Endocrinology - Week 2 Flashcards
(101 cards)
1
Q
what percentage of the population has thyroid disease?
A
2-5%
more common in women - autoimmune
2
Q
what are follicles filled with?
A
colloid (T3 and T4)
3
Q
what do interfollicular cells produce
A
aka parafollicular cells or “c” cells produce calcitonin
4
Q
how is thyroid hormone created?
A
• Iodide ions trapped within the cell and converted into iodine
• Creation begins with thyroglobulin and iodine is added onto this skeleton to create different types of thyroid hormone.
o This reaction is catalysed by thyroid peroxidase and hydrogen peroxide is also involved in the reaction
o One added iodine makes mono-iodothyronine
o Two = di-iodothyronine
o 3 = tri-iodothyronine (T3)
o 4 = tetra-iodothyronine (T4)
- Colloid is reabsorbed into the cell and broken down by lysosomes.
- T3 and T4 are then secreted
- T4 is a pro-hormone and is turned into active T3 by the removal of one iodine which is catalysed by deiodinase enzymes
5
Q
how do thyroid hormones circulate
A
circulate in blood mainly bound to proteins • Thyroxine binding globulin (TBG) – 70% • Transthyretin – 20% • Albumin – 10% • 99.95% of T4 bound to protein
6
Q
what proportions of thyroid hormones are produced where
A
- 20% of T3 produced from thyroid gland
- 80% produced from peripheral conversion of T4 in liver, muscle and kidney
- The thyroid produces hormones at a ratio of 14 T4:T3 1
- The pituitary and hypothalamus control the thyroid – e.g. TSH from pituitary
- Controlled by negative feedback – T3 and T4 inhibit the production of TSH from the pituitary and TRH from the hypothalamus
7
Q
what are the actions of thyroid hormone?
A
- Growth development
- Basal metabolic rate
- Thermogenesis in brown adipose tissue
- Activate mental processes
8
Q
what are some causes of primary hyperthyroidism?
A
• Graves disease – 75%
o Autoimmune disease
o Antibodies attack thyroid to make it overactive
o Can be associated with eye disease
• Toxic multinodular goitre – 15%
o Multiple nodules on an enlarged thyroid (goitre)
o Often one or more lumps will be overactive
o Can get lid lag or lid retraction, but no other features of thyroid eye disease
• Toxic nodule
o Single overactive lump
• Thyroiditis
o Temporary overactivity of thyroid due to damage releasing stored hormone
o Can be followed by a period of underactivity
o Triggered by pregnancy, some drugs or infection
9
Q
what are some symptoms of hyperthyroidism
A
- Weight loss despite good appetite (often very hungry
- Tiredness
- Tremor
- Hot, sweaty
- Eyes: change in appearance, red gritty, painful, double vision)
- Muscle weakness
- Palpitations
- Diarrhoea
- Light/absent menses (periods)
- Mood: irritable, anxiety
10
Q
whats important to ask about in a patient with hyperthyroidism?
A
- Check about asthma an heart disease (relevant to use of propranolol and risk of tachycardia respectively)
- FHx – autoimmune disease
- SHx – smoking (eyes), job and family (radio-iodine)
11
Q
what could be evident in an examination of a patient with hyperthyroidism
A
• Agitated, talk fast
• Warm, sweaty
• Tremor
• Increased heart rate, may be atrial fibrillation
• Smooth goitre (graves) vs nodular thyroid disease
• Bruit heard over goitre almost diagnostic of graves
• Eyes
o Lid retraction and lid lag in any cause of overactive thyroid
o Any other eye signs indicate graves disease
12
Q
what eye symptoms may a graves disease patient have
A
Redness Gritty sensation Dry or watery eyes Pain on eye movement Swelling around the eyes Proptosis – bulging eyes Double vision Loss of colour vision
13
Q
how do you diagnose hyperthyroidism
A
- TRAbs – (TSH receptor antibodies) – significantly positive indicates graves
- TPO (thyroid peroxidase) – antibodies less specific
- If TRAbs are negative, do scintigraphy (often technetium rather than radio-iodine uptake)
14
Q
what are some anti-thyroid drugs, what do they do and some side effects
A
- Carbimazole and propylthiouracil (PTU)
- Decrease production of thyroid hormone
- Not for thyroiditis as gland isn’t actually overactive
- Rare side effect of agranulocytosis
- Propranolol good for tremor and high HR – not in asthama
15
Q
describe radioactive iodine risks
A
- Risk of long term hypothyroidism
- Avoid pregnancy for 6 months
- Restrict contact with children under 12 and pregnant women
- Don’t share bed with partner for 4 days
16
Q
what is the risk of thyroid surgery
A
• Risk of long term hypothyroidism or damage to recurrent laryngeal nerve and parathyroid glands – hypocalcaemia
17
Q
what is graves disease treated with first
A
Graves often treated with tablets first - carbimazole, block and replace, beta blockers
Radio-iodine for reccurent graves or nodular disease
18
Q
how does the risk of I131 different for different thyroid disease
A
Risk of hypothyroidism after I131 is lower for nodular disease than graves
Risk of thyroid eye disease flaring up after I131
19
Q
why do eyes pop out in thyroid eye disease
A
• B cell antibodies that trigger release of hormone from the thyroid also attach to TSH receptor in connective tissue behind the orbit
o Adipocytes which stimulates adipogenesis which pushes eyes forward
o Fibroblasts which stimulates production of glycosaminoglycans which retain fluid and their bulk pushes eyes forward
20
Q
what might turn up in a history for thyroid eye disease
A
- Change in appearance of eyes or periorbital tissues
- Corneal symptoms (grittiness, photophobia, watering)
- Extra-Ocular Muscle (EOM) restriction (eg diplopia/double vision)
- Symptoms of EOM inflammation (pain at extreme gaze)
- Orbital ache unrelated to gaze
- Symptoms of optic neuropathy* (colour vision, blurred vision)
- “Popping” of eye; inability to close lids (globe subluxation*)
21
Q
what is the examination for eye disease
A
• Redness
o (either eyes themselves or eyelids)
• Eyelids:
o thickening or oedema,
o lid retraction
- Chemosis
- Proptosis (eyes pushed forward)
- Test eye movements (“H”)
- Lagophthalmos (inability to close eyelids without forcing)
• Optic nerve
o Visual Acuity (Snellen chart)
o Fundoscopy or slit lamp to visualise head of optic nerve
22
Q
whats important to remember with eye disease
A
- Need to differentiate between active and inactive
- Only active disease responds to steroids
- Severe but inactive disease is treated with corrective surgery
- There are scoring systems to help us
- Eg Clinical Activity Score (looks at pain, redness, swelling and change in function)
- Different classifications for severity, none of which are perfect
23
Q
what is the management of Graves eye disease
A
• Unless mild, should manage in joint thyroid eye clinic
• Achieve euthyroidism
– Both hyper and hypothyroidism are bad
– Can have active eye disease without thyroid being overactive
– Thyroid eye disease can even present many months before thyroid disease develops
– Smoking cessation (smokers have 9x increased risk of developing severe disease and respond less well to treatment)
• Topical lubricants
• Selenium 200mcg daily (antioxidant)
• Steroids (oral or iv if active eye disease)
• Other immunosuppression (eg cyclosporine)
• If these measures do not work
– Consider orbital radiotherapy
– Consider immunosuppressant treatment (eg cyclosporine) as it is TRAbs that drive the eye disease
– Surgical decompression if evidence of optic neuropathy and raised intraocular pressure
• Once active eye disease settles may need:
– Elective decompression to resolve residual proptosis
– Squint surgery if EOM restriction
– Eyelid surgery if residual swelling or retraction
(In that order)
24
Q
describe primary hypothyroidism
A
• Prevalence age and gender dependent • 0.3-2% women and <0.15% men • Symptoms o Tired o Weight gain, puffy eyes and skin o Feeling cold o Slow heart rate 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
25
what are some causes of hypothyroidism
• Hashimoto’s thyroiditis
o Antibodies attack thyroid and make it underactive
o Permanent
o Tendency can run in families
* Iatrogenic (post surgery or radioactive iodine)
* Spontaneous atrophic
These first three account for 90% of cases
• Temporary thyroiditis
o Eg Viral thyroiditis, Postpartum thyroiditis
• Other [Congenital (screening programme), Iodine deficiency (not UK), Drug-induced (e.g lithium)]
26
what happens in iodine deficiency
aka Derbyshire neck
very rare in UK
• Cannot manufacture enough thyroid hormone without iodine
• TSH rises in response to fall in T4
• High TSH stimulates hypertrophy (growth) of the thyroid gland
27
what are the fluctuations of HPT axis hormones
* T4 remains fairly constant throughout the day but drops in the early hours of the morning and rises between about 7 and 10am
* TSH dips down in the course of the afternoon and rises in the late evening so it is highest overnight and falls again in the early hours of the morning
* T3 also follows this pattern of TSH
We give synthetic T4 for hypothyroidism as it is easiest to replace for this reason (levothyroxine)
28
describe treatment of hypothyroidism
Up to 3% of 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 levothyroxine approximately 7 days
Once daily dosing results in stable fT4 and fT3 levels
Commonly around 100 mcg thyroxine (1.6 mcg/kg/day)
Aim to normalise TSH
Usually managed by GPs
No further Inx needed for hypothyroidism if TSH (scans do not change Mx)
Large body of evidence on safety and effectiveness of thyroxine
Taking levothyroxine on an empty stomach before breakfast is preferable than in the evening or with food
```
• Monitoring of therapy
– Annual TFTs once stable
– If dose change, wait at least 6/52 before rpt TFTs
• Some OTC meds impair T4 absorption
– PPIs eg omeprazole/lansoprazole
– H2 antagonists eg ranitidine
– Iron, calcium, aluminium
– Don’t take T4 <4h after these
• Increased T4 requirement if start oestrogen (OCP, HRT) or anticonvulsants
```
29
describe T3 and T4 combination
* Levothyroxine is not the perfect thyroid hormone replacement but current alternatives do not have strong evidence of greater effectiveness (eg combination T3/T4, dessicated thyroid extract)
* T3 (liothyronine) peaks at 2 – 4 hours 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 therapy
30
describe DTE: Dessicated Thyroid Extract
* DTE, “Natural thyroid”, Armour thyroid
* Contains T3 and T4
* Human thyroid T4:T3 is 14:1
* One ‘grain’ (60mg) contains 38μg T4 and 9μg T3 (4:1 ratio)
* Pork thyroid extract is clearly not natural for humans
* Pig thyroid extract contains other substances beyond T3 and T4
* A short-term study (16 weeks) compared DTE with levothyroxine
* 48.6% preferred DTE, 18.6% preferred levothyroxine and 32.9% expressed no preference
* DTE group was 3lb lighter but HDL (“good”) cholesterol was worse. No other clinically significant differences between groups
* No long-term studies so safety has not been established
* Potential placebo effect.
31
which thyroid medication is best?
* Hypothyroid patients with less active deiodinase 2 had slightly better response to combination T3 and T4 than T4 alone
* In the future, genetic markers may help guide therapy
* Levothyroxine alone is adequate for most hypothyroid patients
* Research needed to identify patients who may benefit from T3
* Beware potential placebo effect of less evidence-based treatments
* TSH suppression should be avoided wherever possible
* Safety of T3 and DTE is not well established
32
what is important about TSH
TSH is the most sensitive indicator of thyroid hormone status – earliest indicator of something going wrong
If T4 and T3 are normal but TSH is elevated it is called subclinical hypothyroidism
33
describe clinical hypothyroidism
* Prevalence 4-10%
* Main cause is autoimmune chronic thyroiditis
• Some (weak) evidence of adverse effects
– Lipids
– BP
– Other CV risks eg CRP, arterial stiffness
– No hard end-points evidence (ie no evidence that it increases heart attacks or strokes)
– No convincing evidence that it causes symptoms
• However, TFTs often checked because of symptoms that MAY relate to thyroid so patients often convinced that the two are linked
34
what can low levels of TSH, T3 and T4 be due to?
an indicator of non-thyroidal illness
35
what are the levels of hormones in primary hypothyroidism?
high TSH, low T4, low or normal T3
36
what are the levels of hormones in subclinical hypothyroidism
high TSH, normal T4, normal T3
37
what are the levels of hormones in secondary hypothyroidism
low or normal TSH, low T4, low or normal T3
38
describe non-thyroidal illness
– TSH: can be suppressed acutely then rise on recovery.
– tT3 falls (impaired T4 hepatic uptake and T4 to T3 conversion).
– Illnesses affects thyroid hormone binding proteins, which reduces total hormone and raises free hormone fraction.
– fT4 usually stays within reference 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 metabolic rate; conserve essential body protein stores).
– Many hormones and substances raised in acute illness supress TSH
39
what are the mechanism of TSH supression in NTI
– TRH release suppressed by cytokines and glucocorticoids
– Some drugs e.g dopamine may also inhibit TSH release.
– Carbohydrate residues on TSH dictate its biological activity and plasma half-life. In NTI, the carbohydrate moieties on TSH are modified, leading to diminished bioactivity.
– In illness, thyroid hormone uptake by the liver is impaired, resulting in low circulating tT3.
– Conversion of T3 to T4 by deiodinases is impaired in NTI so T3 levels fall.
– Deiodinases may be affected by oxidative stress, altered redox state of the cell and cytokine release
40
whats important to remember about NTI
* Illness can mimic TFTs seen in patients with thyroid disease.
* For example, acute illness may produce elevated Free T4 and suppressed TSH (similar to primary hyperthyroidism) but low T3 points to NTI
* In patients recovering from illness a raised TSH may be misinterpreted as hypothyroidism.
* No evidence that giving thyroxine helps in this situation
* TFTs should not be performed in patients with chronic or acute illness unless thyroid disease is considered to be the cause of their presenting complaint.
41
describe hypothyroidism in pregnancy
* Fetus needs T4 from 4-5/40
* Uses maternal T4 exclusively up to 10/40 and partially thereafter.
* T4 requirements can increase by 50% by 20/40 then plateau
* Increase T4 dose when pregnancy confirmed
* TFTs each trimester
* Untreated overt hypothyroidism associated with
* Infertility, miscarriage
* Pre-eclampsia, Premature delivery
* Increased foetal mortality, impaired neurological development
* Mild (Subclinical hypothyroidism) associated with
* Neurodevelopmental delays, placental abruption
* Check TFTs pre-pregnancy in autoimmune disease (eg DM), current or PHx/FHx thyroid disease, features of thyroid disease eg Goitre
42
what imaging modalities are used for the thyroid
```
• PLAIN RADIOGRAPHY (X-RAYS)
• ULTRASOUND
• COMPUTED TOMOGRPAHY (CT)
• MAGNETIC RESONANCE IMAGING (MRI)
• RADIONUCLIDE IMAGING
(RNI including PET/CT)
```
43
what is best imaging modality for the thyroid and what are the pros and cons
```
ultrasound
• Pros
o High frequency linear array probe
o Excellent soft tissue resolution
o Real time assessment
o Does not use ionising radiation
```
• Cons
o Operator dependent
o Not all patients are suitable ultrasound subjects
44
how can ultrasound characterise a nodule
```
o B mode assessment (black/white image)
structure, border, size, placement
o Colour flow Doppler
vascularity
o Elastography
stiffness
```
45
what are the gradings for thyroid nodules
* U1: normal
* U2: benign
* U3: indeterminate
* U4: suspicious
* U5: malignant
46
what are the characteristics of a nodule graded U1
normal
• smooth outline
• homogenous echogenic parenchyma
47
what are the characteristics of a nodule graded U2
```
benign
• halo, hyper- / iso-echoic
• cystic change +/- ring down sign (colloid which shows as white flecks in the white cyst) (black with no internal echos)
• micro- cystic / spongiform
• peripheral egg shell calcification
• peripheral vascularity.
```
48
what are the characteristics of a nodule graded U3
indeterminate
• homogenous, isoechoic/hyperechoic, solid, halo (follicular lesion)
• hypo-echoic, equivocal echogenic foci, cystic change
• mixed/central vascularity
49
what are the characteristics of a nodule graded U4
suspicious
• solid, hypo-echoic (cf thyroid)
• solid, very hypo-echoic (cf strap muscle)
• disrupted peripheral calcification, hypo-echoic
• lobulated outline
50
what are the characteristics of a nodule graded U5
malignant
• solid, hypo-echoic, lobulated/irregular outline, micro-calcification (papillary ca)
• solid, hypo-echoic, lobulated/irregular outline, globular calcification (medullary ca)
• intra-nodular vascularity
• shape (taller >wide)
• characteristic associated
51
describe FNA: fine needle aspiration
Indicated for lesions:
U3: indeterminate
U4: suspicious
U5: malignant
Blind vs image guided (US)
Non suction capillary technique
Three passes
Slides (two fixed, two air dried) + needle rinse in Cytolyt solution
Risks
Bleeding
Infection
Iatrogenic injury to surrounding structures
Inadequate sampling requiring repeat FNA/biopsy
52
compare FNA with core biopsy
Core biopsy established technique
Data mixed
Probably more useful than repeat FNA in previous non-diagnostic samples
Generally well tolerated
Probably no excess of complications compared to FNA
53
what are the options for radionuclide imaging (RNI)
(99mTc) Technicium Pertechnetate
(I-123) Iodine (imaging)
(I-131) Iodine (treatment)
Typically used to assess the functionality of a thyroid nodule (context of hyperthyroidism).
Assessment of the cause for hyperthyroidism when the aetiology is not clear.
54
describe RNI for a solitary thyroid nodule
99mTc Pertechnetate scan
Increased 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
what does graves disease look like on 99M-TC pertechnetate scans
homogenously increased uptake so whiter on scans
56
what does a solitary toxic nodule look like on 99M-TC pertechnetate scans
solitary area of increased uptake with a reduction in the rest of the gland
57
what does a cold nodule look like on 99M-TC pertechnetate scans
focal area of reduced uptake
58
describe iodine 131 for imaging
harmless to thyroid
determine activity of thyroid
ectopic thyroid tissue
59
describe iodine 131 for treatment
destroys thyroid cells
hyperthyroidism
thyroid cancer
Whole body planar imaging 10 days post treatment for thyroid cancer.
Uptake of radioiodine in lymph nodes and distant metastases is associated with a favourable prognosis.
Demonstration of disease is essential to ensure optimum follow up and management.
60
describe the role of cross sectional imaging
Role of CT/MRI
Staging of patients with suspected metastatic thyroid cancer
Assessment of patients with metastatic thyroid cancer following treatment or on surveillance
Assessment of patients with suspected recurrence where ultrasound is negative
Also good for assessing goitre and tracheal deviation caused by this
61
what other tests are available for thyroid malignancy
Positron emission tomography
FDG – Fludeoxyglucose
Glucose metabolism scan
Used in staging of a number of cancers (looking for involved lymph nodes + distant disease).
Role in thyroid cancer: useful in patient with known thyroid cancer with suspected recurrence not demonstrated on US/CT/MR.
62
what are the histology features of multinodular goitre
```
dilated follicles
cholesterol clefts (white clefts in the pink tissue)
variably sized follicles
cystically dilated follicles
foamy macrophages
fibrous septae
```
63
what are the histology features of graves disease
pipillary architechture
cells have a more collumnar appearance
little bubbles above the surface of cells called "scalloping"
graves disease diagnosis is not made on histology
64
what are the histology features of hashimotos thyroiditis
lymphoid aggregates with germinal centre formation
| small purple lymphocytes amongst paler oncocytic epithelial cells
65
what are the histology features of follicular adenoma
completely encapsulated lesion
made up of thyroid follicles
clonal population but benign
if capsular or vascular invasion then becomes follicular carcinoma
66
what are the histology features of papillary carcinoma
```
papillary structures
can be encapsulated
intranuclear inclusions
nuclear clearing
nuclear grooves
psammoma bodies
```
also has a follicular variant
67
what rarer types of cancer are there
medullary cancer
| anaplastic cancer
68
describe thyroid cytology
Screening test only
Most important features is colloid
Cell to colloid ratio is a good indicator of malignancy
Colloid is a reassuring feature
For adequacy must have 6 groups of at least 10 cells
69
what is the classification used in the uk
bethesda classification
(dont need to know details but..)
Unsatisfactory, (not enough cells) (Thy1)
Cyst fluid (not enough epithelium to 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)
70
what are the key cytological features in FNA thyroid
Lots of colloid / Variably sized follicles – multi-nodular goitre
Even sized follicles – follicular neoplasm
Papillary structures, nuclear grooves & inclusions – papillary carcinoma
Dispersed small cells – medullary carcinoma
Very pleomorphic cells – anaplastic carcinoma
71
what additional diagnostic aids are there for throid cancer
Cell block
Immunohistochemistry
Molecular pathology
BRAF, TERT, RAS, gene fusions
72
what is normal plasma osmolarity
πp normal ~ 282-296mosmol/kg
calculated approximation: πp is equal to around 2x[Na+] + [urea] + [glucose]
```
hypertonic = hyperosmolar πp > 296 (>299 often used)
hypotonic = hyposmolar πp < 282
```
73
what is DDAVP
DDAVP = a synthetic ADH with little pressor activity = 1-deamino-8-D-arginine vasopressin
74
how much water do we lose every day
Water lost continuously: kidney > 400ml/day
skin, respiration, gut 500ml/day
For body water balance Need to take in water regularly, thirst, normal intake, adult, temperate climate 0.9 to 2-2.5 litres
75
what is normal urine output
Normal urine volume 0.6 to 1.5-2 litres
76
describe ADH release
Supraoptic nuclei and paraventricular nuclei release ADH and it makes its way to the posterior pituitary where it is released into the circulation. This ADH release is triggered by the osmoreceptor in the third ventricle.
Nearby there is also a thirst centre
There are also ascending tracts which feed into the system – when this stimulation is at low level it doesn’t make much difference but when its high, they can interfere and change ADH release.
These come from baroreceptors which tell the body about circulatory status (stimulation goes up in haemorrhage) and pain/nausea from the NTS (nucleus tractus solitarii) can also affect ADH levels
77
what happens when plasma osmolarity increases
this is sensed as thirst and water seeking behaviour occurs, then when water is drunk the plasma osmolarity decreases and the feedback loop closes off – this requires the person to be alert and have access to water
78
how does loss of thirst happen
(adipsia) can occur with hypothalamic damage Difficult to treat – often use fixed fluid intake
Thankfully major thirst disorders = unusual
79
what do ADH feedback loops require
ADH release stimulating the kidney to retain more water requires the kidney to be responsive to ADH and effective feedback stopping ADH release
80
what is the lack of ADH called
cranial diabetes insipidus,
81
what is ADH resistance called
nephrogenic diabetes insipidus
82
what is primary polydipsia
issue in the hypothalamus where the stimulation is high
83
what is adipsia
issue in the hypothalamus where the stimulation is low
84
what is the precursor to vasopressin
pre-pro-vasopressin. It has a component known as neurophysin and a glycopeptide which are cleaved off in processing
85
what are the receptors for ADH
• V1a – lower affinity for AVP than V2
o Maintain blood volume and circulation
• V1b – lower affinity for AVP than V2
o ? – role in ACTH release + stress responses
• V2 – high affinity for AVP
o Appropriate retention of water
o Maintain osmolarity
86
what is important to remember about AVP
also has quite low affinity for a receptor for oxytocin
87
what are vaptans
a class of drug which block the V2 receptor – one which is combined V2 and V1 blocker
88
how does vasopressin work
on the second half of the distal convoluted tubule and the collecting duct by upregulating aquaporin 2
Other minor actions include being involved in the establishment of the medullary concentration gradient by pumping out Na and urea
AVP signals through cAMP to move vesicles containing aquaporin 2 into the membrane. Also increases manufacturing of subunits of aquaporin 2
89
what can vasopressin be released by
Some increase of ADH release due to low BP, pain, nausea or drugs
90
what are the upper and lower limits of osmolarity determined by
Upper osmolarity limit is determined by thirst to lower sodium conc and lower limit is policed by ADH by diluting urine to prevent sodium dropping
91
what can happen in polyuria when a patient cant drink enough
if a patient cannot drink to keep up with losses then they could have high Na and low BP and collapse or be confused
In adipsia, can present as unexplained confusion as Na drops. Can cause fits
92
what are some causes of polyuria
* Diabetes insipidus (cranial or nephrogenic)
* Habitual/psycogenic polydipsia
* Osmotic diuresis e.g. glucose (diabetes mellitus) mannitol, hypercalcaemia
* Renal impairment (unusual)
93
what is the investigation of polyuria
• accurate fluid balance to determine if polyuria >2ml/kg/hr
o Urine volume >2ml/kg/hr
o ?Urine volume high and persistent thirst or [Na]p > 145mmol/l
• check glucose, Ca2+, urea, creatinine - identify cases of (iii) & (iv)
• check urine never normally concentrated
• water deprivation test - show if unable to concentrate urine
• if DI, give DDAVP (1µg im) - if no effect - nephrogenic DI
94
what is a water deprivation test
```
• 12 hours prior to test
o Can have fluids overnight + breakfast
• During test (up to 8hrs)
o no fluids, dry snacks
o Patient supervised
o Hourly weight, BP, urine sample (vol +πu)
o 2 hourly blood (Na+, πp, ± AVP)
• Stop test if πu>600, of if danger (weight loss>3%, hypotensive+dizzy etc) when water depleted (πp>296 or[Na+]>145) give DDAVP
```
95
what are some causes of cranial DI
* Neurosurgery – pituitary or hypothalamus
* Head injury
* “Idiopathic”
* Other Hypothalamic/pituitary disease
* Major Haemorrhage
• Genetic
o Isolated AVP mutation
o DIDMOAD - Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness
• Pregnancy (“gestational DI”)
o Vasopressinases – degrade AVP, little effect on DDAVP
o resolve 1st week post partum
96
what are some causes of nephrogenic DI
• Inherited
o majority V2R
X-linked
reports of v mild DI in females (variable X inactivation)
o others AQP2 Ch12 – A.Recessive or A.Dom
• Acquired
o Hypercalcaemia
o hypokalaemia
o resolution after urinary tract obstructive
o secondary effect of psychogenic polydipsia
o Lithium therapy effect
o Demeclocycline
97
what is the treatment for DI
```
• Address primary cause
o Cranial DI – replace AVP – use dDAVP
dDAVP = long acting, can give just x2/day more selective for V2R renal effects
peptide
• intranasal spray/drops
• tablets (desmopressin)
• injections (inpatients, diagnosis)
```
o Nephrogenic DI
other measures to ↓polyuria
Some treatment of partial benefit consider
• thiazide/amilorids diuretics - paradoxically lower urine volumes
• indomethacin - limit renal prostaglandins
• lower salt diet - limit urinary osmotic load
• ± lower protein diet
98
describe SIADH
* Hyponatraemia
* There are many causes of hyponatraemia and careful fluid balance and patient assessment may be needed
* Is the patient dehydrated? If so Na+ and water loss, identify if urine is site of excess salt loss
* Is the patient oedematous? If so treat the cause of the oedema
* If neither (1) nor (2) check for thyroid or adrenal/ACTH deficiency SIADH - show inappropriately concentrated urine show u>500 or >2x p when plasma [Na+]< 280
99
what are some causes of SIADH
o Intracranial Lesions/disease - of diverse kinds
o Intrathoracic disease, especially infections
o Neoplasms, especially lung/mediastinal
o Drugs
antipsychotics e.g. phenothiazines
sedatives e.g. morphine, barbiturates
5 C’s chlorpropamide, clofibrate chlorpromazine carbamazepine chlorthiazide (and other thiazides)
Miscellaneous
• Nicotine
• pain (especially post-op)
100
what is the treatment for SIADH
o confirm diagnosis
o fluid restrict (1000ml/d, then < 800ml/d if needed)
o occasionally require demeclocycline (cause partial nephrogenic DI)
o normalise [Na+] slowly (<10mmol/l/day)
o New options
aquaretics – V2 receptor antagonists e.g. Tolvaptan –
combined V2-V1a antagonists e.g. conivaptan (roles in SIADH, heart failure etc)
101
what is the difference between addisons and just being glucocorticoid deficient
• both can cause hyponatraemia
• addisons
o will also be aldosterone deficient (±adrenaline) salt wasting→dehydration, ↓BP ↑K+ , acidosis
o will be dehydrated
o three causes of low Na
Aldosterone↓, ADH not↓=imbalance
non-osmotic ADH stimuli –↓vol, nausea, pain
↓GC effects – impair water loss
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• glucocorticoid deficiency
o ↓GC effects - impair water loss
o central effect - ↑ADH/πp gradient
o renal effect - ↓renal water excretion
o ↓glucose a non-osmoticADH stimulus
o Not dehydrated
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