyroid diseases
- Lots of colloid – multinodular goitre
- Variably size follicles – multi-nodular goitre
- Even sized folliclaes – follicular neoplasm
- Papillary structure, nuclear grooves and inclusions – papillary carcinoma
- Dispersed small cells – medullary carcinoma
- Very pleomorphic cells – anaplastic carcinoma
74
what is the normal water uptake and how is water used up in our bodies
Normal uptake, adult, temperate climate – 0.9-2-2,5 litre
Kidney > 400ml day
Skin, respoiration, gut ~ 500ml day (depends on climate etc etc)
75
what area of the brain coordinates water balance and with in this what are important features
DIANCEPHALON
- Coordinates water balance
- Contains hypothalamus
o Important nuclei
Supraoptic nuclei and paraventricular nuclei which both make ADH
Released by posterior pituitary into circulation
Stimulated from osmo centre in third ventricle
Thirst centre nearby produces thirst sensation
76
how do ascending tracts feed into the diencephalon to influence water balance
o When stimulation from these is at low level makes little difference
o When stim. Is at high level can interfere
o Afferents from baroreceptors give info on circulatory status
Eg in haemmorhage stim. From them goes up dramatically
o Pain and nausea from nucleus tractus solitarus can feed up and effect ADH
Part of reason you get SIADH
77
thirst feedback loop
1) Plasma osmolarity rises leading to feelings of thirst
2) That stimulates desire to drink water
3) Osmolarity drops and feedback loop is inhibited
78
causes of high fluid losses
- High insensible losses (traveller in dessert sweating)
- High GI losses (eg GI infection)
- Excess polyuria (in untreated DI or DM)
79
ADH feedback loop
as plasma osmolarity rises so does ADH levels
80
causes of polydipsia and polyurias
```
Hypothalamus
- Primary stimulation of thirst centre (primary polydipsia)
Pituitary
- Lack of ADH
- Cranial diabetes insipidus
Kidney
- Resistance to ADH
nephrogenic diabetes insipidus
```
81
vasopressin receptors - location and actions
```
- V1
o 1a – maintain blood volumes and circulation (vasoconstriction when AVP v high)
o 1b – ACTH release + stress response
- V2
o In kidney – responds to ADH
o Allows water retention
o Highest sensitivity
- OT (oxytocin)
o Affinity for receptors
```
82
whats the action of ADH in the kidney
Major action is in the collecting duct
- Aquaporin 2 present on apical surface of cells
- Highly sensitive to ADH
o When ADH turns off the aquaporin channel becomes rare in the membrane
o Water permeability drops
o Extra water leaves the body as aquaporin isn’t there to reabsorb it
Other actions (minor compared to major effects)
- Affect NaCl transport in thivk ascending limb
- Affects urea concentrations
- Overall affecting osmolarity of the medulla
- Pulling water out of tubule through osmotic tubule
83
what is SIADH
The syndrome of inappropriate antidiuretic hormone secretion
- when ADH doesn't switch off properly there's inc. water reabsorption
- Typically produces very concentrated urine
84
how is ADH affected in Haemorrhage
When haemmorhage
- Aldosterone and adrenaline turn on to maintain circulatory volume
- ADH (vasopressin) turns on to constrict vessels in gut
- Only involved in constriction of blood vessels at vv high levels
- AVP at low-normal levels solely involved in water reabsorption
85
the importance of thirst and ADH in keeping plasma osmolarity in it's normal range
ADH Important in policing the lower end of normal range
- Allows an inc. of sodium by switching off when osmalarity low
- Disorders in ADH cause low sodium
Thirst important in policing upper part of normal range
- Allows person to become thirsty, and take in more water
- If they don’t take in more water they can’t drop sodium
- Disorders in thirst cause high sodium
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excess water retention - symptoms and effect on water/ electrolyte balance
- Usually little symptoms initially
- Later Na dec., and plasma osmolarity dec.
- Confusion, drowsiness, nausea, even fits
- Presents as unexplained confusion
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excess water loss - presentation, water/ electrolyte levels, causes
Polyuria
- Thrist all the time – drink water to keep up with output
- If intake inadequate Na inc., plasma osmolarity inc, BP dec.
- Collapse and confusion
Causes
- Diabetes insipidus (cranial or nephrogenic)
- Habitual/psychogenic polydipsia
- Osmotic diuresis (eg glucose, mannitol, hypercalcaemia)
- Renal impairment (unusual)
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investigations into excess water loss
- Urine volume >2ml/kg/hr
- Urine volume high and persistent thirst or (Na)p >145mmol/l (normal level)
- Measure things that can caused increased osmolarity (aka glucose, Ca, urea, creatinine)
- Check for diabetes insipudus (check if they actually can concentrate the urine)
o Ask patient to go overnight wihtout drinking water
o This urine is in a dehydrated state so should have osmolarity >600mosmol/kg
o If they continue to pass dilute urnine in this situation – could be DI
89
water deprivation test
o Usually doesn’t take long after not drinking water for osmolarity to rise in blood
o Can see if the urine osmolarity is >600 or not, if reaches 600 stop test as this excludes (and is dangerous)
o Don’t take water for 12 hrs before test – supervised on wards
o Test lasts all day (8hrs)
o If fails to reach 600 and plasma Na and osmolarity go above normal they do have DI
o Distinguish types by giving vasopression
If osmolarity rises above 600 after giving DDAVP = lack of production of ADH as they respond to exogenous AVP
• This is cranial DI
If osmolarity doesn’t respond after this = lack of sensitivity
• This is nephrogenic DI
90
hypertonic saline test
- Inject with saline solution that’s more concentrated than blood
- During this infusion plasma osmolarity rises
- Measure blo od samples and send them away fro analysis – plot graph
- If blood salt conc. Responds to normal ramnge rise in osmolarity = normal
- If it’s flat = diabetes insipidus
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cranial diabetes insipidus causes
- Neurosurgery – pituitary/ hypothalamus
- Head injury
- Tumours
- Haemmorhage
- Genetic
o Isolated
o AVP gene mutation
o DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deathness)
Pregnancy (gestational GI)
- In placenta there are enzymes that break down AVP
- Is there’s a borderline deficiency of vasopressin sometimes it can be unmasked
- Goes away after pregnancy
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nephrogenic diabetes insipidus causes
Kidney unresponsive to ADH
Can be partial
Causes
- Inherited – x-linked or recessive, mutations in receptors or aquaporin
Acquired
- Hypercalcaemia
- Hypokalaemia
- Resolution after urinary tract obstructive
- Secondary effect of pstchogenic polydipsia
- Lithium therapy effects
- Demeclocycline
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treatment of cranial and nephrogenic diabetes insipidus
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Cranial
- Replacement dDAVP to replace AVP
o Long acting, can give 2x day, more selective for V2 receptor = renal effects
o Given via
Intranasal spray/drops
Tablets (desmopression)
Injections (inpatients, diagnosis)
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Nephrogenic DI
- Harder to treat – address causes (eg low K, high Ca)
- Other measures to dec. polyuria
- Paradoxical bemnefit through giving thiazide diuretics
o Inc. extracellular fluid volume
o Water reabsorption increases in proximal tubule
o Less water reaches distal tubule where DI is prominent
- Low salt, low protein diet
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questions to ask to diagnose SIADH
1- Is the patient dehydrated
a. If so Na and water loss, identify if urine is site of excess salt loss
2- Is the patient oedematous?
a. If so treat cause of the oedema
3- If not 1 or 2
a. Thyroid or adrenal/ACTH deficiency
b. SIADH – show inappropriately concentrated urine
i. Show urine conc >500
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causes of SIADH
- Lesions in the head
- Intrathoracic disease, especially infections
- Neoplasms, especially lung/mediastinal
- Drugs
o Antipsychotics
o Sedatives
o 5 Cs
- Miscellaneous
o Nicotene, pain (esp. post-op)
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treatment of SIADH
- Confirm diagnosis (exclude other causes)
- Fluid restrict patient
o As if retaining too much water this issue subsudes if they don’t take in too much water
- Occasionally require demeclocyline (reduce kidneys ability to concentrate urine)
o Esp. in old confused patients
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aquaretics
- New drug
- Studies show good short term response but unremarkable lonterm response
- Could be used in heart failure?
- Also potential treatment for polycystic kidney disease
o liscensed for use
o Reduced rate of decline in GFR
98
Addisons disease
In addison’s disease
- dehyrdation
- Lose mineralocorticoid and glucocorticoid
o If you lose ACTH you only lose glucocorticoids
- Lose aldosterone
o = salt wasting – dehydration, dec. BP, inc. K, acidosis
o Dec. plasma volume
This gives symptoms of naseua and pain
This inc. ADH release
o ADH will be unaffected
So you get loss of Na but inability to retain water
o As you lose plasma volume you feel unwell so through baroreceptor reflex you get inc. ADH
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ACTH/GLUCOCORTICOID DEFICIENCY
dec. in glucocorticoid
- high glucocorticoid/ cortisol Central effect reducing amount of ADH release at a given osmolarity
so low cortisol means that ADH is higher
- Kidney can’t clear water as well
- body hangs onto more water
Glucose levels drop = nasuea and discomfort – SIADH through this
100
Diabetes insipidus/ SIADH after neurosurgery
After neurosurgery can get DI then SIADH then DI (purple line)
- Due to damage midway along pituitary stock
- Release of mediators that have a long half lfie so not cleared form blood quickly
- So initially not making ADH like normal
- Then mediators were released for several days (made too much)
- When cleared form body posterior pituitary didn’t recover = diabetes insipidus
101
what additional molecules are in the precursor of AVP
neurophysin and glycopeptide
