Endocrinology
Handbook
ICSM Endocrine Unit at
Hammersmith Hospital
Du Cane Road
London W12 ONN
UK
January 2003
Available as a 212 kB .pdf file
on:
THYROTROPHIN
RELEASING HORMONE (TRH) TEST
GONADOTROPHIN
RELEASING HORMONE GnRH/LHRH TEST
COMBINED
PITUITARY FUNCTION TESTS (CPT)
VISUAL
FIELD TESTING (GOLDMANN PERIMETRY)
LOW DOSE DEXAMETHASONE SUPPRESSION TEST + CRH
HIGH DOSE DEXAMETHASONE SUPPRESSION TEST
BILATERAL SIMULTANEOUS INFERIOR PETROSAL SINUS
SAMPLING (IPSS) WITH CRF
TREATMENT OF
PATIENTS WITH CONFIRMED CUSHING’S SYNDROME.
PERIPHERAL
VENOUS SAMPLING FOR SOURCES OF ECTOPIC ACTH
OVERNIGHT DEXAMETHASONE SUPPRESSION TEST
CRH
TESTING (without dexamethasone).
CORTISOL DAY CURVE (Cushing’s syndrome only)
OPERATIVE
MANAGEMENT OF PITUITARY TUMOURS (CXH)
HYDROCORTISONE
DAY CURVE (HCDC)
ORAL
GLUCOSE TOLERANCE TEST FOR ACROMEGALY
FOLLOW
UP FOLLOWING PITUITARY SURGERY AND RADIOTHERAPY
POST OPERATIVE MANAGEMENT OF ADRENAL TUMOURS
PLASMA AND URINE ALDOSTERONE, AND PLASMA RENIN
ACTIVITY
Selenium
cholesterol scanning for Conn’s tumours
ADRENAL VENOUS SAMPLING FOR ALDOSTERONE
MANAGEMENT
OF SUSPECTED PHAEOCHROMOCYTOMA
Protocol for the
post-radioiodine treatment telephone clinic
Instructions for
those running the phone clinic.
PENTAGASTRIN TEST
FOR MEDULLARY THYROID CARCINOMA
CALCIUM INFUSION
TEST FOR MEDULLARY CA THYROID
Screening for
mutations of MEN1, MEN2a, MEN 2b or FMTC.
FINE NEEDLE
ASPIRATION OF A THYROID NODULE (FNA)
POST OPERATIVE
INVESTIGATION OF THYROID CARCINOMA
MANAGEMENT
OF STABLE INSULINOMAS PRIOR TO SURGERY
SELECTIVE
ARTERIAL INJECTION FOR LOCALIZATION OF GASTRINOMAS AND INSULINOMAS
CARCINOID AND NEUROENDOCRINE TUMOURS
FOODS TO AVOID
DURING 24 HOUR URINE COLLECTION FOR 5-HIAA
HEPATIC
EMBOLIZATION OF METASTASES
CHEMOTHERAPY FOR NEUROENDOCRINE TUMOURS
HYPOGONADOTROPHIC HYPOGONADISM
REVERSE
CIRCADIAN PREDNISOLONE.
OTHER MISCELLANEOUS CONDITIONS
Hydrocortisone Day
Curve (HCDC)
Diagnosis
and appropriate treatment in clinical endocrinology rely heavily on the
accurate use and interpretation of diagnostic tests. This handbook was devised
as a means of guiding new junior staff (and refreshing the memories of their
seniors!) when confronted by clinical problems and their investigation. This
bible is meant to be brief and didactic with the inevitable costs as well as
benefits of such an approach. It is envisaged that it will be reprinted at 6
monthly intervals incorporating corrections and additions, any suggestions and
comments from readers are welcome.
Grateful
acknowledgements are due to: Professor Stephen Bloom, Dr Simon Wallis,
Professor Graham Joplin, Professor Kaye Ibbertson, Professor James Jackson, Dr
Jacky Burrin, and all our colleagues for their help and encouragement.
|
Andrew Hattersley |
Maria Barnard |
John Wilding |
Stephen Gilbey |
Peter Hammond |
|
Michela Rossi |
Duncan Bassett |
Arshia Panahloo |
Rachel Batterham |
Maha Barakat |
|
John Franks |
Bernard Khoo |
Jeannie Todd |
Sarah Stanley |
Elaine Murphy |
|
Carel LeRoux |
Waljit Dhillo |
Karim Meeran |
|
|
ICSM Endocrine Unit at
Hammersmith Hospital
Du Cane Road
London
W12 ONN
Assessment of ACTH and
cortisol reserve.
Assessment of growth
hormone reserve in children with definite growth retardation and a subnormal
growth hormone stimulation test (see exercise test).
Differentiation of
Cushing's syndrome from depression.
GH response in adults.
Ischaemic heart disease,
Epilepsy,
Untreated hypothyroidism
(impairs the GH and cortisol response).
The patient should fast
overnight (water permitted) and be recumbent during the test.
ECG must be normal and
the patient's weight known.
In peri-pubertal
children (bone age > 10 years) priming is needed
M: 100 mg testosterone i.m. 3 days before
testing
F: 100 mcg ethinyloestradiol p.o. each for
three days before the test.
Calculate
Actrapid Insulin dose:
Normal pituitary
function 0.15 U/kg
Hypopituitary 0.10 U/kg
Acromegaly, diabetes,
Cushing's 0.2-0.3
U/kg
If
the patient is hypoadrenal for any reason (or on hydrocortisone), the case must
be discussed with senior medical staff before administration of insulin.
50mls
50% dextrose available for immediate administration (but only use if
persistent hypoglycaemia).
Indwelling
cannula gauge 19.
Glucometer.
6
fluoride oxalate tubes (grey top Vacutainers)
6
serum (clotted) tubes (red top Vacutainers)
Sweating,
palpitations, loss of consciousness and rarely convulsions.
1.
Site indwelling cannula.
2.
At 0 minutes, take baseline bloods and then inject insulin i.v.
3.
Take samples for GH, cortisol and glucose at 30, 60, 90, and 120 mins,
flushing the cannula with saline between samples.
4.
At 30 minutes check whole blood glucose with Glucometer and repeat the
insulin dose if not hypoglycaemic (this will mean prolonging sampling by 30
min).
5.
Adequate hypoglycaemia (£2.2mmol/l) should be
symptomatic. Record symptoms in the notes. Once this has been achieved,
patients need not remain hypoglycaemic.
6.
There must be at least 2 specimens following adequate hypoglycaemia.
This does not mean that the patients need spend that long hypoglycaemic.
7.
At all times a doctor or nurse must be in attendance. A doctor should be
present to administer the insulin but can leave once glucose levels start to
rise following hypoglycaemia. The lowest glucose level following IV insulin is
usually at 20-30 minutes, with spontaneous resolution.
8.
Reverse hypoglycaemia with simple oral treatment (biscuit or milk). If symptoms very severe or patient
unrousable (rare) consider giving i.v. 50% dextrose (10-15 ml), or 1 mg i.m.
glucagon (1 amp), and continue sampling.
9.
Obtain specimen for glucose before reversal of symptoms.
10.
Check whole blood glucose on glucometer every time a specimen is taken.
11.
If a patient has a hypoadrenal crisis they should receive i.v. 0.9%
saline and hydrocortisone 100 mg.
12.
Once test completed, give supervised meal.
13.
Patient should not drive for 2 hours after the test.
·
The test cannot be interpreted unless hypoglycaemia (£2.2mmol/l) is achieved.
·
Adequate cortisol response is defined as a rise of greater than 170
nmol/l to above 500 nmol/l. Patients with slightly impaired cortisol responses
may only need steroid cover for major illnesses or stresses. They will need
instruction about this and should carry a steroid card.
·
In Cushing's syndrome there will be a rise of less than 170 nmol/l above
the fluctuations of basal levels of cortisol.
·
Adequate GH response is a rise to >20 mU/l. In adults this may be a
sensitive indicator of hypopituitarism but its principal role is in children
who may require GH treatment. In children a rise to greater than 39 mU/l
(15ng/ml) is considered normal (2.59 mU/l = 1ng/ml). Appropriate priming is
very important if they are peri-pubertal. Before treatment with growth hormone
children should have two stimulatory tests.
If
there is adequate hypoglycaemia and the patient is not hypothyroid then
cortisol response is a good test of ACTH/adrenal reserve. 5-15% of normals will
show a suboptimal response as defined by these two criteria.
20%
of patients with Cushing's syndrome will show a rise greater than 170nmol/l but
a rise of less than this is rare in depression or alcoholic pseudo-Cushing's.
GH responses
are reduced in 20% of normal children and some small children whose peak GH is
10-20mU/l may benefit from GH replacement.
Plumpton
et al., Br. J. Surg. 56, 21 (1969). Greenwood et al., J. Clin. Invest. 45, 429
(1965).
Assessment of growth
hormone and ACTH/cortisol reserve especially when insulin-induced hypoglycaemia
is contra indicated.
Phaeochromocytoma or
insulinoma (may provoke an attack)
Starvation >48 hours
or glycogen storage diseases (inability to mobilise glycogen may result in
hypoglycaemia)
Severe hypocortisolaemia
(0900h level <55 nmol/l)
Thyroxine deficiency may
reduce GH and cortisol response.
Nausea
is common (30%) and patients may rarely vomit.
Fasting
from midnight. The patient does not need to be continually observed as
hypoglycaemia is not provoked.
Calculate glucagon dose:
adults: 1 mg, (1.5mg if > 90kg)
children: 15 mcg/kg
6
fluoride bottles (grey top Vacutainers) and 6 plain tubes (red top Vacutainers)
1.
Insert an indwelling cannula.
2.
Take basal samples for glucose, cortisol and GH.
3.
Give the glucagon i.m. (the deltoid may be a suitable site).
4.
Take further samples at 90, 120, 150 and 180 minutes.
Adequate
cortisol response is defined as a rise of greater than 170 nmol/l to above
550nmol/l. Adequate GH response is a rise to a value greater than 20 mU/l.
This
test is probably slightly less reliable test of somatotroph and corticotroph
function than the ITT. It is an excellent alternative in patients who can not
tolerate hypoglycaemia because of epilepsy, ischaemic heart disease or
hypopituitarism. The false negative rate for cortisol response is 30% (but only
8% of normals will not show either a peak value of 550nmol or a rise of
170nmol/l). Only 4-8 % of normals will not show an adequate rise in GH: this is
usually in patients over 50.
Rao
R.H. et al., Metabolism 36, 658-663 (1987).
ATH
12/89.
To
assess TSH reserve. Differential diagnosis of pituitary and hypothalamic causes
of TSH deficiency.
As
patients should be off thyroxine for 3 weeks prior to test so this test, it is
rarely used in people on thyroxine.
Overnight
fast not necessary.
200
mcg TRH
i.v.
cannulae 19 or 21 gauge.
3
x clotted tubes (red top Vacutainers): 6 ml per sample.
Patients
should be warned that they may have transient side effects after the injection
such as a metallic taste in the mouth, flushing and mild nausea.
1.
Site indwelling cannula.
2.
Take baseline bloods for TSH and thyroxine.
3.
Inject TRH slowly i.v. over 2 minutes.
4.
Flush butterfly with heparin/saline.
5.
Take samples for TSH at t = 30 mins and 60 mins.
The
normal result is a TSH rise to >5 mU/l with the 30 min value exceeding the
60 min value.
If
the 60 min sample exceeds the 30 min value then this usually indicates primary
hypothalamic disease.
In
hyperthyroidism, the TSH remains suppressed and in hypothyroidism there is an
exaggerated response. With the current sensitive TSH assays basal levels are
now adequate and dynamic testing is not usually needed to diagnose
hyperthyroidism.
An
inadequate rise of TSH is not an indication for thyroxine replacement unless
the serum thyroxine, free T4 or free T3 is reduced. The TSH is not only
undetectable in pituitary disease and thyrotoxicosis but also in some cases of
euthyroid ophthalmic Grave’s disease and multinodular goitre.
A
late rise in TSH may be seen rarely in thyroid and pituitary disease as well as
hypothalamic disease.
Hall
et al., Lancet i: 759-63 (1972).
ATH
11/89
1)
To further investigate possible gonadotrophin deficiency.
2)
To confirm precocious puberty.
Overnight
fast not necessary if done alone.
In
women with a normal menstrual cycle the test should be performed in the
follicular phase (day 3-7 of the cycle).
Larger
dose or priming with LHRH if suspected of hypogonadism may be necessary.
(N.B.
Do not prime with sex steroids if indication 2 above)
100
mcg LHRH (GnRH – Gonadorelin).
3
clotted tubes (red top Vacutainers – 7 ml)
1.
Site indwelling cannula.
2.
Take baseline bloods: LH, FSH and testosterone (M) or oestradiol (F).
3.
Inject GnRH intravenously.
4.
Flush cannula with saline.
5.
Take samples for LH and FSH at t = 30 and 60 mins.
· The normal peaks can occur at either 30 or 60 minutes. LH should exceed 10 U/l and FSH should exceed 2 U/l. An inadequate response may be an early indication of hypopituitarism.
· Gonadotrophin deficiency is diagnosed on the basal levels rather than the dynamic response. In males this is based on low testosterone in the absence of raised basal gonadotrophins and in females low oestradiol without elevated basal gonadotrophins and no response to clomiphene.
· Pre-pubertal children should have no response of LH or FSH to LHRH. If sex steroids are present (i.e. the patient is undergoing precocious puberty), the pituitary will be “primed” and will therefore respond to LHRH. Priming with steroids MUST NOT occur before this test.
This test has a low sensitivity and specificity for hypogonadotrophic hypogonadism. The response may be normal or even exaggerated (especially in patients with hypothalamic disease). Basal levels are better discriminants. Serial investigations in patients with pituitary disease especially irradiation may give early indication of the development of hypopituitarism.
Mortimer
et al., BMJ, 3: 267-271.
ATH
11/89, AP 1/98.
Assessment
of all components of anterior pituitary function used particularly in pituitary
tumours or following tumour treatment.
Ischaemic
heart disease.
Epilepsy.
Untreated
hypothyroidism (impairs the GH and cortisol response).
Sweating,
palpitations, loss of consciousness and rarely convulsions with hypoglycaemia.
Patients
should be warned that with the TRH injection they may experience transient
symptoms of: a metallic taste in the mouth, flushing and nausea.
The
patient should fast overnight and be recumbent during test.
ECG
must be normal and the patient's weight known.
In
peri-pubertal children (bone age >10 years) priming is needed
M: 100 mg testosterone i.m. 3 days before testing
F: 100 mcg ethinyloestradiol p.o. each for three
days before the test.
Calculate
Actrapid Insulin dose:
Normal pituitary
function 0.15 U/kg
Hypopituitary 0.10 U/kg
Acromegaly, diabetes,
Cushing's 0.2-0.3 U/kg
TRH
(Roche) 200 micrograms as slow i.v. injection.
LH/FSH
releasing hormone (GnRH) – 100 mcg as i.v. bolus.
50mls
50% dextrose available for immediate administration.
Cannula,
18-20g.
Glucometer.
6
fluoride tubes (grey top Vacutainers).
7
clotted tubes (red top Vacutainers) for samples.
500
ml bag 0.9% saline to flush cannula.
3
way tap to assist the taking of samples.
1.
Site indwelling cannula.
2.
Take baseline blood samples for testosterone/oestradiol, prolactin,
thyroxine, LH, FSH, TSH, GH, cortisol (14 ml clotted) and glucose (2 ml
fluoride).
3.
Then at T = 0 inject insulin and GnRH i.v. as boluses followed by the
TRH over 2 minutes.
4.
Take samples for LH, FSH, TSH, prolactin, GH, cortisol (7 ml clotted) and glucose (2 ml fluoride)
at 30, 60 minutes and GH, cortisol, glucose at 90 and 120 minutes.
5.
Flush the cannula with saline between samples.
6.
At 30 minutes check blood glucose with Glucometer and repeat the insulin
dose if not hypoglycaemic. Adequate hypoglycaemia (≤2.2mmol/l) should be
symptomatic. Record symptoms in the notes.
7.
Hypoglycaemia should be reversed by giving i.v. 50% dextrose, or i.m.
glucagon (1 amp) and continue sampling. Take further samples for GH, cortisol
and glucose at 90 and 120 minutes. There must be at least 2 specimens following
adequate hypoglycaemia.
8.
At all times a doctor or nurse must be in attendance.
9.
If the patient has a hypoadrenal crisis with hypotension then they
should be given i.v. 0.9% saline and hydrocortisone.
10.
Once test completed, give supervised meal.
11.
Patient should not drive for 2 hours after the test.
This
test is no longer used, but the details are kept for historical reasons and for
those sitting the part 1 MRCP (!) In patients with prolactinomas, and in some
acromegalics with near-normal GH levels, it is useful to monitor the responses
to TRH and GnRH alone. This test is only useful after treatment if it is known
there was an abnormal test result prior to treatment. In these patients, the
test is "split" as follows:
|
Time |
Glucose |
TSH |
T4 |
PRL |
GH |
LH |
FSH |
Testo/E2 |
Cortisol |
|
0 |
|
Take |
Take |
Take |
Take* |
Take |
Take |
Take |
|
|
Give GnRH 100 mcg IV bolus and TRH 200 mcg IV over 2 mins |
|||||||||
|
30 |
|
Take |
|
Take |
Take* |
Take |
Take |
|
|
|
60 |
Take |
Take |
|
Take |
Take |
Take |
Take |
|
Take |
|
Give insulin IV bolus as calculated above. |
|||||||||
|
90 |
Take |
|
|
|
Take† |
|
|
|
Take |
|
120 |
Take |
|
|
|
Take† |
|
|
|
Take |
|
150 |
Take |
|
|
|
Take† |
|
|
|
Take |
|
180 |
Take |
|
|
|
Take† |
|
|
|
Take |
*only if an acromegalic with low GH
†not
needed if acromegalic with low GH
The
interpretation of the different components of the standard CPT is listed under
the insulin tolerance test, the TRH test and the GnRH test.
In
the "split" protocol it is possible to observe the isolated response
of GH and Prolactin to TRH. In normals the prolactin will rise by 100% of its
basal value while in patients with prolactinomas there is frequently a
subnormal response. In normals there is a reduction in GH with TRH but there is
a rise in 80% of acromegalics. It is only worth using the "split"
protocol on a patient following treatment if they were tested by this protocol
pre-treatment. The loss of the paradoxical rise to TRH in acromegaly is a good
indicator of successful treatment.
ATH
12/89
Before
and after pituitary surgery and before and during pregnancy in patients with
macroprolactinomas.
At Charing Cross this
is done by the Orthoptists. Contact Caroline Calcutt (x1497 or 1132). At
Hammersmith they are done on Monday mornings or all day on Tuesday (usually by
Kemi), but still phone her on 1132 to book . If you are doing it yourself,
follow the instructions below.
1.
There is an automated Visual field (Allergan Humphrey) testing machine
in the eye room of clinic A (room A11). It is computer controlled and fairly
user friendly.
2.
Switch machine on. It will perform a self test taking about 5 minutes.
Once this is complete the computer will ask you several patient details, such
as which eye you are testing. These can be easily fed in using the screen touch
sensitive pen.
3.
Cover one eye with the eye patch present on top of the machine. Place
the patient's chin on the rest at the centre of the hemisphere and the head
against the upper band. You will need to manually adjust the position of the
chin rest (using the rotating control) until the patient, when looking straight
ahead, can see a yellow dot.
4.
The patient must be given the hand held pushbutton and told to fix on
the yellow dot. He must press the button whenever he sees a flash of light
anywhere in the sphere. The patient may need his glasses to allow him to see
the object.
5.
When the patient is ready, simply select "AUTOMATIC DIAGNOSTIC
TEST" from the menu. The machine will automatically find the blind spot
and proceed to check the entire visual field by flashing lights at random. It
will also check that the patient continues to fixate on the yellow dot by
occasionally checking his blind spot.
6.
When complete, a printout of the field can be obtained. Repeat the
procedure for the other eye.
Formal
perimetry is highly accurate and reproducible. Field loss is always
significant; it can occur as the result of the pituitary tumour or from the
treatment of the tumour. If an increasing field loss is noted it is vital that
the patient has a CT scan on that admission.
Overnight
dexamethasone suppression testing and isolated CRH testing are not used in our
department, but the methods are at the end of the section for completeness.
Screening
test for Cushing's syndrome, especially if the result of the overnight
suppression test contradicts other investigations. In women with a high
testosterone this test may be used to differentiate PCO and partial hydroxylase
deficiencies (CAH) from autonomous androgen secreting tumours.
Patients
on enzyme inducing drugs e.g. anti-convulsants may rapidly metabolise
dexamethasone.
Oestrogens
(e.g. pregnancy, HRT or COC) may induce cortisol binding protein and
artificially increase total cortisol levels.
Care in diabetes mellitus and patients who are psychologically unstable.
This
is usually an inpatient test with no particular patient preparation.
Occasionally the test can be done as an outpatient if you believe the patient
is likely to have their tablets on time. They need a 9am cortisol at the start
and end of the test. The final (9th) dose is given with the patient
nil by mouth, and the CRH given 2 hours later.
Stop
all oral oestrogen therapy 6 weeks prior to test. Patients on sex steroid
implants might generate results that are difficult to interpret. Measuring SHBG
and CBG might be helpful in this circumstance. A sample for gut hormones (in a
green topped (heparinised) bottle with trasylol (200 mcl)) should be sent with
each of the cortisol samples.
1.
The patient takes 0.5 mg dexamethasone p.o. at strict 6 hour intervals (i.e. 0900h, 1500h, 2100h and 0300h) for 48
hours.
2.
The cortisol (red top), ACTH
(purple top) and gut hormones (green top with trasylol) are measured at 0900h
(before the first dose) on the first day (“2+0”) of the test and 24 (“2+24”)
and 48 hours later (6 hours after the last dose) (“2+48”). Samples are taken in
red top Vacutainers (serum) for cortisol and purple top tubes on ice for ACTH.
The red topped sample can be used to measure SHBG and CBG if needed.
3. A total of eight doses of dexamethasone should be written up (9am, then 3pm, 9pm, 3am, 9am, 3pm, 9pm, 3am). The ninth dose should be written up AFTER the blood sample at 9am has been collected on day 2. If the test starts on a Sunday morning (day 0), the CRH test will be done on Tuesday (day 2). It is important that no food is taken that morning, as variability in absorption of dexamethasone for those 2 hours may result.
4. Blood taken on day 1 at 9am (“2+24”)(immediately before that dose) and day 2 at 9am (“2+48”) and a FURTHER dose (dose 9) of dexamthasone is given at 9am. A CRH test should follow exactly 2 hours after that dose of dexamethasone (11am on Tuesday if the test starts on Sunday (common at Charing Cross) and 11am on Wednesday if the test starts on Monday (more common at Hammersmith)) (“2+50”). This timing after the last dose of dexamethasone seems to be critical, as it will affect the 11.15 sample (“2+50+CRH”). The patient must FAST from midnight before the CRH test, as food will affect dexamethasone absorption in the 2 hours before the CRH test. Thus blood is taken at 11am (called “2+50” as it is 50 hours into the test) and again 15 minutes after CRH (at 11.15 (“2+50+CRH”))
5.
A high dose dex suppression test can then be commenced (at 11.30
am) to finish at 9am on Friday, or on Thursday morning to finish on Saturday
morning.
If
the 0900h cortisol (“2+48”) value is less than 50nmol/l the patient has shown
suppression. Failure to suppress is seen in the autonomous secretion of
cortisol found in Cushing's syndrome. In virilisation from PCO or partial
hydroxylation deficiencies there will be suppression of testosterone. This is
not seen in ovarian or adrenal tumours.
The
11.15am (“2+50+CRH”) plasma cortisol following the CRH test that follows the
LDDST (2h after the last dose of dexamethasone and then 15 minutes after the
CRH) should be <38 nM. A cortisol > 38nM at this timepoint is indicative
of Cushing’s syndrome.
There
is as yet no data as to the value of the “2+50” sample (just before CRH
administration).
Suppression
in patients with Cushing's syndrome is rare (2-5%). Some reported cases
metabolise dexamethasone slowly and so achieve higher circulating levels than
expected. This test is more specific than the overnight suppression test with a
lower false positive rate. Failure of suppression in patients is rarely seen in
patients with systemic illness, endogenous depression, or on enzyme inducing
drugs e.g. phenytoin or rifampicin.
In
virilisation some cases of PCO do not show suppression so imaging and venous
sampling is required to exclude ovarian or adrenal tumours.
For
the CRH test after dexamethasone, a cortisol >38nM at t=15 minutes is 100
sensitive and 100 % specific. (Yanovski).
Crappo
A., Metabolism 28, 955-979 (1979). Yanovski (1993) : JAMA: 269(17): 2232-2238
Newell
Price: Endocrine reviews: 19(5): 647-672.
ATH
11/89, KM 07/02, KM 01/03
Patients
with definite Cushing's syndrome of unknown aetiology.
Patients
on enzyme inducing drugs e.g. anti-convulsants may rapidly metabolise
dexamethasone.
Oestrogens
(e.g. pregnancy, HRT or COC) may induce cortisol binding protein and
artefactually increase total cortisol levels. Take care in patients with severe
depression or hypomania.
Stop
all oral oestrogen therapy 6 weeks prior to test. Again implants can cause
problems.
This
is an inpatient test and should only be performed after at least 2 baseline
values for 24 hour urinary free cortisol and 0900h cortisol and ACTH levels
(see below).
1.
This test often follows the LDDST. The final sample from the LDDST
(2+48) can often be used as the basal sample for this test. Basal 0900h
cortisol (red top Vacutainer) and ACTH (purple tops Vacutainers on ice) are
measured (“8+0”).
2.
During the test the patient takes 2 mg dexamethasone p.o. at strict 6 hour intervals (i.e. 0900h,
1500h, 2100h and 0300h) for 48 hours.
3.
The cortisol and ACTH are measured at 0900h on the first day of the test
and 48 hours later (“8+48”). In some
patients the dexamethasone may be continued for 72 hours in which case an
additional 0900h serum cortisol and ACTH are taken (“8+72”).
If
the 0900h cortisol is less than 50% (some say 90%) of the basal value after 48
hours of dexamethasone this is classified as showing suppression. Suppression
with high dose dexamethasone is usually seen in Cushing's disease but not in
ectopic ACTH production or adrenal tumours.
The high dose dexamethasone test is useful but not totally reliable in the differential diagnosis of Cushing's syndrome as it is neither very sensitive nor specific. Suppression occurs in 75% of patients with Cushing's disease, 10-25% of patients with ectopic ACTH and 0-6% of patients with adrenal tumours. Patients with ectopic ACTH who show suppression tend to have occult and relatively benign tumours with lower levels of ACTH and cortisol. These patients are very hard to differentiate from Cushing's disease.
The
0900h cortisol after 48 hours is considered to be the best parameter to use to
discriminate between Cushing's disease and ectopic ACTH. The criterion of 50%
suppression at 48 hours should not be applied too rigidly as many cases of
Cushing's disease will suppress by 40 or 45% or suppress after 72 hours. In
difficult cases it is advisable to repeat the test as no patients with an
adrenal tumour have been shown to have reproducible suppression and cases of
Cushing's syndrome may show cyclical variation.
Crappo
A., Metabolism 28, 955-979 (1979).
Patients with Cushing's
syndrome and high ACTH levels in whom there is not a clinically definite
pituitary source. The aim of this test is to differentiate pituitary from a
non-pituitary source of ACTH and to lateralise a corticotroph adenoma.
(Discuss
with interventional radiology x34943)
Allergy to contrast dye.
Ischaemic Heart Disease.
Orthopnoea.
Bleeding tendencies (severe).
Metyrapone
and ketoconazole need to be stopped 1 week before IPSS.
Order
synthetic human (or ovine) CRF in
advance from Pharmacy (allow 5 days). DDAVP (10 micrograms IV) is a poor but
possible alternative if CRH is not available. Document (in the notes) what type
of CRH is being used.
Warn
endocrinology lab (34681) 48 hours in advance.
Consent
patient (risks of bleeding from cannula sites, CVA, dye allergy, pulmonary
embolus).
Fast
for at least 4 hours.
2
people to attend to assist sample processing.
18
red Vacutainers.
18
EDTA Vacutainers, labelled before the study.
Syringes
for sampling and flushing cannulae.
Ice.
Arrangements
to transfer for immediate centrifugation.
CRF
can cause flushing and hypotension but this is rare with 100 mcg.
No
complications of IPS sampling have been reported in over 50 patients reported
in the literature, but we have had one patient who had a pulmonary embolus
following the procedure and one who became asystolic during the procedure, but
recovered when the procedure was abandoned.
1.
One catheter is placed in each inferior petrosal sinus (IPS) and their
position confirmed on screening. A third catheter is placed peripherally (P) in
the arm.
2.
Two baseline samples are taken at approximately -5 and 0 minutes. Ask
the radiologist for 10 ml from each site: one purple for ACTH and one red
Vacutainer at each site. At T = 0 the
CRF is injected intravenously as a bolus over 1 minute peripherally. For adults
the dose is 100 mcg or 60mcg per square meter body surface in children.
3.
Simultaneous samples from the 3 sampling sites are taken at T = 2, 5,
and 10 minutes. At the same time as one of the sets of basal samples an
arterial sample may be taken from the femoral artery if a pulmonary source of
ACTH is possible, and peripheral samples may be taken at T = 60 and 90 minutes
(see below). Only samples taken for ACTH should be stored in ice and spun within
15 minutes.
4.
ACTH is measured in all samples. Cortisol is measured in the basal
samples from all sites and in all the peripheral samples. Prolactin is measured
in both IPS series.
·
A basal IPS:P ratio ³ 2.0 indicates a pituitary source with 95% sensitivity
and 100% specificity. A CRH stimulated
ratio ³
3.0 increases the sensitivity to 100%, the 2 and 5 minute samples usually being
sufficient. Pituitary ACTHomas are usually paramedian or lateral and there is
suppression of the normal corticotrophs on the contralateral side (Crooke cell
changes).
·
If in addition the basal or stimulated ACTH level for one IPS sample is
1.5 times as high as the simultaneous contralateral side, this localises the
pituitary tumour to the ipsilateral side with a sensitivity of 99% and a
specificity of 82%. It has also been
reported that prolactin and GH are often raised on the side of the tumour and
that this is augmented by CRF.
·
In IPS sampling the principal difficulty arises from the positioning of
the sampling catheter. Jugular venous samples do not consistently show
lateralisation. The measurement of prolactin can be used as a marker of
proximity to the pituitary.
·
Using the peripheral samples it is possible to look at the response to
CRF of venous levels of Cortisol. The interpretation of this response is
difficult but in general patients with Cushing's disease tend to have an
exaggerated response (>850 nmol/l) and ectopic ACTH sources have a reduced
response. The interpretation of the CRF test at present is uncertain as the
reported series use different end points, varying doses of CRF and small
numbers of patients. Until there is more local experience (see above) of this
test it should not be used to differentiate sources of ACTH.
·
It appears that in ectopic ACTH production a cortisol response greater
than normal has not been described. It is not a sensitive test as approximately
25% of Cushing's disease do not respond to CRF with cortisol responses greater
than normals.
IPS
sampling: Clinical Endocrinology 25, 687-96 (1986).
CRF
test: A. Grossman et al., Clinical Endocrinology 29, 167-178 (1988).
Petrosal
sinus sampling: NEJM 325, 897-905 (1991).
ATH;
PJH 8/92.; KM 07/02
If
the IPSS confirms pituitary Cushing’s, the patient should be booked for
pituitary surgery at Charing Cross in about 6 weeks. As soon as the diagnosis
is confirmed, medical treatment with ketoconazole (200mg bd) should be
commenced. Monitor cortisol and LFTs weekly. If cortisol > 250 nM, double
ketoconazole to 400 mg bd. A week later, add metyrapone 250 mg tds, if cortisol
>250 nM. Aim for cortisol of 150-300 nM in the weeks before surgery.
This is no longer performed at Hammersmith in view of its low sensitivity.
Initial
screening test for Cushing's syndrome in a patient with a low clinical
suspicion of Cushing’s. If you have a high index of suspicion of Cushing’s,
omit this test and go directly to the LDDST + CRH.
Patients
on enzyme inducing drugs e.g. anti-convulsants may rapidly metabolise
dexamethasone.
Oestrogens
(e.g. pregnancy, HRT or COC) may induce cortisol binding protein and
artefactually increase total cortisol levels.
Urine
collection for 24 hr urinary free cortisol must not occur during this test.
Outpatient
test with no particular patient preparation.
1. The patient takes 1 mg
dexamethasone p.o. at 2300h and the 0900h cortisol is measured the next morning
(7 ml clotted blood, in red top Vacutainer).
2. If the patient is
collecting a 24hr urine sample for urinary free cortisol this should be
completed before taking the dexamethasone.
If the 0900h cortisol
value is less than 35 nmol/l the patient has shown suppression. Failure to
suppress is seen in the autonomous secretion of cortisol found in Cushing's
syndrome. With this cut off, there will be a high false positive rate.
Suppression
in patients with Cushing's syndrome is rare with this test (2%). The reported
cases metabolise dexamethasone slowly and so achieve higher circulating levels
than expected. If there is strong clinical or biochemical evidence for
Cushing's syndrome this test should be repeated or a formal low dose
dexamethasone test performed.
Normal
subjects rarely (2%) fail to suppress with overnight dexamethasone unless they
are depressed (10-50%), obese (10%) or systemically unwell (10-20%). The formal
low dose dexamethasone test is more specific.
This
is a good screening test especially if combined with urinary free cortisol.
Samples for ACTH should be collected in purple topped EDTA tubes and stored on ice in transit and taken rapidly to the lab to be centrifuged. This test will thus need regular transport to the lab. Samples for cortisol are red topped and can clot.
Fast
from midnight.
Label eight (8) tubes for ACTH (purple top) and eight (8) tubes for cortisol (red top).
Admit Monday 8.30 am. Cannulate and take basal Cortisol and ACTH at 8.30am.
Patient to remain recumbent until 9am (and fasted).
(Two further baseline samples at –15 mins (8.45 am) and 0 mins (9am) for ACTH and Cortisol).
Administer 100 micrograms human CRF at t=0.
Then sample at 15, 30, 45, 60, 90 and 120 mins (final sample 11am: for ACTH and cortisol at all timepoints.).
A
rise in cortisol from basal
to peak of >20% suggests a pituitary source.
A
rise in ACTH from basal to
peak of > 50% suggests a pituitary source.
Ref:
Kaye and Crappo (1990). Ann Intern Med. 112: 434-444
A
rise by 35% in ACTH at +15
and +30 minutes (mean) in comparison to the basal (-1 and –5 minutes) values
suggests a pituitary source. Ref: Nieman etal (1993). JCEM 77: 1308-1312.
Please
note that ovine (oCRF) was used in most studies. Human (hCRH) appears less
potent, so smaller rises may be acceptable, suggesting Cushing’s disease.
Assessment
of control of Cushing’s disease on therapy or after discontinuation of
treatment.
None
None
Stop
all oestrogen therapy 6 weeks prior to test.
Non-fasting:
breakfast and normal dose of tablets are taken at the usual time.
18-20g
cannula.
6
red top Vacutainers.
Syringes.
0900h }
1200h } Take blood
1500h } for cortisol
1800h } measurement
(2400h) }
Normal
response is a mean serum cortisol between 150 and 300 nmol/l, and should be
maintained while patients are awaiting an adrenalectomy.
Higher
levels indicate a need for increased therapy.
Random
concentrations of cortisol can also be used on a day to day basis to determine
effectiveness of cortisol suppression on medical treatment (with Ketoconazole
(up to 400 mg bd), Metyrapone (up to 750 mg tds) or etomidate (3mg per hour by
IV infusion).
Trainer
et al., Clin. Endo. 39, 441-443 (1993).
KM
07/01
Patient should have had:
·
Full endocrine assessment.
·
Neurosurgical assessment.
·
Neuro-ophthalmological assessment including Humphrey fields in previous
6/12
·
Baseline investigations:
CT/MRI brain
Free T4, TSH, prolactin, oestradiol (females),
testosterone (males), FSH, LH, profile.
ECG and CXR if age >60 years.
IGF-1, GH, with oral GTT if clinically indicated
·
If prolactinoma confirmed, treat with dopamine agonist drug (eg.
Cabergoline), then repeat CT/MRI scan (1-3 months after prolactin normalised or
at minimum plateau). Surgery indicated if tumour non-responsive.
·
Check TFTs. If patient is hypothyroid need short synacthen test to
exclude associated steroid dependency. Replace with T3 20 mcg tds for 4 days
pre-op if surgery urgent, or thyroxine if surgery not imminent.
·
Cushing’s disease: start patient on drugs, titrating to random cortisol
150–300 nmol/l:
Ketoconazole: 200 mg bd
– needs weekly LFTs initially, can cause hepatitis
Metyrapone: 250 mg bd to
750 mg tds – side effects are lethargy, peripheral oedema, hirsutism
Etomidate: up to 3mg per
hour by IV infusion.
·
Confirm neurosurgical operating date (day 0) with consultant
neurosurgeon, Mr. Nigel Mendoza (Day 0, Usually a Thursday). If surgery is on
Wednesday, call this day –1, so that the protocol below is not affected.
(Thursday remains day “0”). If surgery is on Friday, treat this as “day 1” and
proceed directly to dexamethasone over the weekend.
·
Admit 1-2 days pre-op. (Surgical decision).
·
For trans-cranial surgery: dexamethasone 4 mg qds, start 1 day pre-op.
·
For trans-sphenoidal surgery:
Hydrocortisone 100 mg i.m. qds starting with
pre-medication. (An IV infusion of 4.2 mg per hour (100 mg over 24 hours) is an
alternative).
·
Write up:
Day 1: Three doses of hydrocortisone 50 mg i.m.
on day 1 (9am, 3pm, 9pm (usually Friday). (Or continue the IV infusion of 4.2
mg per hour = 100 mg over 24 hours).
Day 2 + 3 (Sat + Sun) dexamethasone 0.5 mg 6
hourly starting at 9am. This serves both as replacement steroid and a low dose
dexamethsone suppression test. (8 doses, last at 3am on Monday morning).
Day 4 (Mon) NIL BY MOUTH until 11.15 am (food
may affect dexamethasone absorption). An urgent morning (9am) cortisol sample
needs to be sent to lab and then a ninth
dose of 0.5 mg dexamethasone administered with the patient NIL BY MOUTH.
Blood should be taken at 11am for cortisol and
CRH 100 mcg administered intravenously
immediately. A further sample for cortisol should be taken exactly 15 minutes later.
After the test, the patients should not have any
further steroid that day (0.5 mg dexamethsone will cover them for the
day).
Day 5: The following morning, (usually Tuesday)
an urgent 9am cortisol should be sent.
After the test, start HC 10mg + 5mg + 5mg and
discharge on this dose.
·
Interpretation of cortisol result from day 5 (not Cushing’s disease –
usually non functioning):
If cortisol >450 nmol/l, then can be sent
home without hydrocortisone.
If 400 – 450 nmol/l, then use clinical grounds
and pre-op assessment.
If < 400 nmol/l, then continue
hydrocortisone.
·
Interpretation of cortisol result (if Cushing’s disease):
If cortisol is detectable, use the results of
the dexamethsone suppression test to determine whether further pituitary
surgery is urgently indicated.
If surgery is on a Monday or Tuesday,
dexamethasone should be started on Wednesday, so that the CRH test will be on
Friday.
·
Fluid balance charts should be kept. A spot urine osmolality is checked
every 4 hours.
·
If urine output >1l per 4 hrs consider desmopressin (adult dose 0.5-1.0 mcg s.c. q6h). Prior to
administration check paired plasma and urine osmolality.
· DI is confirmed by the presence of a high plasma osmolality (>295) in the presence of an inappropriately low urine osmolality (U:P ratio <2:1). (urine SG < 1.005).
· If the plasma osmolality is low the patient may be over-drinking due to a dry mouth. A low urine osmolality is appropriate.
·
Discharge drugs HC 10mg + 5mg + 5mg
·
Advise patient regarding increasing dose with illness etc.
·
Arrange electrolytes (esp Na) to be measured the following Monday (10
days postop) as there is a risk of hyponatraemia, especially if the patient had
Cushing’s disease.
·
Steroid card and contact details of MEDIC ALERT (see index).
·
Pituitary stimulation tests and ITT (±OGTT for acromegaly) to be
performed 3-4 weeks post-op following cessation of steroids from the night
before test. Hydrocortisone to be resumed after test until results known.
·
Endocrine follow up should be 6 weeks post-op.
·
Joint pituitary endocrine clinic 3 months post-op (list F27), when Nigel
Mendoza should organise an MRI. (Discuss with Laura – ward clerk).
·
Radiotherapy referral if appropriate.
·
If patients have had Cushing’s disease, and do not need hydrocortisone
replacement, dexamethasone suppression tests should be performed regularly (at
least 2-3 yearly). (risk of recuerrence).
·
Urinary free cortisols can be used to monitor patients on
hydrocortisone.
·
Patients on hydrocortisone should be offered an ITT 2 years after
surgery as there is a chance of recovery of corticotrophs (or recurrence).
AP
01/98, KM 07/01
To
establish the correct dose and distribution of hydrocortisone replacement
therapy throughout the day.
None
None
Stop
all oestrogen therapy 6 weeks prior to test.
No
need to fast.
Take
normal morning hydrocortisone and patient should note down actual time taken.
18-20g
cannula.
Red
top Vacutainers.
Syringes.
Take
blood at the following times:
·
Blood sample on arrival, noting time of sample and time and dose of
hydrocortisone.
·
Pre lunchtime (2nd) dose
·
1 hour post lunchtime (2nd) dose
·
pre evening (3rd) dose
·
post evening (3rd) dose or at 6pm.
Aim
for adequate cortisol levels throughout the day (peak <900 nmol/l, trough
>100 nmol/l).
Once
adequate levels are achieved, this rarely needs to be repeated, unless there is
a significan change in other medication (eg. Starting HRT).
KM
7/00.
2.59 mU=1 mcg. This is controversial, and some authorities use 2mU as 1mcg and others use 3mU as 1mcg. This is because mU were originally defined using a bioassy, and hence their value varies between laboratories. In this document, please use 2.59 mU as 1 mcg. This is important both because administration of GH is now changing to mcg of GH. Thus a “safe” level of GH in acromegaly is <5mU/l or <1.9 ng/ml.
Used
in a child with definite growth retardation preferably as assessed by reduced
growth velocity and a random serum growth hormone (GH) of <15 mU/l. It is a
physiological screening test used before formal testing of GH secretion (e.g.
insulin tolerance test, arginine stimulation test).
1.
If child has difficult veins, cannulate before the test (butterfly is
sufficient).
2.
Take blood sample for GH (into a red top Vacutainer) at T = 0.
3.
Take child to the outpatients staircase and note the time
4.
Child should then run up and down the first flight of stairs, as hard
and as fast as possible, for at least 10 mins and until the child becomes
breathless and moderately fatigued
5.
Take blood sample for GH 30 mins after the onset of exercise
A normal GH response of > 15 mU/l (5.7 ng/ml) absolves the endocrinologist of any further investigation of GH deficiency. It excludes the need for proceeding to the more laborious and hazardous formal tests. A subnormal response (GH < 15 mU/l) means the child should be considered for a formal test though a repeat exercise test may be valuable (see below).
A
child with GH deficiency will not respond to this test. The percentage of
children who are not GH deficient and who show a normal response varies
depending on the test used and the peak GH value taken as "normal".
Values vary from 68–91%. Repeating the test can also improve the detection rate
of normals from 80–92%.
Milner
R.D.G. & Burns E.C., Arch. Dis. Child. 57, 944-947 (1982).
MLB
12/89
Used in a child with
definite growth retardation and a subnormal physiological growth hormone (GH)
stimulation test (i.e. GH < 15 mU/l or 5.7 ng/ml).
Child
should be fasting overnight
If
the child's bone age is >10 years, the test should be done after sex steroid
hormone priming:
M: 100 mg testosterone i.m. 3 days before testing
F: 100 mcg ethinyloestradiol p.o. each for three
days before the test.
1)
Cannulate child.
2) Take blood into a plain
tube (red top Vacutainer) for baseline GH measurement (0 mins).
3)
Infuse 0.5 g/kg L-arginine monohydrochloride (maximum dose 40 g) as a
10% solution in normal saline over 30 minutes.
4)
Take blood for further GH estimation 30, 60, 90, 120 and 150 mins after
start of arginine infusion.
· A normal GH response of >15 mU/l (>5.7 ng/ml) excludes GH deficiency.
·
A GH response of 7–15 mU/l may indicate partial GH deficiency and should
be investigated by a second formal stimulation test.
· A GH response of <7 mU/l (<2.7 ng/ml) should also generally be confirmed by a second test. However, if there are other compatible clinical and auxiliary findings, the child may be directly considered for GH replacement therapy.
·
A child with pubertal growth delay may show a subnormal GH response if
the test is performed without sex hormone priming. However, there should be a
normal response after priming.
A
child with GH deficiency will not respond to this test.
The
percentage of children who are not GH deficient and who show a normal response
varies from 45 – 93%. Generally, 20% of normal children fail to respond to a
formal test and this is the reason for doing 2 tests before proceeding to GH
therapy. For example, 71% of normals will respond to both insulin tolerance and
arginine stimulation tests. However, the others will respond to at least one
test: 13% to insulin, 16% to arginine.
Raiti
et al., Lancet 1183 (1967).
MLB
12/89
Finger
size is an objective measure of soft tissue over growth. It can be used to
follow the response to treatment in Acromegaly.
Measurement
should be between 0900h and 1000h before any intravenous cannula is inserted.
Ring size is assessed on the proximal surface of the proximal interphalangeal
joint of the fourth finger. The size is that of the tightest fit. A recording
is made from each hand and clearly recorded in the notes. If the finger is too
large for size Z then the fifth finger is used.
ATH
11/89
Skin-fold
thickness is used in acromegaly and Cushing's syndrome as an index of skin
involvement and therefore disease activity.
1.
The skin is measured using the
skin-fold calliper on the dorsum of the hand over the mid point of the third
metacarpal bone.
2.
Set the scale on the callipers to zero.
3.
Place the patient's hand flat on the table with the wrist in a neutral
or extended position.
4.
A small skin-fold in the long axis of the hand is lifted up and placed
between the blades of the calliper so the fold reaches exactly to the top of
the jaw-blades.
·
Skin thickness has only a limited role in the diagnosis and the
monitoring of acromegaly and Cushing's.
·
Mean skin thickness (see reference) in men is 2.8 mm when 20 yrs old
decreasing to 1.75 mm when 70 yrs. Women's skin is approximately 0.2 mm thinner
than similarly aged men.
·
77% of acromegalics have abnormally thick skin (mean + 2 s.d. in 40 year
old males >3.4mm).
·
All patients with Cushing's had skin-fold thickness below the mean value
but only 42% were abnormally thin (mean - 2 s.d. in 40 year old females <1.5
mm).
A.D.
Wright and G.F. Joplin, Acta Endocrinologia 60, 705-711 (1969).
ATH
12/89
Used
where a clinical diagnosis of acromegaly is suspected.
Fasting
from midnight.
18-20g
cannula.
6
Red top Vacutainers.
6
grey top fluoride oxalate tubes
1.
Take blood sample for GH and IGF-1 (into a red top Vacutainer) and
glucose (into grey top tube) at T = 0.
2.
Administer 75 grams oral glucose in 300 ml water over about 10 minutes.
3.
Take blood for GH and glucose at t=30, 60, 90 and 120 minutes.
4.
A synacthen test can be carried out at the end of this test, with
samples for cortisol taken at t=120, 150 and 180. Synacthen 250 mcg is
administered at t=120.
In normal individuals, GH levels fall following oral glucose, and at least one of the samples during the test should have undetectable GH levels. Failure of suppression or a paradoxical rise in GH suggests acromegaly. Following treatment, “cure” is not an appropriate word. A “safe level” of GH has been thought to be less than 10mU/l (3.8 ng/ml). More recently, this has been revised to 5mU/l (1.9ng/ml).
False
positives sometimes occur in patients with anorexia nervosa, or other causes of
chronic starvation, although the IGF-1 level is usually normal.
Following
irradiation, endocrine testing should be performed on a yearly basis until
failure of a cortisol response is apparent for at least 10 years, and then 5
yearly. Once failure is clear, the patient should be put on hydrocortisone
replacement and further insulin tolerance tests are not required.
If
patient had pituitary Cushing’s, they need LDDST ever 2-3 years to confirm
cure.
If
acromegaly, and random GH >5, then need annual OGTT + GH to confirm cure.
Patients are often on somatostatin analogues following radiotherapy, and once
it appears that the radiotherapy has worked, reassessment (OGTT + GH) off these
analogues is essential.
Acromegalics
should also have a colonoscopy every 3-5 years.
KM/01
Principle:
dehydrate till ADH secretion concentrates urine
Used
in differential diagnosis of polyuria, separating Cranial Diabetes Insipidus
(CDI), Nephrogenic Diabetes Insipidus (NDI) and Primary Polydipsia/Compulsive
Water Drinking (PP).
If
in the basal state plasma osmolality > 295 mosmol/kg, plasma Na > 145
mmol/l and urine is hypotonic (< 300 mosmol/kg), PP is excluded and
investigation goes straight to DDAVP administration.
Exclude other causes of polyuria: diuretics,
chronic renal failure, hypercalcaemia, hypokalaemia.
Anterior pituitary hormone deficiency: renders
results meaningless as, in particular, steroid and thyroxine deficiencies
impair excretion of a free water load.
Up
to 8.30 hrs:
1.
No tobacco/alcohol for 24 hrs before the test
2.
Stop interfering medication (e.g. DDAVP (last dose 24 hours before the
start of the test), diuretics) but not hormone replacement
3.
Light breakfast (do not fast or limit fluids overnight).
Equipment:
a) Blood is taken into yellow top Vacutainers,
urine into Sterilin universal containers
b) urine measuring jug.
c) scales.
d) DDAVP: if given intranasally, must acquaint
yourself with the spray as it is not easy to use.
Supervision
by nursing staff or SHO is essential.
If true CDI or NDI, risk
of excessive dehydration.
Stage 1 (exclusion of
PP):
8.30 – 16.30 hrs
1. No fluid allowed but dry food permitted (e.g. toast)
2.
Weigh patient at time 0 and hourly intervals: stop test if >3% weight
loss (positive test)
3. Urine passed and discarded at time 0; urine then passed hourly and hourly volume estimated
4.
Urine specimen taken for osmolality from the total hourly sample passed
over 8.30 – 9.30hrs (U1), 11.30 – 12.30 (U2), 14.30 – 15.30 (U3), 15.30 – 16.30
(U4)
5.
Blood taken for osmolality at 9.00hrs (P1), 12.00 (P2), 15.00 (P3),
16.00 (P4)
6. Note down urine volumes in chart as shown below (U1-U4).
Stage 2
(differential diagnosis CDI from NDI): 16.30 – 20.30 hrs
7. Patient may now eat and
drink freely
8. At 16.30 hrs, administer
DDAVP: 20 mcg intra-nasally or 2 mcg i.m.
9. Continue to measure
hourly urine volumes and take samples for osmolality from each hourly sample.
There is no point measuring plasma samples (or taking any blood), as the
patient are now eating and drinking freely, and we are only interested in the
effects of the administered DDAVP on urine volume and osmolality.
10. Note down urine volumes
in chart as shown below (U5-U8).
|
TIME |
URINE / VOLUME |
PLASMA |
|
0830 |
Discard urine |
|
|
0900 |
Þ |
Collect P1 |
|
0930 |
Collect U1 ml |
|
|
1130 |
Discard urine |
|
|
1200 |
Þ |
Collect P2 |
|
1230 |
Collect U2 ml |
|
|
1430 |
Discard urine |
|
|
1500 |
Þ |
Collect P3 |
|
1530 |
Collect U3 ml |
|
|
1600 |
Þ |
Collect P4 |
|
1630 |
Collect U4 ml |
|
|
Now give DDAVP i.m. or intranasally |
||
|
1730 |
Collect U5 ml |
|
|
1830 |
Collect U6 ml |
|
|
1930 |
Collect U7 ml |
|
|
2030 |
Collect U8 ml |
|
1) Normal
With
dehydration, plasma is concentrated but to <300 mosmol/kg. Urine also
concentrates to >600 mosmol/kg.
2) PP or partial DI
Start
with a low plasma osmolality, which concentrates to normal during stage 1.
Urine concentrates, though may be subnormal response (see below).
3) CDI
Patient
excessively concentrates plasma to >300 mosmol/kg with inappropriately
hypotonic urine (U3:P3 or U4:P4 = <1.9). After DDAVP: CDI patient, deficient
in ADH, is still able to concentrate urine to >150% of previous highest
level. In NDI, patient is unable to respond to ADH or DDAVP, and concentrates
urine to <150% of previous highest value.
|
Diagnosis |
After dehydration |
After DDAVP |
|
Normal |
>750 |
>750 |
|
PP or partial CDI/NDI |
300-750 |
<750 |
|
CDI |
<300 |
>750 |
|
NDI |
<300 |
<300 |
Urine
osmolality (mosmol/kg)
If
there is a partial response, this test does not reliably differentiate between
PP and partial CDI or NDI because the response to dehydration and DDAVP may be
very similar:
·
Polyuria of any origin (e.g. PP or CDI) washes out medullary
concentration gradient, blunting maximal urinary concentration
·
CDI may increase renal sensitivity to very low levels of AVP. If patient
has only a partial deficiency of AVP, dehydration may therefore rapidly
increase urine osmolality to maximum of which they are capable.
·
Some patients with NDI can concentrate urine if plasma AVP increases to
supra-physiological levels, e.g. with exogenous DDAVP.
IF THERE IS A PARTIAL
RESPONSE, FURTHER INVESTIGATION IS INDICATED.
When
well performed, the WDT has a sensitivity and specificity of 95% for diagnosing
and differentiating severe CDI and NDI. The incidence of false positive and
false negative results for PP or partial CDI/NDI is 30-40% (investigate
further).
Vokes
et al., Endo. Metab. Clin. N. Amer. 17(2), 281 (1988).
MLB
10/89; reformatted BK 7/00.
Used when partial
response to water deprivation test to differentially diagnose Primary Polydipsia
(PP) and partial Cranial Diabetes Insipidus (CDI) or Nephrogenic Diabetes
Insipidus (NDI).
Water
intoxication in PP
1. Admit to hospital
2. Monitor daily: fluid
input and output, body weight, U+Es and urine osmolality.
3. Patient observed for 2
days and then 10 mcg DDAVP given intranasally od for at least 2-3 days.
·
Partial CDI: prompt improvement in
thirst and polyuria
·
NDI: no effect; can be
treated for further 2–3 days with a 10 fold increased dose to see if defect
partial or complete
·
PP: decreased polyuria
with no change in polydipsia. Causes weight gain, increased urine osmolality
and progressive dilutional hyponatraemia, which may develop rapidly and
severely (hence need for hospitalisation)
Small
possibility of false diagnosis of PP as hyponatraemia may occur in 5% of CDI
who continue to drink excessively on DDAVP because of associated abnormal
thirst or prolonged habit
Vokes
et al., Endo. Metab. Clin. N. Amer. 17(2), 281 (1988).
MLB
10/89; reformatted BK 7/00.
Used
in the diagnosis of hypoadrenalism as a screening test.
It
is an increasingly used alternative to the insulin tolerance test to diagnose
secondary hypoadrenalism due to pituitary hypofunction.
May
also be used to ascertain that the adrenals are functioning normally after a
prolonged course of corticosteroids.
Diagnosis
and characterization of 21-hydroxylase deficiency and other causes of adrenal
hyperplasia.
Not
needed for hypoadrenalism if random cortisol > 550nmol/l. If a random
cortisol . 450, patients are very likely to pass the short synacthen test, and
some feel that in this circumstance, the test is not warranted.
None
If
on steroids ensure that none is taken the night prior to the test. The final dose should be at 9am, 24 hrs
prior to the test.
Admission
is required if there is a risk of Addisonian crisis (virtually never).
18-20g
cannula
Saline
flush
10ml
syringes x 4
3
red top Vacutainers for cortisol (same samples for 17-OH progesterone)
1
EDTA tube (purple top Vacutainer) for ACTH basal sample.
1
ampoule of 250 micrograms tetracosactrin (Synacthen)
1. 0900h: take 7 ml
blood for cortisol (red top Vacutainer)
and ACTH (purple top, on ice to lab immediately).
2. Give 250micrograms
tetracosactrin IM (ideally) or IV.
3. 0930h: Take 7 ml blood
for cortisol.
4. 1000h: Take 7 ml blood
for cortisol.
5. For the diagnosis of
congenital adrenal hyperplasia the samples taken for cortisol are also analysed
for 17-OH progesterone to exclude 21-hydroxylase deficiency. In some cases
17-OH pregnenolone is measured to differentiate between 21-OH and 3ß-HSD
deficiency.
Normal
response if test done at 0900h (considerable diurnal variation):
Stimulated plasma cortisol >550 nmol/l
Incremental rise of at least 170 nmol/l
·
If impaired cortisol response, and ACTH >200 ng/l then diagnosis is
primary adrenal failure.
·
If ACTH <10ng/l then diagnosis is secondary adrenal failure
·
Response of 17-OH progesterone in suspected 21-hydroxylase deficiency
(cryptic): marked rise after ACTH stimulation, which varies according to
whether the patient is homozygous or heterozygous. Reference for nomogram: New
et al., JCEM 57, 320-326 (1983).
A
normal cortisol response does not exclude adrenal failure, since impending
adrenal failure might be associated with a much greater loss of zona
glomerulosa function. The latter would
be suggested by an elevated plasma renin activity.
If
equivocal result and no urgency, repeat test after a few weeks.
An
abnormal response is consistent with primary or secondary adrenal failure, and
should be investigated further. Consider long synacthen test or pituitary
function testing.
Hypoadrenalism
Clayton
R.N., BMJ 298, 271-272 (1989).
Burke
C.W., Clin. Endo. Metab. 14, 947-976 (1985).
Adrenal hyperplasia
Savage
M.O., Clin Endo. Metab. 14, 893-907 (1985).
JW
12/89 updated KM 07/01
Confirmation of
diagnosis of hypoadrenalism.
Differentiating primary
and secondary hypoadrenalism (note that measurement of basal 0900h ACTH levels
is far more sensitive than cortisol response in the long synacthen test).
The first 3 samples
should give the same result as the short synacthen test.
None
None
Patients
who have already been taking corticosteroids should have the last dose 24 hours
before the start of the test. Admit the
patient if there is a risk of an Addisonian crisis (virtually never). Patients
with pituitary disease are usually safe if they have an intact
rennin-angiotensin (aldosterone) axis. Once the test has commenced,
dexamethasone will not interfere with the cortisol result. (Do not use
prednisolone, which will interfere with the cortisol assay). Use 0.75 mg for
5mg prednisolone equivalent.
1
mg tetracosactrin (depot preparation). This is not the same as ordinary
Synacthen!
18-20g
cannula.
6
red top Vacutainers.
1
purple top Vacutainer for ACTH.
Syringes.
Saline
flush.
0900h insert
cannula and flush
take
blood for baseline cortisol and ACTH
give
1mg depot synacthen i.m.
0930h }
1000h } Take blood
1100h } for cortisol
1300h } measurement
1700h } (i.e. additional 2, 4, 8 and 24h)
0900h }
·
Normal response: baseline cortisol
>170 nmol/l with rise to >900 nmol/l (peak)
·
Samples at 9.00, 9.30 and 10.00 can
be interpreted as for a short synacthen test.
·
Primary adrenal
insufficiency: little or no response
·
Secondary adrenal
insufficiency: some patients may show a rise in cortisol, which may be delayed (but a
subnormal response does not exclude this – measure ACTH levels).
·
Patients with a subnormal response can still have their steroids weaned
(by 1mg pred per month).
More
sensitive than short synacthen test for primary adrenal insufficiency (for
nomogram see Burke et al 1985).
Burke
C.W. et al., Clin. Endo. Metab. 14, 947-976 (1985).
KM 01/97 updated KM 07/01
Discuss
with anaesthetists in advance.
Hydrocortisone
should be started on day 0 on induction with either 100 mg qds IM or with an IV
infusion of 8.3 mg per hour (write up 200 mg over 24 hours). IV boluses are not
appropriate, as the half life of cortisol is short, and plasma cortisol levels
fall to undetectable levels in between doses in endocrine patients. These are
very different from asthmatics, where IV boluses are given in ADDITION to
normal adrenal function.
Start
infusion with the premed: hydrocortisone for 24 hrs at 8.3 mg/hr i.v.
Post operatively – if no
complications:
|
Day |
Hydrocortisone |
Fludrocortisone |
|
0 |
100 mg/24 hrs i.v. (4.2 mg/hr) or
100 mg IM qds |
|
|
1 |
100 mg/24 hrs i.v. (4.2 mg/hr) or
50 mg IM qds |
50 mcg p.o. od |
|
2-4 |
20 mg p.o. qds |
50 mcg p.o. od |
|
5-6 |
50 mcg p.o. od |
|
|
7+ |
10mg (6am) + 5 mg (noon) + 5 mg (6pm)
PO |
50 mcg p.o. od |
Non
cortisol secreting adenomas (eg Conn’s or phaeochromocytomas) can stop
hydrocortisone postoperatively, provided morning cortisol > 450nmol/l. Cushing’s syndrome caused by a unilateral
adenoma can cause suppression of both the pituitary and the contralateral adrenal,
and this can take over one year to recover. These patients require synacthen
tests before hydrocortisone can be discontinued. Obviously bilateral
adrenalectomies will require hydrocortisone and fludrocortisone for life.
Post operatively – if
complications:
If on day 1
it appears that patient may need prolonged parenteral hydrocortisone, measure
plasma cortisol and adjust dose as necessary.
·
Hydrocortisone 10mg / 5 mg / 5 mg.
·
Fludrocortisone 50 mcg od.
·
They should be given a steroid card.
·
An HCDC should be organised at their first clinic visit.
·
Further reduction in dose in patients with unilateral adrenalectomies
will depend on the result of the short synacthen tests. Careful follow-up is
required.
Contact
details for MEDIC alert should be given. Bracelet is free if on benefits (£30 otherwise). Full address in index.
AP
1/98; revised BK, MR 7/00, and KM and MB 07/01
·
Accelerated hypertension.
·
Hypertension with hypokalaemia, spontaneous or easily provoked, i.e. by
diuretics or sodium loading – consider if plasma potassium is <3.6mmol/L. As
the treatment of hyperaldosteronism is far more effective in correcting
hypokalaemia rather than the hypertension extensive investigation in
normokalaemic patients is not justified.
·
Assessment of early/impending adrenal cortical failure (Addison's) – see
short synacthen test.
None
None
Remember
liquorice ingestion and carbenoxolone may mimic hyperaldosteronism.
Discontinue
drugs:
Spironolactone,
oestrogens 6 weeks
Diuretics 4 weeks
ACE Inhibitors 2 weeks
NSAIDs 2 weeks
Calcium antagonists 1 week
Sympathomimetics 1 week
Beta-blockers 1 week
If
anti-hypertensive therapy needs to be continued then prazosin, doxazosin or
bethanidine may be used.
Patient
should be on unrestricted sodium intake before admission – in general the salt intake in this
part of the world is adequate and patients do not require salt-loading prior to
investigation.
First Line
Investigation:
Outpatient
procedure
Supply
details of all therapy on request form
Ensure
adequate salt intake – NOT loading
Correct
severe hypokalaemia first, as a low potassium directly will reduce aldosterone
secretion.
Sit patient
quietly for at least 10 minutes
1 X Lithium
heparin sample (green top vacutainer)
Send
urgently to lab (within half an hour) – NO ice needed: Ice will cause
cryoactivation (conversion of pro-renin into renin), artificially giving a high
apparent renin activity).
Analysis
Carried out
in Dept of Chemical Pathology, St Mary’s Hospital
Contact: Dr
P Kyd : Tel. 020 7886 1618 Fax. 020 7886 1904
If clinical
details and list of medications are provided then St Mary’s are very helpful in
supplying a full interpretation of results.
Aldosterone/renin ratio
>2000 almost certainly Conn’s
>1000 Possibly Conn’s, investigate further
<800 excludes Conn’s
For diagnosis of Conn’s: low renin expected
Plasma renin <0.5pmol/ml/hr (ref. 0.5-3.1)
Aldosterone >250pmol/l (ref. 100-800) ie. may be normal or high
Postural studies
It is
advisable to discuss the results of first line investigations before proceeding
with further investigations.
Syringes.
A
18-20g cannula.
Saline
flushes.
2
EDTA tubes (purple top Vacutainers).
2
Lithium heparin tubes
(green top Vacutainers).
Plain
24 hour urine collection bottle for urinary aldosterone.
|
Day 1 |
|
Place on liberal sodium intake – 100 mmol/day (e.g. sodium chloride
tablets 2g p.o. tds) Take blood for electrolytes – get results on same day. If potassium is low (<3.5 mmol/l) then give oral potassium
supplements. Discuss diet with dieticians. |
|
Day2 |
0700h |
Cannulate peripheral vein. Tell patient to remain in bed until told
otherwise. |
|
|
0800h |
Take blood with patient supine (for at least 30 mins) for: Electrolytes and cortisol. Plasma aldosterone (clotted, red topped
sample) Plasma renin activity (Lithium heparin NOT on
ice. Take to lab immediately). Plasma ACTH (purple topped bottle on ice). Start 24 hour urine collection for aldosterone. Ask patient to get up and mobilise at least from 11.30 for 30 minutes. |
|
|
1200h |
Take blood for plasma aldosterone, plasma renin activity. |
|
Primary
hyperaldosteronism |
Normal ranges |
|
Suppressed upright renin <2.8 pmol/ml/hr |
2.8–4.5 pmol/ml/hr upright 1.1–2.7 pmol/ml/hr supine |
|
Raised supine aldosterone >450 pmol/l |
100-450 pmol/l supine variable range upright |
|
Raised urinary aldosterone >50 nmol/24 hrs |
10-50 nmol/24 hrs |
·
If plasma and urine aldosterone are low then consider other causes of
hypokalaemia.
·
If aldosterone is raised but plasma renin activity is not suppressed
then the diagnosis is likely to be secondary hyperaldosteronism.
·
It is possible to differentiate the two main causes of primary
hyperaldosteronism on the basis of the response to time and posture. In
bilateral hyperplasia there is a >33% rise in aldosterone on rising (at noon)
while in an adrenal adenoma there is an anomalous fall in aldosterone.
The
tests have greater than 90% accuracy of correctly diagnosing primary
hyperaldosteronism.
The
changes with posture may help in the differentiation between adenoma and
bilateral hyperplasia but should be interpreted in the light of the results of
CT scanning. Interpret results with caution in patients with renal impairment.
Melby
J.C., Clin. Endo. Met. 69,4; 697-703 (1989).
JW
11/89; revised BK 7/00. revised EM 07/01
For
functional lateralization of Conn’s tumours. Now only available on a named
patient basis.
Caution
if diabetic.
1.
Admit. Start dexamethasone 2mg bd at Day -7, i.e. one week before the
injection. Monitor blood glucoses qds. Continue dexamethasone to Day 3.
2.
On day 0 nuclear medicine will inject 8 MBq of 75Se Scintadren and
image.
3.
Start 5mg bisacodyl for 2 days.
4.
Discharge home once dexamethasone completed.
5.
Nuclear medicine will arrange for further images on Day 7, 14 and 21.
The
images will be reported by nuclear medicine, but a Conn’s tumour should take up
label with no uptake on the contralateral side.
Differential
diagnosis of primary hyperaldosteronism, between aldosterone producing adenoma
and idiopathic hyperaldosteronism where CT has demonstrated no definite tumour
and when the results of selenium cholesterol scanning are ambiguous.
Discuss
with radiologist:
Bleeding tendency.
Accelerated Hypertension.
Allergy to contrast.
Significant ischaemic heart disease.
Bleeding.
Adrenal
infarction rarely.
Remember
liquorice ingestion and carbenoxolone may mimic hyperaldosteronism.
Discontinue
drugs:
Spironolactone,
oestrogens 6 weeks
Diuretics 4 weeks
ACE Inhibitors and
NSAIDs 2 weeks
Calcium antagonists 1 week
Sympathomimetics 1 week
Beta-blockers 1 week
If
anti-hypertensive therapy needs to be continued then prazosin, doxazosin or
bethanidine may be used.
Patient
should be on unrestricted sodium intake before admission.
Consent
(risks of bleeding from sheath sites, venous thrombosis).
Fast
overnight.
8
Plain tubes (red top Vacutainers).
Tetracosactrin
250 micrograms (Synacthen).
Arrangements
for immediate transfer of samples to laboratory. Two assistants required for
this.
Catheter
inserted via femoral vein and adrenal veins selectively cannulated under X-ray
control. Bolus of Synacthen may be given 20 minutes prior to sampling. Samples
taken simultaneously for cortisol, DHEAS, androstenedione and aldosterone.
Normal
adrenal vein aldosterone 100–400 ng/dl. In aldosterone producing adenoma the
ipsilateral value is 1000–10000 ng/dl. Ratio of >10:1 between sides is
considered diagnostic.
Confirm
that adrenal veins have been cannulated by comparing cortisol and adrenal
androgen levels on the two sides.
The
main problem with this procedure is difficulty in catheterising the right
adrenal vein, this is because it enters the inferior vena cava at an acute
angle and may be multiple. Even in the best hands cannulation is not possible
in 26% of patients.
In
patients in whom both adrenal veins are successfully cannulated (as
demonstrated by a symmetrical cortisol response to ACTH) this procedure is
90-95% successful in correctly distinguishing between idiopathic
hyperaldosteronism and aldosterone producing adenoma by demonstrating a
unilateral increase in aldosterone secretion.
Young
W.F. Jr., Klee G.G., Endo. Metab. Clin. N. Am., 17,2; 367-395 (1988).
Melby
J.C., J. Clin. Endo. Met., 69,4; 697-703 (1989).
Before
any procedures involving IV contrast:
·
Patients should be well filled prior to administration of alpha blockade
with crystalloids (e.g. 1l 0.9% saline). Complete alpha blockade is achieved at
3 days. Warn patient of side effects of alpha blockade including postural
hypotension, nasal stuffiness.
·
Alpha blockade with phenoxybenzamine (0.5 mg/kg i.v. over 2-4 hours in
500 ml normal saline).
·
Within 24 hours, beta blockade should be commenced with either
metoprolol 50 mg tds or propranolol 80 mg tds. Side effects of beta blockade
include: cold peripheries, bradycardia, postural hypotension.
·
In the event of a crisis, use i.v. phentolamine (0.5 – 1mg) boluses,
which can be repeated until BP controlled.
This works rapidly. If patients are not well filled, this can
precipitate severe hypotension and a watershed cerebral infarction. Rehydration with crystalloid must therefore
be started at the same time.
To
try and exclude the diagnosis of phaeochromocytoma in patients with
hypertension and borderline changes in plasma catecholamines or 24 hour urinary
catecholamines.
No
absolute contraindications but beware frail patient and patients with severe
coronary or carotid vascular disease.
May
cause severe transient hypotension
Order
the Pentolinium from pharmacy (difficult to obtain). It comes as 10 mg/ml.
Stop
hypotensive treatment (incuding labetalol) for at least 24 hours before the
test (especially centrally acting drugs such as methyldopa).
Fast
overnight. (Large meals can cause variation in catecholamines).
Quiet
environment.
Sphygmomanometer
or Critikon BP monitor.
Cannula,
18-20g.
Ice.
Lithium
heparin tubes (green top Vacutainer).
Contact
biochemistry laboratory who measure catecholamines before doing the test,
enquire how they would like the samples taken and arrange for their delivery.
1.
Patient should empty bladder before lying down as they might not be allowed to stand for a
while.
2.
Insert cannula and flush.
3.
Rest for 1/2 hour.
4.
Monitor BP and pulse at onset and every time blood taken.
5.
Take 2 baseline samples at 5 minute intervals for catecholamines. Blood
needs to be taken into Lithium heparin, kept on ice, spun at 4°C, frozen until
assay.
6.
At time 0, give 2.5 mg Pentolinium i.v.
7.
Take blood at one hour.
Pentolinium
is a sympathetic ganglion blocker. Normal subjects may show an initially
elevated plasma adrenaline and noradrenaline but these will fall to within the
normal plasma range with Pentolinium. In contrast the autonomous secretion of a
phaeochromocytoma will not suppress.
This
test has a low false positive and false negative rate as determined in series
of known phaeochromocytomas and normals but published information is very
scanty. The most likely theoretical problem is a fall in plasma catecholamine
levels in a phaeochromocytoma patient whose tumour is only secreting
episodically.
Brown
MJ et al. Lancet 1981; 1: 174-7
SGG
1/90; revised BK, KM, RB and JT 7/00.
To
try and exclude the diagnosis of phaeochromocytoma in patients with
hypertension and borderline changes in plasma catecholamines or urinary
catecholamine metabolites.
Frail
patient with a history of hypotensive episodes or severe coronary or carotid
disease.
Hypotension and
sedation.
Order
the clonidine from pharmacy (readily obtainable).
Stop
hypotensive treatment for at least 24 hours before the test if possible.
Fast
overnight.
Quiet
environment.
Sphygmomanometer
or Critikon monitor.
Cannula,
18-20g.
Ice.
Lithium
heparin tubes (green top Vacutainers).
Contact
biochemistry laboratory who measure catecholamines before doing the test,
enquire how they would like the samples taken and arrange for their delivery.
1.
Insert cannula.
2.
Rest for 1/2 hour.
3.
Monitor BP and pulse at onset and every time blood taken.
4.
Take 2 baseline samples at 5 minute intervals.
5.
Give, at time 0, 0.3 mg clonidine hydrochloride orally.
6.
Take blood at hourly intervals for 3 hours.
Clonidine
acts via the alpha pre-ganglionic receptors to reduce catecholamine secretion.
In
normals, even if they are anxious, the plasma catecholamines will suppress into
the normal range 3 hours after clonidine (noradrenaline 0.2–0.8 ng/ml,
adrenaline 0.04–2 ng/ml). Phaeochromocytoma patients should not.
This
test gives similar information as the Pentolinium test; there have been no
formal comparisons of the two tests. Case reports (see Halter et al., New Engl.
J. Med. 306, 49-50 – 1982) have illustrated false negatives. The 24 hr urinary
metanephrines/catecholamines have replaced VMAs as the cornerstone of screening
for phaeochromocytoma. If a dopamine
secreting phaeochromocytoma is suspected on the basis of normo- or hypotension
then urinary dopamine and its metabolites should be assayed
Bravo
E.L. et al.. New Engl. J. Med. 305, 623-626 (1981)
SGG
1/90
The
123I MIBG scan is a useful, qualitative, method of locating the site
of a phaeochromocytoma.
It
should not be undertaken without biochemical evidence for a tumour being
present (24 hour urine VMA, circulating catecholamines, clonidine or
pentolinium test), and should be backed up by ultrasound, CT scanning, and,
where indicated, venous sampling. It is particularly useful for extra-adrenal
and metastatic or residual phaeochromocytoma.
No
absolute contraindications except pregnancy or its possibility, allergy to
iodine.
Caution
in any patient with any drug allergies.
Many
drugs may interfere with the study – nuclear scanning have a list. These include
tricyclic antidepressants, SSRIs, calcium channel antagonists, catecholamine
receptor agonists and antagonists, phenothiazines, butyrophenones (e.g.
haloperidol etc.), guanethidine and reserpine.
Liase
with nuclear medicine at least 1 week in advance of planned scan.
Avoid
IV phenoxybenzamine, although p.o. phenoxybenzamine is OK.
Thyroid
uptake should be blocked by potassium
iodide 60 mg bd for 48 hours beforehand and for 5 days afterwards.
123I metaiodobenzylguanidine is injected intravenously (this molecule is
similar to noradrenaline, transported in similar fashion and stored in
catecholamine vesicles). The patient is scanned twice at 24 and 48 hours.
Spots of increased uptake on scanning are the tumours. Most common sites: adrenals, organ of Zuckerkandl (usually pelvis). May be multiple.
In
patients with a proven phaeochromocytoma but uncertain site the scan has 90-96%
sensitivity and 98-99% specificity (Shapiro et al., Cardiology 1985; 72: suppl.
1, 137-142).
Sisson
J.C. et al., New Engl. J. Med. 305: 12-17 (1981).
SGG
11/89
AIM:
Our aim following radio-iodine treatment is to render patients hypo(eu)thyroid. The purpose of the telephone clinic is to rapidly determine when thyroxine replacement should be started, thus avoiding unnecessary outpatient appointments or leaving patients with untreated hypothyroidism, which has many undesirable effects, including possible worsening of thyroid eye disease. See http://radioiodine.info.
THYROID EYE DISEASE.
Worsening of thyroid eye disease only occurs in smokers. There is thus no indication for the use of prophylactic steroids in non-smokers. Even in smokers, the number of patients needed to treat with high dose steroids (40 mg prednisolone daily for 1 month, then taper) means that there will be many patients given steroids with radioiodine for no benefit. All patients should be referred to Veronica Ferguson if there is any doubt (consultant ophthalmologist at Charing Cross). It is preferable to avoid steroids in the majority, and treat the few who develop worsening eye signs with steroids at that stage. Smokers may have a 25% risk of worsening eye disease however.
WHO IS SUITABLE FOR TELEPHONE FOLLOW-UP?:
This service is only available to patients who;
· Are contactable by telephone during office hours (9am – 5pm).
· Speak reasonable English and are able to follow instructions regarding medications.
· Consent to regular blood tests, preferably at the hospital phlebotomy department.
HOW DO I ARRANGE FOR RADIO-IODINE TREATMENT:
Antithyroid drugs should be stopped as soon as the decision to use radioiodine is made. Ideally they will be stopped for at least a week. If you know roughly when the patient wants radioiodine, further planning can be made. If it is clear that the patient will defer treatment for more than 2 months, then the antithyroid drugs should be continued until closer to the date of RAI. As a guide, the antithyroid drugs should be stopped at least 1 week and at most 2 months before RAI.
Give the patient an appointment for list M30 at Charing Cross Hospital as soon as possible. This is currently run by Elaine Murphy on bleep 3509. She will organise all the rest of the protocol ! If you are at Hammersmith, you will need to give the patient an appointment on M30 and also write on the frontsheet for SUE BROWN to actually book this on the Charing Cross system (she normally works at CX, but is based at Hammersmith Hospital on Wednesdays).
Send a referral letter (or fill in web form on http://meeran.info) to:
Chloe Barrett-Dickson, Thyroid File co-ordinator,
c/o Dept of Endocrinology
9th Floor, East Wing, Charing Cross Hospital (Fax: 020 8846 1862).
Make sure to include as many contact telephone numbers as possible in the letter.
WHAT IS THE PROTOCOL FOR RADIO-IODINE TREATMENT?:
Day –7
|
Thyroid function tests. Information session & signing of consent form in Department of Nuclear Medicine, Charing Cross Hospital. Send information letter to patient’s GP. Stop anti-thyroid medication. |
|
Day -3 |
Start Lithium carbonate (Priadel) 800mg nocte. |
|
Day 0 |
Thyroid function tests. Lithium level. Radio-iodine treatment. |
|
Week +1 |
Thyroid function tests. Lithium level. STOP lithium treatment. |
|
Week +3 |
Thyroid function tests. Lithium level. |
|
Week +6 |
Thyroid function tests. |
|
Week +9 |
Thyroid function tests. |
|
Week +12 |
Thyroid function tests. |
|
Week +14 |
Outpatient clinic visit. |
If the patient agrees to take part in the randomized placebo controlled trial, they might receive placebo instead of lithium. These patients should collect the drugs from Charing Cross pharmacy when they attend nuclear medicine there 7 days before their RAI.
WHAT
DO YOU NEED TO GIVE THE PATIENT?:
1. Information sheet on Radio-iodine treatment.
2. Give the patient an appointment for list M30 at Charing Cross. Everything else (below) is for information only, and will be carried out from that clinic.
They will be given:
1. An X-Ray request form to Nuclear Medicine for I-131 Therapy.
2. Seven (7) request forms for TFTs (Weeks –1, 0, +1, +3, +6, +9, +12 as above).
3. 2 request forms for a lithium level (week 0 and +1 as above).
4. A prescription for lithium 800mg (specify Priadel) nocte for 10 days.
5. A prescription for thyroxine 100μcg, NOT to be started until they are telephoned.
6. An appointment for the out-patient clinic, 14 weeks after treatment.
7. Make sure to note the patients’ telephone number in the notes and on the X-Ray form. If they need to ring and enquire regarding results/treatment they should be given the switchboard number and bleep 3509.
WHO
WILL FOLLOW PATIENTS UP BY TELEPHONE?:
All computerised results are updated and reviewed on a weekly basis by a designated Endocrine/Clinical Chemistry Specialist Registrar and patients telephoned if they become either biochemically hypo- or hyperthyroid following treatment.
WHAT HAPPENS IF A PATIENT DEVELOPS SIGNIFICANT SYMPTOMS AFTER RADIOIODINE?
If at any stage a patient becomes symptomatic or develops Grave’s opthalmopathy the Department of Endocrinology can be contacted by either the patient or the GP and arrangements made to review the patient urgently at the next outpatient clinic.
Blood samples will be checked on the day of RAI, and 1 week later for lithium levels. Thyroid function tests will also be monitored, but no action taken (as the FT4 may be lowered by the lithium).
When the Ft4 falls to 14.5 pM or less, then thyroxine will be commenced by telephone. Samples will be collected at 3,6,9 and 12 weeks, and the patient should see someone at about 14 weeks. If they are still toxic, further telephone appointments can be made at 15, 18 and 21 weeks.
If at review (after 12 weeks), the TSH is still not detectable, then this is either due to excess thyroxine, or due to failed RAI. A FT3>5 suggests autonomy, and the thyroxine should be discontinued. If the FT3<5.0, then the dose of thyroxine can be slowly lowered with 3 weekly phone reviews.
EM 07/01, KM 01/03
Patients will be expecting phonecalls to tell them whether or not to start thyroxine.
First look on computer for results of FT3/ FT4/TSH. Ask someone else to phone for lithium level, and let Dr. Meeran know if they are lithium toxic. Some will have a zero level.
Ask the patient their weight in kilograms (or stone/lbs and convert).
Find out how they feel. Ask specifically about nausea. Check that they have been compliant with the lithium/placebo. How many tablets did they take? Which ones did they miss?
If the patient feels toxic (tremor, tachycardia etc), and the FT4 > 40pM, then suggest atenolol 100 mg daily until next (3 weeks) review, as they might still rapidly become hypothyroid.
If FT4< 14.6, then start thyroxine 100 mcg daily. The patient should have a supply of these at home, and should be able to start these the day you make the phonecall.
After week 12, if TSH suppressed, then check FT3. If FT3>5, then stop thyroxine. If FT3<5, then reduce thyroxine slowly.
This page to be filled in with each phonecall in the thyroid clinic made and stored in the thyroid file.
Name:
Hospital Number:
Date of phoncall:
Date of blood test:
Date of RAI:
Weeks since RAI:
Results: FT4
FT3
TSH
Lithium level checked (yes/no). Do NOT get result.
Phone call:
Comments about how patient feels:
Weight of patient (at home).
How many lithium tablets did you take and how many did you forget? Which ones did you forget? (Get exact dates).
Do you smoke ? How many?
What tablets are you CURRENTLY taking:
If FT4 < 14.6pM, then start thyroxine 100mcg daily. Advice given: start thyroxine or wait until further samples taken:
If FT4>30 and patient feels unwell (tremor, tachycardia etc), then consider atenolol 100 mg daily.
After week 12, if TSH suppressed, then
check FT3. If FT3>5, then stop thyroxine. If FT3<5, then reduce thyroxine
slowly.
PATIENT
INFORMATION (RADIOIODINE)
What is radio-iodine treatment?
Your consultant has asked us to see you about iodine (iodine 131) therapy for thyrotoxicosis. Iodine therapy uses a form of iodine that is radioactive. Iodine is taken up by the thyroid gland and the radioactivity will “slow down” the thyroid’s production of certain hormones. Radio-iodine therapy has been used for more than 40 years and is a well-established technique. We have been using radioactive iodine therapy in this Department for many years and are highly satisfied with the results.
Where else in the body does radio-iodine go?
Most of the radio-iodine goes to the thyroid. The rest will pass from your body, mostly in the urine, during the first few days.
How is the radio-iodine given?
The radio-iodine is given as a capsule to swallow with water. This is similar to any other tablet and is taken in much the same way. Occasionally the radio-iodine can be given as a drink which tastes just like water.
Is there any preparation before the treatment?
Yes, and it is important to follow the instructions exactly otherwise the treatment may not be effective.
· Medication - You must tell us about all the medication you are taking, even health products or supplements bought over the counter.
·
It will be necessary to stop taking certain medication before the
treatment - for example carbimazole (CBZ) and propyl-thiouracil (PTU) must be
stopped at least seven days before the treatment. You will start the Lithium
(for which you will have been given a prescription) for a total of 10 days, starting
3 days before the RAI, and continuing 7 days after. You will also have been
given a prescription for thyroxine. Hold this until told to start taking it.
·
Food - Do not eat
any fish or seafood for two days before the treatment. A low iodine diet is
repeated on page 58.
·
On the day - You
may have a light breakfast but no lunch.
You should drink normally.
Can I have treatment if I am pregnant or breast-feeding?
No. Women who are pregnant or breast-feeding
must not be given radio-iodine. If
there is any possibility that you may be pregnant, you must tell us. You
are advised not to become pregnant for at least four months following the
treatment. You must take adequate
contraceptive care.
Will there be any danger to my family or friends?
We wish to keep all radiation levels as low as reasonably practical. We aim to ensure that your family and friends will not receive radiation above the levels experienced by members of the public in their daily lives. We will discuss with you in detail how you can achieve this. The essential precautions to reduce radiation are:
·
Avoid
non-essential close contact with babies, young children and pregnant women. For
people with day to day contact this can be for a period of 2-4 weeks. At
consultation we will discuss how this can be practically carried out.
·
You may need to
take some time off work depending on your specific job.
·
You will need to
avoid close contact with other people for several days
·
You must sleep
alone for one week after treatment.
·
Please check if
you can travel by public transport.
Usually there will be no restriction.
·
Women should not
become pregnant nor men father a child in the 4 months after treatment
On the day of treatment you will be given specific advice about these precautions. The exact length of time for which these precautions apply depends on the amount of radioiodine the doctor prescribes.
Investigations that will
be needed during the course of treatment.
You will need several blood tests, as follows:
· On the day of the preliminary consultation
· On the day of treatment
· One week after treatment
· 3,6,9 and 12 weeks after treatment
You will have been given request forms for all these tests by the Clinic Doctor, and they will be numbered.
Will I need to see a doctor after the radioiodine treatment?
Yes, either the doctor you saw at the clinic or your GP. Blood tests will be required to monitor the effect of the treatment on your thyroid. Full instructions will be given at the time of treatment.
How many treatments will I need?
Usually one treatment is enough, although sometimes more than one is needed. The blood tests will help decide.
Are there any side effects?
Very occasionally after receiving the radio-iodine you may get a sore throat. This should last for only a few days and if it does happen to you, it can be relieved by drinking plenty of fluids and sucking boiled sweets. Your thyroid may become underactive. This could happen within a few months or many years after the treatment. Again the blood tests will check the state of your thyroid. If it does become underactive you will be given thyroxine tablets.
What should I do if I
cannot keep my appointment?
Please contact the Nuclear Medicine Department on the telephone number below if you are unable to keep an appointment. The radio-iodine has to be ordered specially for each patient and it would be appreciated if any unavoidable appointment cancellation or rearrangement could be made at least one week before the appointment date so that the order for your dose can be changed accordingly.
If you have any questions
at all or need further advice please do not hesitate to ring the telephone
number given below:
Telephone: 020 8746 8412 or 020 8846 1428
Dr. Meeran’s secretary: 020
8846 1065.
JF 07/01
CONSENT
FORM FOR THE ADMINISTRATION OF RADIOACTIVE IODINE FOR THYROTOXICOSIS
I confirm that I have explained the nature and
purpose of radioactive iodine treatment to the patient in terms that in my
judgement are suited to the understanding of the patient.
Signature ......................................................
Name of Doctor ...................................................... Date ..............................
PATIENT
I agree to the proposed treatment that has been
explained to me by the doctor. I have
been given written information about the nature, purpose and consequences of
the treatment. I understand that the
treatment will be carried by the staff of doctors, physicists and their
colleagues.
Signature ......................................................
Print Name ..................................................... Date .............................
ON THE DAY OF TREATMENT
I have been instructed about precautions which I
must take following the treatment. I
have been advised particularly that women should not get pregnant and men
should not father any child for four months after this treatment.
.................................................................. ..................................................
Patient’s signature Confirmed by
(Staff)
All women must complete the following section
I am not pregnant
I am not breastfeeding.
..................................................................
.................................................
Patient’s signature Confirmed by (Staff)
Updated
6/2001 Dr Frank
Suspected
medullary carcinoma of thyroid.
Screening
of families with medullary carcinoma of the thyroid.
Patients
with suspected MEN type 2. Remember to inform the MEN2 registry.
Allergy/anaphylaxis
on repeat administration.
Nausea,
epigastric discomfort
Check
electrolytes and serum calcium.
Cannula,
18-20g.
Pentagastrin
0.5 mcg/kg body weight.
6
x 7 ml Lithium heparin tubes (green top Vacutainers) with 0.2ml Trasylol added.
Centrifuge.
Ice
or facilities to transfer samples immediately to lab
1.
Patients should be fasted, as food can increase calcitonin.
2.
Insert cannula and flush.
3.
Take baseline sample for calcitonin.
4.
Give bolus i.v. of pentagastrin 0.5 mcg/kg body weight and flush
cannula.
5.
Take samples at 1, 2, 3, 5 and 10 minutes for calcitonin.
6.
Take immediately to lab on ice.
An
abnormal peak calcitonin (> 200 ng/l) is suggestive of medullary thyroid
carcinoma and surgical treatment should be considered especially if there is a
family history. Potentially affected family members should be screened
biennially until 65.
Pentagastrin
stimulates calcitonin best in medullary carcinoma, whereas calcium infusion is
best in normals.
Combining
two studies only two out of 25 patients with medullary thyroid carcinoma had
normal responses to pentagastrin. Many normals have been described with an
exaggerated response to pentagastrin and the reproducibility of this test is
poor.
Reference: McLean G.W. et al.,
Metabolism 33, 790-796 (1984).
Suspected
acalcitoninaemia.
Suspected
medullary carcinoma of thyroid.
Screening
of families with medullary carcinoma of the thyroid.
Patients
with suspected MEN type 2.
Bleeding
disorders
Unpleasant
flushing sensation
No
major side effects
Patient
should fast overnight.
Check
electrolytes and serum calcium.
Cannula,
18-20g.
Saline
flush.
Calcium
gluconate 10% (10 - 20 ml required).
6
x Lithium heparin tubes (green top Vacutainer) with 200 µl Trasylol.
Syringes.
Ice
and facilities to transfer samples immediately to lab.
Insert
cannula and flush.
Take
baseline sample for calcitonin.
Give
calcium gluconate 0.2 ml/kg body weight i.v. over 1 minute.
Flush
cannula.
Take
samples at 1, 2, 3, 5 and 10 minutes for calcitonin.
Send
immediately on ice to the lab for centrifugation and freezing.
In
medullary carcinoma of the thyroid there is often a raised fasting serum
calcitonin (>90 ng/l) but this may be in the normal range. Provocative tests
improve the sensitivity of calcitonin measurement. Normal range for peak
calcitonin following calcium infusion is 100 to 200 ng/l
In the study quoted
below 8/12 subjects with medullary thyroid carcinoma had increased responses to
calcium infusion. Two of the four who failed to respond had a raised baseline
calcitonin. There is a high false positive rate especially in young men. The
pentagastrin test is better in this situation.
Charib
H. et al., Mayo Clinic Proc., 62, 373 (1987).
JW
12/89
Because
thyroidectomy prevents medullary thyroid cancer provided it is performed before
the age of 5, children must be screened for the MEN2 gene before they develop
thyroid cancer. Send 10 ml blood in an EDTA tube to: Dr. J Whittaker, East
Anglian Medical Genetics Service, Molecular Genetics laboratory, Box 158,
Addenbrookes Hospital, Hills Road, Cambridge. CB2 2QQ. Tel: 01223 217971/217973.
An
alternative laboratory for MEN1,
and MEN 2 genetic screening runs in Exeter under the auspices of Dr. Andrew
Hattersley. Tel : 01392 403089. Fax: 01392 403027. E-mail:
A.T.Hattersley@ex.ac.uk:
Screening
for MEN1 costs £400, for MEN2a, £250 and for MEN2b, £100.
Testing for a known mutation in a family member costs £75 for both conditions.
Lab contact: S. Ellard (01392 402910).
A
request form is available via http://meeran.info
KM
01/03
Investigation
of thyroid nodule(s). 80% of all thyroid nodules are "cold" on
technetium or iodine scan, and 85 to 90% of these cold nodules are benign. Thus
the prime aim of FNA is to exclude malignancy (note however that 9% of nodules
that are apparently functioning on isotope scanning turn out to be malignant,
i.e. scanning alone is a poor test to exclude malignancy and may be becoming
obsolete as a first line investigation of nodules).
None
None
Rarely: local bleeding.
Avoid by applying local pressure
1.
Contact cytology department who will come almost immediately and bring
their prepared slides.
2.
Lie patient in supine position with neck flexed backwards.
3.
Insert 25 gauge needle into nodule and aspirate (usually more than one
pass). Local anaesthesia is usually necessary.
The needle should just be passed in and out. Don't draw back as this results in a bloody tap.
4.
At Charing Cross, if the nodule is palpable, draw a clear diagram of
where it can be felt, and book the patient to return the following Thursday at
1.30 pm on list M70. The FNA is usually performed by Dr. Naomi Livni,
consultant cytopathologist, who teaches endocrine SPRs how it is done.
Possibilities
are:
1)
"Negative" or benign: obvious epithelial cells ± colloid
2)
Hashimoto's (hypercellular)
3)
Suspicious of neoplasm: papillary etc.
4)
Diagnostic of neoplasm
5)
Non-diagnostic: insufficient cells to make a diagnosis
1)
and 2) do nothing, ?follow up if necessary. No indication for T4 treatment to
"suppress" nodule unless function tests show raised TSH (i.e.
"subclinical hypothyroidism").
3)
Repeat FNA, radioisotope scan: if focal abnormality refer to Mr Lynn
4)
Refer Mr Lynn
5)
Consider repeat FNA. Do isotope scan ± ultrasound.
Depends
on the centre. At the Hammersmith we have as yet little experience and cannot
say. Experienced centres report 98% sensitivity and over 99% specificity. The
major limiting factor may be the quality of the sample.
Gabib
H et al., Endo. Metab. Clin. N. Am. 17, 511-26 (1988).
SG
10/89 KM 07/01
· Subtotal thyroidectomy
· Ablation dose 131I,
day 5 post-operatively, 2 hours after i.v. TRH
· Replacement therapy (T4)
started 3 days post ablation, and increased to 200 mcg
daily.
· Follow-up, with TSH and
thyroglobulin levels.
· 131I scan only if
recurrence suspected clinically.
· Subtotal thyroidectomy
· Ablation dose 131I
· Replacement therapy (T3)
started 3 days post ablation, and increased to 20 mcg twice daily
· Regular follow-up with 131I
scanning (3 and 6 months, and then at years 1, 2, 3, 5 and 7)
· If no evidence of
recurrence after 2nd 131I scan, switch to T4 suppression (200mcg
daily).
· T3 needs to be discontinued
8 days prior to 131I scan and TSH measured on day of scan to ensure
appropriate interpretation.
AP
1/98
This diet is used for patients who have previously been treated for papillary or follicular thyroid carcinoma and who have had a total thyroidectomy. In these patients, it is taken for 2 weeks prior to a whole body iodine scan, as the smallest amount of iodine might cause reduced uptake. It can also be used (for 2 days) before radioiodine ablation in hyperthyroid patients, but this is less critical. The dose of radioiodine is much less than used in thyroid carcinoma.
Please avoid the following foods that have a high iodine content:
· Iodised salt, including sea salt and processed meat products, which all contain iodised salt and red food colourants
· All foods containing red food colourants (E127). Please look on the product label for this food dye, which is found in things like glacee cherries, red biscuits, etc.
· Seafood, including fish, shellfish, kelp and seaweed
· Try and restrict your intake of milk, since milk contains iodine. Use soya milk instead
In general, check all food labels for
additives, and if possible avoid those containing iodides, iodates, algin,
alginates, agar, and carraganeen
·
Elevated corrected Ca2+.
·
Low PO43-.
·
Normal alkaline phosphatase.
·
Normal or elevated serum PTH.
·
High 24 hr urinary Ca2+.
·
To
exclude Familial Hypocalcuirc Hypercalcaemia (FHH), the calcium clearance to creatinine
clearance ratio should be > 0.01. This is calculated as follows:
Calcium Clearance
Creatinine Clearance (This
may be calculated already)
Plasma
creatinine is normally expressed in umol/l and needs to be converted to mmol/l
by dividing by 1000.
However,
this ratio can be reduced to
Urine
Calcium (mmol/l) x [Plasma Creatinine (umol/l) / 1000]
Plasma Calcium (mmol) x Urine Creatinine
(mmol/l)
Urine
calcium 1.0 mmol/l Ratio
= 1.0 x [130/1000] = 0.0079
Plasma
creatinine 130 umol/l
Plasma
calcium 2.65 mmol/l
Urine
calcium 2.2mmol/l Ratio = 2.2 x [74/1000] = 0.035
Plasma
creatinine 74 umol/l
Plasma
calcium 3.3 mmol/l
None
of the techniques are reliable and often a combination of methods are used.
·
Ultrasound of neck.
·
Sesta-MIBI scanning.
·
123I and sesta-MIBI double isotope scan (higher sensitivity, ask nuclear
medicine).
·
MRI of neck.
·
CT neck (+ upper mediastinum).
·
Selective venous sampling for PTH is not routinely used and reserved for
difficult cases. Patient requires
hospital admission, and investigation needs to be booked with Dr Jackson well
in advance.
· Usual pre-operative
bloods, including U+E, Ca2+, PO4, alkaline phosphatase,
albumin.
· Maintain adequate
hydration.
· Replace deficit and
maintain 3-4 l fluids /day i.v. and then orally if patient able to drink.
· If above measures do not
reduce corrected Ca2+ <2.8 mmol/l give bisphosphonates (e.g.
pamidronate 30 mg in 1l 0.9% saline over 4 hrs). This will not start to work
for 24hrs, with maximum effect 5-6 days.
Plan in advance to avoid severe post-operative hypocalcaemia.
· Enquire for symptoms of
hypocalcaemia (paraesthesiae, cramps etc.).
· Trousseau’s and
Chvostek’s test daily.
· Daily U+E and corrected
Ca2+.
· If mild symptoms and
corrected Ca2+ >2.0 mmol/l, give effervescent Ca2+
(Sandocal).
· If severe symptoms and
corrected Ca2+ <2.0 mmol/l, give Ca2+ infusion
(calcium gluconate 15 mg/kg i.v. in 1l 0.9% saline over 4 hours).
· If hypocalcaemia
persists, introduce alfacalcidol (0.125 ng od).
AP
1/98 updated SS 07/01
·
Suspected diabetes mellitus. An oral glucose tolerance test is not
required if the diagnosis of diabetes is not in doubt or if a fasting venous
plasma glucose is greater than 7.0 mmol/litre or a random venous plasma glucose
is greater than 11.1 mmol/l.
·
In acromegaly, to establish the diagnosis and to follow patients after
treatment with surgery or irradiation.
·
Suspected reactive hypoglycaemia.
None
Nausea
and occasional vomiting
The
subject should have been on a diet containing an adequate amount of
carbohydrate (250g/day) for at least 3 days before the test
Overnight
fast.
75g
anhydrous glucose.
Fluoride
oxalate tubes x 3 (grey top Vacutainers).
18-20g
cannula.
Saline
flush.
Syringes
x3.
·
Diabetes
Insert cannula.
Take a baseline glucose at time 0.
Give oral glucose load (75 g anhydrous glucose
in 250–350ml water).
Repeat blood samples at 60 and 120 min after
glucose load.
·
Acromegaly
See under “growth hormone” above.
·
Reactive hypoglycaemia
Take blood glucose at -30, 0, 30, 60, 90, 120,
150, 180, 210, 240, 270 and 300 min.
WHO (established June 2000) for diabetes and
impaired glucose tolerance
|
Plasma Glucose
(mmol/l) |
Fasting |
2 hrs after glucose
load |
|
Diabetes mellitus |
³7.0 |
³11.1 |
|
Impaired glucose tolerance |
|
>7.8 – 11.0 |
|
Impaired fasting glucose |
>6.1 – 7.0 |
|
|
Normal |
≤6.1 |
≤7.8 |
75
g oral glucose tolerance test.
In
the absence of diabetic symptoms at least 2 abnormal values are necessary to
establish a diagnosis of diabetes mellitus
Gestational
diabetes: women who have IGT in pregnancy should be treated as if they have
GDM.
These
criteria were revised by the WHO in 1997 and remain arbitrary. Remember that acute illness (e.g. myocardial
infarction) and drugs may affect glucose tolerance.
In
acromegaly it is very rare for GH to suppress to the normal range with a
glucose load. In fact there is often a paradoxical rise in GH. Some normals
especially if stressed do not suppress. The definition of "cure" in
acromegaly is very difficult. Patients may show dramatic clinical improvement
but not suppress with glucose.
Keen
H., Medicine International May, 2672-2675 (1989).
Diabetes
Care, 21 S1, 5-19 (1998).
Suspected
diabetic autonomic neuropathy.
Shy-Drager
Syndrome.
Suspected
autonomic failure from other causes.
Patients
with proliferative retinopathy should not perform the Valsalva manoeuvre
because of the risk of retinal haemorrhage.
Atrial
fibrillation (tests uninterpretable, except postural hypotension and handgrip
tests).
None
Sphygmomanometer.
Mouthpiece
to attach to sphygmomanometer (5ml syringe minus plunger).
ECG
machine (old fashioned type as long rhythm strips recorded).
1. Heart rate response to the Valsalva manoeuvre
Start ECG machine (limb leads only, use lead II)
Patient blows into sphygmomanometer and
maintains pressure at 40mmHg for 15 seconds, continue recording for 30 seconds
after release of pressure.
Measure shortest R-R interval during manoeuvre
and longest after.
Valsalva
ratio =
longest after/shortest during.
Take mean of three readings.
2. Heart rate variation during deep breathing
Start ECG machine
Ask patient to breathe quietly at a rate of six
breaths over one minute (5 seconds in and 5 seconds out).
Mark ECG at start of each inspiration and
expiration.
Measure maximum and minimum R–R interval for
each cycle and convert to beats/min.
Result is mean difference (max – min) for heart
rate during deep breathing.
3. Heart rate response to standing
Start ECG recording with patient lying.
Ask the patient to stand, continue recording ECG
for 1 minute.
Measure shortest R–R interval around the 15th
beat after standing and the longest around the 30th beat.
Calculate longest/shortest = 30:15 ratio.
Blood pressure response to standing
Measure blood pressure lying and then 2 minutes
after standing
Record postural difference
|
TESTS |
Normal |
Borderline |
Abnormal |
|
Valsalva
ratio |
≥1.21 |
1.11-1.20 |
≤1.10 |
|
(max–min)
HR |
>15 |
11-14 |
<10 |
|
(30:15
ratio) |
>1.04 |
1.01-1.03 |
≤1.00 |
|
fall in BP |
≤10 |
11-29 |
≥30 |
These
tests can be used to determine the degree of abnormality present: if two or
more of the parasympathetic tests plus the sympathetic tests are clearly
abnormal then this indicates significant autonomic damage, earlier damage is
signified by abnormalities in at least two parasympathetic tests.
Caution
should be taken in interpreting these tests in patients who are poorly
co-operative and in the elderly.
Clarke
B.F. and Ewing D.J., BMJ 285, 918-920 (1982).
Used
to demonstrate fasting hypoglycaemia and diagnose insulinoma if not shown
spontaneously or after an overnight fast.
Admit
to perform test under close supervision with glucose (p.o./i.v.) available.
Leave
a copy of this protocol sheet in the nurses’ notes and a copy above the
patient’s bed.
·
Cannulate patient and commence 72 hr fast.
·
Water/non-caloric beverages allowed. Patient should be active during
waking hours.
·
Blood glucoses should be done at regular (4–6 hr) intervals and whenever
the patient has symptoms suggestive of hypoglycaemia. Decrease to 2 hr
intervals if the patient consistently has glucoses <3.0 mmol/l.
·
If blood glucoses are ≤2.2 mmol/l or symptoms are convincing:
- Bleep endocrine SHO
(9053/9054 or on-call) urgently.
- Take blood for glucose,
insulin and C-peptide in a plain clotted tube (7 ml) and a fluoride oxalate
tube.
- Take blood and spot
urine for sulphonylurea screen in a plain clotted tube (7 ml) and a Sterilin universal
container.
- Take to chemistry labs
to be separated and frozen within 30 mins. Ring biochemistry up for an urgent
glucose.
- Do not reverse
hypoglycaemia until the lab confirms hypoglycaemia, or unless the patient
becomes unconscious or fits.
·
If no symptoms during the fast, finish with 15-30 mins exercise, e.g. a
brisk walk around the hospital.
·
Take final samples for glucose, insulin and C-peptide, sulphonylurea
screen.
·
Normals do not become hypoglycaemic, although young women can run glucoses
in the region of 2.2–3.0 without symptoms.
·
True hypoglycaemia must be demonstrated (glucose ≤2-2.2 mmol/l),
before we are able to either interpret insulin results or consider insulinoma.
·
If hypoglycaemia with raised insulin but low C peptide, consider self
administration of insulin.
·
If hypoglycaemia with raised insulin, and raised C-peptide, make sure
sulphonylurea screen is negative!
·
With hypoglycaemia, insulin and endogenous insulin production (estimated
by C-peptide) should be low.
-
Insulin >6 mU/l (>50 pmol/l); C peptide >300 pmol/l =
insulinoma (check ratio of c-peptide to insulin high enough).
-
Insulin >3-6 mU/l (25-50
pmol/l); C peptide 100-300 pmol/l = possible insulinoma but needs further tests
-
Insulin <3 mU/l (<25 pmol/l); C peptide <75 pmol/l = normal
response
·
Ketones should be suppressed with insulinoma even though patient is
fasting because of the excess insulin.
By
24 hrs, 66% insulinomas develop hypoglycaemia and by 48 hrs, >95%
insulinomas can be diagnosed. After 72 hrs fast plus exercise, if no
hypoglycaemia, insulinoma is very unlikely.
Friesen,
S.R. Surg. Clin. N. Amer. 67(2). 379 (1987).
MLB & PJH 10/91
1.
Dietician review. Multiple,
regular, small meals usually help.
2.
Guar gum 5g tds also helps by slowing gastric absorption.
3.
Diazoxide 50–200 mg tds, but beware of hypokalaemia and severe oedema
4.
NG feeding can be considered.
5.
Steroids can help for a short period.
6.
Octreotide can be helpful but beware hypoglycaemia if glucagon levels
are suppressed.
7.
Calcium channel antagonists may be useful for nesidioblastosis.
Used
in the diagnosis of Zollinger-Ellison syndrome.
Consider
syndrome if:
1)
Raised gastrin (>40 pmol/l) in the absence of other causes (e.g. H2
antagonists, PPIs, pernicious anaemia, other causes of achlorhydria, renal
failure).
2)
Associated upper gastrointestinal disease, i.e. peptic ulcer disease
with poor response to treatment; multiple duodenal or jejunal ulcers; peptic
ulcer disease with unexplained diarrhoea; fulminant peptic ulcer disease
(perforation, haemorrhage, oesophagitis and stricture); ulcer in upper part of
ligament of Treitz.
Measuring
gastric output distinguishes secondary hyper-gastrinaemia (due to achlorhydria)
from primary hyper-gastrinaemia. Administration of pentagastrin i.v. does not
improve the diagnostic accuracy.
Book
with endoscopy suite since the end couch next to the apparatus will be
required.
Liase
with Gastro research fellow to ensure that equipment is not being used.
Stop
H2 antagonists for 72 hrs and stop PPIs for 2 weeks.
Stop
antacids 24 hours before blood sample.
Patient
should be fasting.
Check
that the autotitrator is available, otherwise you will need to obtain a
burette, conical flask, pH meter and 0.1M NaOH.
1. Pass the special double
lumen naso-gastric tube (obtained from sister in endoscopy) with plenty of
Xylocaine spray to the nose and throat, and lignocaine jelly to the nose. Pass
the NG tube as far as the 50cm mark at the nostril.
2. Ask the patient to drink
50mls of water and then aspirate this via the NG tube to check that it is in
the most dependent part of the stomach.
3. Connect NG tube to the
pump and collect four samples of gastric juice, each over 15 min into
polystyrene cups. Alternatively, aspirate regularly and periodically with a
50ml syringe to collect gastric juice over each 15 min period.
4. Measure total volume of
each sample. Decant 10mls of each into
a fresh polystyrene cup and titrate against 0.1M NaOH with the automated
titrating equipment, or carry out a standard neutralisation titration manually.
5. Calculate the acid
production of each 15 min collection:
A = (N/100) ´ V
A = mmol of acid production
N = volume (ml) of 0.1M NaOH solution needed
to neutralise 10mls of gastric juice
V = volume (ml) of gastric juice in 15 min
collection
A sum of the acid production for each 15 min
will give the total hourly production.
Spontaneous basal acid outputs of 20 - 25 mmol/hr are almost diagnostic, >10 mmol/hr is suspicious. Post ulcer surgery >5 mmol/hr is indicative.
Hypergastrinaemia
and raised gastric acid are also found with:
1. gastric outlet
obstruction: resolves with NG decompression
2. massive small bowel
resection: resolves a few months post op
3. antral G cell
hyperplasia: excess cells on histochemistry
Deveney
et al., Surg. Clin. N. Amer. 67(2) 411 (1987).
MLB
& PJH 2/91; corrected equation BK 7/00.
The intravenous secretin test should, whenever
possible, be performed only after the results of basal plasma gastrin and acid
output – both performed off PPIs for 2 weeks, H2 blockers for 3 days and fasted
- are available.
The indications for the test are:
1. Strong clinical
suspicion of a gastrinoma with equivocal results of acid studies and fasting
gastrin.
2. Inability to wean
patients off antisecretory therapy for long enough to perform acid studies and
gastrin estimation because of recurrence of severe symptoms.
Warn fasting gut hormone lab (34549/33949) 48
hours in advance.
Fast overnight. If possible, stop antisecretory
therapy for 24 hours.
Secretin (Kabi) ordered in advance from
Pharmacy.
7 x 7 ml Lithium Heparin tubes (green top
Vacutainers) with 200μl Trasylol labelled
before the study.
Syringes.
Ice.
Arrangements to transfer for immediate spinning.
1. Site indwelling cannula.
2. Take two baseline
samples at T = -15 and 0 mins.
3. Secretin 2U/kg injected
as bolus at T = 0.
4. Blood samples taken at T
= 2, 10, 15, 20 and 30 minutes.
5. Samples stored on ice
and spun within 15 minutes.
6. All samples assayed for
gastrin.
The criteria for diagnosing a gastrinoma are
based on gastrin assays from other laboratories where results may not be
directly comparable. The best criterion
is a rise in gastrin of 200 pg/ml – equivalent to about 100 pmol/l. This gives a sensitivity of 85% when
performed on all patients with a fasting gastrin of less than 400 pmol/l. A rise of 50% over basal values gives a
sensitivity of 78%. Gastrin levels FALL in normal individuals in response to
secretin.
Few false positives have been reported, but
massive rises occasionally occur in association with achlorhydria and common
duodenal ulcer disease, hence the need to have acid studies and fasting gastrin
as the initial investigations, if possible.
Frucht et al., Ann. Intern. Med. 111, 713-722
(1989).
This investigation is performed in conjunction
with highly selective angiography for patients with proven gastrinomas or
insulinomas, whose tumours are too small (usually less than 1 cm) to be
detected by CT or USS. This comprises
about 50% of patients with these syndromes. Gastrinomas can be stimulated with
intra-arterial secretin or calcium; insulinomas with intra-arterial calcium.
Much better results are obtained with calcium, and secretin is no longer really
available.
(Discuss with radiology S.R.)
Allergy to contrast dye.
Ischaemic Heart Disease
Orthopnoea
Bleeding tendencies
(severe)
Order Secretin (Kabi) or 10% calcium gluconate
in advance from Pharmacy.
Warn fasting gut hormone lab (34549/33949) or
endocrinology lab (34681) 48 hours in advance.
Stop diazoxide 24 hours before procedure.
Consent patient (may have flushing, nausea and
hypoglycaemia following calcium injection, risks of bleeding from sheath sites,
thrombosis/dissection of femoral artery and visceral arteries, dye allergy).
Blood for U+Es, clotting, and G+S.
Fast for at least 4 hours and run in 5% dextrose
to maintain blood glucose at about 3.0 mmol/l.
2 people to attend to assist sample processing.
7 tubes per arterial run (prepare 4 runs and
have more tubes to hand):
7 ml Lithium Heparin
tubes (green top Vacutainers) containing 200 µl Trasylol marked before the
study starts for gastrinoma.
7 ml plain bottles (red
top Vacutainers) for insulinoma. (for
insulin AND c-peptide).
Syringes.
Ice.
Stopwatch.
Arrangements to transfer for immediate spinning.
No serious complications of this procedure have
been reported in the 30 patients reported in the literature. Flushing and
nausea may follow calcium injection. One of our insulinoma patients had a hypoglycaemic
episode following injection of calcium and so BMs should be monitored and the
glucose maintained at 3 - 5 mmol/l with dextrose infusion if necessary. The other potential side effects are those
of the angiography itself.
1. A catheter is placed in
the right hepatic vein prior to routine highly selective visceral angiography.
2. Following angiography
each artery (usually proximal gastroduodenal, proximal splenic, hepatic and
superior mesenteric) is recatheterised in turn, preferably starting with the
vessels least likely to be supplying the tumour.
3. Take two baselines at T
= -120 and 0 secs.
4. At T = 0 secretagogue is
rapidly injected as a bolus into the artery – 30U secretin in 5ml normal saline
or 1 ml of 10% calcium gluconate as appropriate.
5. Blood is sampled at T =
30, 60, 90, 120 and 180 secs (give a 10 sec countdown before each sample).
6. Samples for gut hormone
assay should be stored in ice and spun within 15 minutes, and samples for
insulin assay should be separated within 30 minutes. Do not store insulin
samples on ice unless procedure is very prolonged.
·
Secretin injection: localization to a
specific region of the pancreas or duodenum (regionalization) is based on a
gradient of greater than 50% on the 30 sec sample. Using these criteria the NIH
group successfully regionalized 54% of tumours and in combination with
angiography, 77% of lesions were localized.
·
Calcium injection: 4 patients have been
reported in the literature (by the NIH group). All were localized using the
criterion of a two-fold rise in insulin in the 30 or 60 sec hepatic vein
samples. There has also been one report of a PPoma being localized by selective
arterial calcium injection.
Secretin: Doppman J.L. et al., Radiology 174,
25-29 (1990).
Calcium:
Doppman J.L. et al., Radiology 178, 237-241 (1991), Fedorak I.J. et al.,
Surgery 113, 242-249 (1993), O'Shea et al., JCEM (1996): 81(4): 1623-1627
Turner
etal (2002): Clin End (Oxf). Calcium stimulation tests for localisation of
gastrinoma.
PJH 9/93; minor corrections BK 07/00, KM 07/02
Avocados, bananas, plums, walnuts, pineapples,
tomatoes, aubergines, cough medicine.
The liver has a dual blood supply (hepatic
artery and portal vein) so that interruption of hepatic arterial supply by its
embolization using foreign substances (e.g. polyvinyl alcohol) in the presence
of a patent portal circulation (necessary to sustain liver function).
Undertaken under local anaesthetic by Professor Jackson's radiology team.
ENSURE JAMES JACKSON IS AROUND ON WEEK OF BOOKED ADMISSION.
1. Palliation of clinical
consequences of hormone production from hepatic secondaries in the carcinoid
syndrome and other neuroendocrine tumours. Diagnosis should be fully
established.
2. More controversially:
reduction of tumour load in these patients to improve the well being of the
patient or to reduce local symptoms (e.g. "dragging" abdominal pain
from hepatomegaly).
Prolonged prothrombin time
Non-patent portal circulation
Obvious end-stage illness
Ischaemic heart disease
Contrast allergy
Arterial thrombosis (e.g. femoral artery).
Bleeding from sites of sheath insertion.
Malaise, mild hypotension and fever due to the
release of tumour necrosis factor and other vasoactive compounds from necrotic
tissue. This can last for weeks after the procedure.
Occasionally life threatening hypovolaemia with
renal failure due to severe vasodilatation. This is now rare when octreotide is
used, but patients must be well hydrated pre- and immediately
post-embolization.
Rarely infarction of other intra-abdominal
organs including the gallbladder.
Rarely infection introduced during procedure and
rarely abscesses in the liver, which can develop late.
Rarely tumour lysis syndrome, which is why
allopurinol has been added to protocol.
1 week before procedure:
-
Dual-phase contrast CT abdomen to establish baseline for size, location
of metastases.
-
Optional Doppler USS liver to
establish portal vein patency (this is always established by Prof Jackson
immediately before embolization).
-
Take blood for FBC, U+Es, clotting, G+S.
-
CXR, ECG.
-
Echocardiogram if carcinoid and no previous echo.
Day before:
-
May need to put in central venous catheter and urinary catheter (low
threshold).
-
Insert three large cannulae, if not using central venous catheter.
-
Document foot pulses.
-
No evidence of infection.
-
Informed consent.
-
Premed (discuss with radiologist).
-
Discuss with anaesthetic SR on call regarding possible need for ITU bed.
-
Start 1l 0.9% saline with 20 mmol KCl from midnight before procedure.
-
Write up protocol medication:
Start on admission:
-
Allopurinol 300 mg p.o. od for 10 days.
-
Cyproheptadine 4 mg p.o. tds (histamine blocker – in carcinoids) for 72 hrs post procedure.
-
Nicotinamide 250 mg p.o. qds or 500 mg bd (for carcinoids – may cause flushing) for 72 hrs post procedure.
To start on morning of procedure and continue for 48
hrs:
-
Octreotide: 1600 mcg in 48 ml 0.9% saline, i.v. at 6 ml/hr (i.e. 8 hrs).
Write up 6 syringes.
-
Trasylol (aprotinin): 50 ml neat (10,000 U/ml) i.v. at 5 ml/hr
(i.e. 10 hrs). Write up 5 syringes.
One hour before procedure:
-
Methylprednisolone 1g i.v.
-
Premedication (discuss with Prof Jackson).
Antibiotic cover:
Pre-procedure
-
Amoxycillin
1g i.v. (or Teicholplanin 400 mg 12 hourly if penicillin allergic).
-
Metronidazole
500mg i.v.
-
Gentamicin
120mg i.v.
Post-procedure
2 further doses of
-
Amoxycillin
1g i.v. 8 hourly
-
Metronidazole
500mg i.v. 8 hourly
Have available:
-
Hydralazine i.v. for hypertension (alternatively nitroprusside,
labetalol).
-
Colloids for hypotension.
-
Methylprednisolone.
Usual post angiogram observations (i.e. foot
temperature, peripheral pulses, Tº, BP and HR).
Careful attention to fluid balance is needed.
Daily biochemistry including GGT, CRP, and
haematology for at least 3 days.
Monitor specific tests, e.g. urinary 5-HIAA in
carcinoid syndrome or gut peptides, every other day.
Expect pyrexia and malaise for up to ten days
but perform blood cultures daily until pyrexia subsides.
If abdominal symptoms persist, arrange
appropriate investigations (erect and supine X-rays, U/S abdomen) and ask for a
surgical opinion.
In approximately 60%-80% of patients who have
symptoms from secreting hepatic secondaries there will be an improvement with
embolization. Revascularisation will occur with a recurrence of symptoms after
weeks, months or years. Embolization can be successfully repeated.
Hepatic embolization is not known to prolong
life – this is purely a palliative procedure.
Allison D.M., Br. J. Hosp. Med. 20, 707-715
(1978).
Adjani J.A. et al., Ann. Intern. Med. 108(3),
340-4 (1988).
SGG 11/89; revised BK 7/00 and SS 07/01
Coordinate with
oncology: Prof Waxman’s team.
Patients with established neuroendocrine tumour,
to reduce tumour bulk and improve symptoms
(to monitor renal, hepatic and bone marrow
function, and response to treatment)
·
24.hr urine for creatinine clearance: chemotherapy contraindicated if
<60 ml/min.
·
Urinalysis twice daily during treatment and abandon if persistent proteinuria.
·
FBC and biochemical profile on alternate days.
·
Gut hormone screen and urinary 5HIAA before and after treatment.
·
CT scanning and ultrasound where appropriate.
Streptozotocin 500 mg/m2 | on
alternate days
5-Fluorouracil 400 mg/m2 | for
10 days
Chemotherapy given
during 2nd litre saline, each drug diluted in 10ml normal saline and
administered slowly (1ml/min) via a fast-flowing drip.
Administered with:
1.
0.9% saline i.v. – 3 litres over 12 hours
2. Lorazepam 2mg i.v. | after
1st litre saline
3. Dexamethasone 4mg i.v. | and
30 mins before
4. Metoclopramide 1mg/kg
i.v. over 15 minutes | treatment commences
3–4 courses of chemotherapy are given every 2–3
months.
Response of the tumour is assessed after a
further 6 months
Partial response occurs in
25% carcinoid
20% gastrinoma
60% malignant insulinoma
80% VIPoma
Oberg et al., Acta Oncol. 28, 425 (1989).
To confirm ovulation in a woman WITH PERIODS presenting with
infertility.
1. LH and FSH rise for
approximately 48 hours ("surge") at the onset of the ovulatory phase
of the menstrual cycle.
2. Progesterone production
rises in the ovulatory phase to a maximum during the luteal phase.
3. Basal body temperature
rises by >0.5ºC during the ovulatory phase peaking about 8 days after the LH
surge.
Confirm menstruation. Exclude other causes of
infertility including hyperprolactinaemia, chromosomal problems, and thyroid
dysfunction.
1. Arrange for blood to be
taken on days 18, 21 and 24 for progesterone. Should be undertaken for at least
2 cycles.
2. A more intensive
screening regimen is undertaken in the IVF clinic, and referral is an
alternative option.
3. Blood for progesterone
is taken in red top Vacutainers and may be posted to the lab.
Progesterone >30
nmol/l between days 18 and 24 indicates an adequate luteal phase (production of
progesterone by granulosa cell).
Evidence of ovulation and adequate luteal phase
should prompt further investigation of causes of infertility unrelated to
ovulation or menstrual cycle (husband's sperm count, tube problems etc.). A
postcoital test should be considered if there is no evidence for any of these.
If there is no evidence of ovulation: review
screening tests for other systemic causes of infertility or consider clomiphene
test.
Sverdloff R.S. et al., Endo. Metab. Clin. N.
Amer. 17, 301-332 (1988).
Fertility possible, but may need subcutaneous
gonadotrophins:
Gonal F: 75u twice weekly (=FSH) + profasi
(=hCG) 500 u twice weekly.
Referral to gynaecologists for follicular
tracking essential.
Demonstration of the capacity for ovulation to
be induced in a woman with infertility and anovulation, using clomiphene, a
selective oestrogen receptor modulator.
Pregnancy.
Timing of cycle needs to be explained (first day
of period = day 0).
Women without cycles have to start test at an
arbitrary time.
Rarely causes abdominal bloating. Small risk of
multiple pregnancy.
Rarely, ovarian hyperstimulation with
cardiovascular collapse, ascites and pleural effusions.
1. Give clomiphene for 5
days at dose of 50 mg/day starting at day 5.
2. Blood is taken for
baseline measurements on day 6 and at 2 day intervals between days 18 and 24,
measuring LH, FSH, progesterone and oestradiol.
3. Keep a temperature
chart.
4. If the test is
unsuccessful over 2 cycles, repeat using higher doses of clomiphene (100 and
200 mg/day), cautiously.
A rise in LH and FSH occurs, probably as a
consequence of an anti-oestrogen effect giving a rise in GnRH. This in turn
leads to follicular maturation, oestrogen production, LH release, and
ovulation.
Thus a positive result is a:
rise in LH (to >20
U/l). rise
in FSH (to >10 U/l).
rise in progesterone to
>30 nmol/l.
rise in temperature by
>0.5ºC to help confirm ovulation.
The sensitivity and specificity is poorly
defined. The difficulties with this test are:
a variable response to a
given dose
the mechanism of
clomiphene action is not known
therefore no clear-cut
guidelines for a negative result
The potential value is that a positive result
confirms relatively minor hypothalamo-pituitary dysfunction causing anovulation
that should resolve spontaneously or be easily treated.
Sverdloff R.S. et al., Endo. Metab. Clin N.
Amer. 17, 301-332 (1988).
Steroid levels are usually peaking at about 6am,
and this can be suppressed by 5mg of prednisolone last thing at night. If this
is given, there may be borderline deficiency of steroid first thing in the
morning, so administer 2.5 mg on waking. The nightime dose will suppress not
only adrenal cortisol, but also androgen production, and the morning dose will
prevent hypoadrenalism in the morning.
In a hirsute woman, an adrenal or ovarian
androgen producing tumour must be excluded if testosterone > 5nM (unlikely
anyway, so some authors ignore this and simply repeat testosterone). Tumour can
be excluded if testosterone is suppressed to <3nM after 1 week of reverse
circadian prednisolone.
If ovulation does not occur in confirmed PCOS
(suggested by LH:FSH ratio>3, low SHBG, testosterone between 3 and 5 nM),
give reverse circadian prednisolone. Start with a 3 month course.
Reduce prednisolone as follows if pregnancy
occurs:
Change to normal circadian prednisolone (5mg
mane + 2.5 mg nocte) for 1 week.
Then reduce to 2.5 mg twice daily for 1 week.
Then reduce to 2.5 mg once daily for 1 week.
Then stop prednisolone (within 3 weeks therefore
of discovering pregnancy).
If no pregnancy after 3 months, add clomiphene,
50 mg daily for 5 days of each cycle.
If this also fails, try 100 mg clomiphene daily
for 5 days each cycle.
If this also fails, refer for a gynae opinion.
Metformin can be helpful at regularising
menstruation, but this drug is not licenced for PCOS. Metformin must be stopped
when pregnancy occurs. Metformin is poor in patients looking for reduction in
hirsutism.
1. Collect a sample of
urine shortly after an attack for urinary methyl histamine, which will be
excreted in the following hour. A spot urine is adequate.
2. Also collect a clotted
sample of blood for serum tryptase.
3. Collect a further sample
of urine and blood 24h later to serve as a baseline for comparison.
-
Thus two samples of serum and two samples of urine should be sent
together for assay of urinary methyl histamine and serum tryptase to Chemical
Pathology on a white miscellaneous form.
-
Assays for urinary methyl histamine and serum tryptase are carried out
by Dr John Watkins, Department of Immunology, Northern General Hospital, P.O.
Box 894, Sheffield S5 7YT. Tel: 01742 434343 ext 5728 Fax: 01742 619893
Normal methyl histamine: 5–20 ng/ml.
Typical patient with systemic mastocytosis: >100 ng/ml
Typical patient following beesting: >2000
ng/ml
Normal plasma tryptase <1
KM 7/94
Suspected metabolic muscle disease.
This protocol is from Professor Land at Queen’s
Square.
Contact numbers: 020 7837 3611 / 020 7833 9391.
None.
Warn biochemistry 24 hrs prior to test that
assays for pyruvate, ammonia and lactate will be required.
Tubes for pyruvate: Tubes prepared
in the lab by the addition of 2mls perhexilene and refrigerated overnight. Add
1ml of blood to each tube accurately. Specimens for pyruvate must be handled
carefully and placed on ice and taken to the lab immediately.
Tubes for lactate: Grey top
fluoride oxalate bottles (samples stored on ice).
Tubes for ammonia: 9 paediatric
lithium-heparin tubes (samples stored on ice). The 9th tube is a control, to
measure the background ammonia levels in the samples.
1. Fast from midnight.
2. The patient must spend
the day relaxing, not doing any exercise.
3. 2 people needed to
assist with sampling.
4. Insert i.v. cannula into
large forearm vein with a three-way tap.
5. All specimens should be
free flowing blood.
6. Take baseline bloods (-2
min) for lactate, pyruvate, ammonia, CK, phosphate and uric acid.
-
At each time point
discard 3mls of blood from the cannula, take 1ml for pyruvate in a 2ml syringe
so that the volume is accurate, and 6mls in a 10ml syringe for the rest. Flush
the cannula with normal saline and put the bottles on ice immediately.
7. Place sphygmomanometer on
the cannulated arm and inflate the cuff above systolic pressure. The patient
exercises the arm rhythmically by squeezing some rolled up paper towels or a
ball. The hand must be fully extended
between squeezes. Exercise the hand for 2 minutes.
8. Release the cuff, this
is time = 0.
9. At time 0, 1, 2, 4, 6, 8
and 10 min take blood for lactate, pyruvate and ammonia as above.
-
Normally the lactate rises by 3–5 x baseline.
-
The ammonia rises from 40 µmol/l to about 100 µmol/l.
-
The normal lactate:pyruvate ratio is 10-20 which rises to 30-40 on
exercise.
The lactate test is positive when the patient
exercises and they can’t open their hand fully. The lactate level remains
unchanged, as glycogenolysis is defective. The ammonia level rises dramatically
to 300-400 µmol/l. The lactate to pyruvate ratio is 10-30 and does not change
on exercise.
AP, LS 01/98
|
Compound [MW] |
Conditions |
Reference range |
Sample |
|
STEROIDS & RELATED |
|||
|
Oestradiol [272] |
Early follicular |
<300 pmol/l |
A |
|
|
Late follicular |
400 – 1500 pmol/l |
A |
|
|
Luteal |
200 – 1000 pmol/l |
A |
|
|
Pre–ovulatory |
420 – 1470 pmol/l |
A |
|
|
Post–menopausal |
<250 pmol/l |
A |
|
|
Male |
<250 pmol/l |
A |
|
Oestrone |
Post menopausal |
<260 pmol/l |
A |
|
Testosterone [288] |
Female |
<3.0 nmol/l |
A |
|
|
Male |
10 – 28 nmol/l |
A |
|
5-dihydrotestosterone |
Female |
<1.0 nmol/l |
A |
|
|
Male |
1.0 – 3.0 nmol/l |
A |
|
Androstenedione |
Female |
<10 nmol/l |
A |
|
DHEAS |
Female |
<10 μmol/l |
A |
|
Sex Hormone Binding
Globulin |
Male |
20–40 nmol/l |
A |
|
|
Female |
40–80 nmol/l |
A |
|
Progesterone |
Follicular |
<8 nmol/l |
A |
|
|
Luteal |
30 – 70 nmol/l |
A |
|
|
Post–menopausal |
<8 nmol/l |
A |
|
|
Male |
<8 nmol/l |
A |
|
17-OH progesterone |
|
<10 nmol/l |
A |
|
11-deoxycorticosterone |
|
18–51 nmol/l |
A |
|
Compound S [345] |
Basal |
<23 nmol/l |
A |
|
|
After metyrapone |
230 – 725 nmol/l |
A |
|
Cortisol [362] |
0900h |
200 – 700 nmol/l |
A |
|
|
2400h |
<55 nmol/l |
A |
|
Not acid
bottle unless cats also |
24h urine free (plain bottle) |
55 – 270 nmol/24hr |
U1 |
|
ANTERIOR PITUITARY |
|||
|
ACTH [4500] |
0900h |
<30 ng/l |
C |
|
|
2400h |
<10 ng/l |
C |
|
β-hCG |
non-pregnant |
<2.0 U/l |
A |
|
LH [28000] |
Follicular |
2 – 10 U/l |
A |
|
|
Luteal |
4 – 14 U/l |
A |
|
|
Mid–cycle |
20 – 60 U/l |
A |
|
|
Postmenopausal |
>50 |
A |
|
|
Male |
4 – 14 U/l |
A |
|
FSH [28–41,000] |
Follicular |
1.5 – 8 U/l |
A |
|
|
Luteal |
1.5 – 8 U/l |
A |
|
|
Mid-cycle |
9 – 12 U/l |
A |
|
|
Postmenopausal |
>20 U/l |
A |
|
|
Male |
1.5 – 8 U/l |
A |
|
Prolactin [21000] |
Female |
125 – 625 U/l |
A |
|
|
Male |
75 – 375 U/l |
A |
|
GH [21500] |
During ITT |
>20mU/l |
A |
|
|
During GTT |
<2mU/l |
A |
|
THYROID |
|||
|
TSH [27000] |
|
0.3 – 3.8 mU/l |
A |
|
Free T4 [711] |
|
10.0 – 26.0 pmol/l |
A |
|
Free T3 |
|
2.5 – 5.7 pmol/l |
A |
|
Thyroglobulin |
|
<1 μg/l |
A* |
|
Thyroxine binding
globulin |
|
7 – 17 mg/l |
A |
|
CALCIUM METABOLISM |
|||
|
Calcitonin |
|
<0.08 μg/l |
D |
|
Intact PTH |
Urgent to lab. |
1.1 – 6.8 pmol/l |
C |
|
25-OH vitamin D |
|
7 – 50 μg/l |
B |
|
PEPTIDE HORMONES |
|||
|
Insulin [5807] |
Fasting |
3 – 20 mU/l |
B |
|
C-peptide |
Fasting |
~30 – 75 x insulin |
B |
|
IGF-1 |
Age 41-60 Dependent on age and sex |
7.1 – 30.0 nmol/l |
A |
|
Somatostatin |
Fasting |
<150
pmol/l |
E |
|
GAWK |
Fasting |
<150
pmol/l |
E |
|
Proglucagon |
Fasting |
<50
pmol/l |
E |
|
Gastrin |
Fasting |
<40
pmol/l |
E |
|
VIP |
Fasting |
<30
pmol/l |
E |
|
Neurotensin |
Fasting |
<100
pmol/l |
E |
|
Pancreatic polypeptide |
Fasting |
<300
pmol/l |
E |
|
OTHER ADRENAL HORMONES |
|||
|
Renin |
Erect |
2.8 – 4.5 pmol/ml/h |
F |
|
|
Supine |
1.1 – 2.7 pmol/ml/h |
F |
|
Aldosterone |
Supine |
100 – 450 pmol/l |
A |
|
24 hr urine adrenaline |
|
0.03 – 0.10 μmol/24 hrs |
U2 |
|
24 hr urine
noradrenaline |
|
0.12 – 0.50 μmol/24 hrs |
U2 |
|
24 hr urine dopamine |
|
0.65 – 2.70 μmol/24hrs |
U2 |
|
CARCINOID SYNDROME |
|||
|
24 hr urine 5-HIAA |
|
15.0 – 40.0 μmol/24hrs |
U3 |
A. 7 ml blood into a plain
glass tube (red top Vacutainer) delivered to the lab the same day or kept in a
refrigerator overnight
B. 7 ml blood in a plain
glass tube (red top Vacutainer) delivered to the lab within 30 minutes
C. 4 ml blood in EDTA
(purple top Vacutainer) delivered to the lab IMMEDIATELY to be spun, separated
and frozen.
D. 7 ml blood in a lithium
heparin tube (green top Vacutainer) brought to the lab IMMEDIATELY on ice to be
separated and frozen.
E. 7 ml blood in a lithium
heparin tube (green top Vacutainer) containing 200 μl Trasylol (10,000 KIU
aprotinin/ml) brought to the lab immediately on ice.
F. As for D but NOT on ice.
*Samples analysed off site. Specimens dispatched once a week on Monday.
Three main types of bottles are available for 24
hour urine collections.
1. No Preservative: ELUC (Na+, K+, urea,
creatinine), creatinine clearance, total protein, uric acid, amylase, cortisol,
urinary steroid profile.
2. 10% HCl: (hydrochloric acid): ELUC (Na+, K+,
Urea, Creatinine), creatinine clearance, calcium, phosphate, magnesium,
oxalate, catecholamines, VMA.
3. 25% Acetic Acid: 5-HIAA (5 hydroxy indole acetic acid).
· Requests must be made in
person to a Clinical Scientist (Dr Mandy Donaldson or Mrs S Fernandez)
extension 34681.
· For localisation
studies:
Give at least 1–2 days
notice
Provide lab with
patients name and type of study and starting time.
Keep lab informed if
samples likely to arrive after 5 pm, or if procedure cancelled.
If the samples are to be
delivered within an hour of collection, it is not necessary to collect samples
for PTH and insulin on ice.
ACTH and gut peptides
must be collected on ice.
Diabetes UK 10 Queen Anne Street
London W1M OBD
Tel: 020 7343 1531
Society for
Endocrinology 17/18 The Courtyard
Woodlands
Bradley Stoke
Bristol BS32 4NQ
Tel: 01454 201612
The British Thyroid
Foundation Mrs J Hickey
PO Box HP22
Leeds LS6 3RT
National Osteoporosis
Society Dr J A Dixon
PO Box 10
Radstock
Bath BA3 3YB
Tel: 01761 471771
The Pituitary Foundation 17/18 The Courtyard
Woodlands
Bradley Stoke
Bristol BS32 4NQ
Tel: 01454 201612
National Society for the 1 Church Road
Relief of Paget’s
Disease Eccles
Manchester M30 0DL
Tel: 0161 707 9225
CAH Support Group The Child Growth Foundation
2 Mayfield Avenue, Chiswick
London W4 1PW
Tel: 020 8995 0257
MEDIC alert foundation. 1 Bridge Wharf, 156 Caledonian Road,
London N1
9UU
Tel: 020 7833 3034
Date:
Patient SURNAME: Patient
First name:
Hospital
Number: Date of Birth:
Telephone Number(s):
Next Endocrine OPA:
Diagnosis:
Drugs:
OGTT
Time Glucose GH
(and basal IGF-1)
0
30
60
90
120
150
180
210
240
270
300
Date:
Patient SURNAME: Patient
First name:
Hospital Number:
Date of Birth:
Telephone Number(s):
Next Endocrine OPA:
Diagnosis:
Drugs:
24hr
urinary free cortisols:
midnight
cortisol:
9am
cortisol:
LDDST
cortisol ACTH
9am (“2+0”) basal:
48 hr(“2+48”)
50 hr (“2+50”)
post CRH (2+50+CRH)
HDDST
9am (“8+0”)
(may be same as “2+48”)
48
hr(“8+48”)
24hr Urinary free cortisol
during HDDST:
Date:
Patient SURNAME:
Patient First name:
Hospital Number:
Date of Birth:
Telephone Number(s):
Next Endocrine OPA:
Diagnosis:
Drugs:
Hydrocortisone dose with
timings:
HYDROCORTISONE DAY CURVE
Time cortisol
On arrival
Pre 2nd dose
Post 2nd dose
Pre 3rd dose (or
6pm)
Post 3rd dose
Date:
Patient SURNAME:
Patient First name:
Hospital Number:
Date of Birth:
Telephone Number(s):
Next Endocrine OPA:
Diagnosis:
Drugs:
SST
Time Cortisol ACTH
(basal only)
0
30
60
(LST continues:)
2 hrs
4hrs
8hrs
24hrs
Date:
Patient SURNAME: Patient
First name:
Hospital Number: Date
of Birth:
Telephone Number(s):
Next Endocrine OPA:
Diagnosis:
Drugs:
|
TIME |
URINE / VOLUME |
PLASMA |
|
0830 |
Discard
urine |
|
|
0900 |
Þ |
Collect
P1 |
|
0930 |
Collect U1 ml |
|
|
1130 |
Discard
urine |
|
|
1200 |
Þ |
Collect
P2 |
|
1230 |
Collect U2 ml |
|
|
1430 |
Discard
urine |
|
|
1500 |
Þ |
Collect P3 |
|
1530 |
Collect
U3 ml |
|
|
1600 |
Þ |
Collect P4 |
|
1630 |
Collect
U4 ml |
|
|
Now give DDAVP i.m. or intranasally |
||
|
1730 |
Collect
U5 ml |
|
|
1830 |
Collect
U6 ml |
|
|
1930 |
Collect
U7 ml |
|
|
2030 |
Collect
U8 ml |
|
Date:
Patient SURNAME:
Patient First name:
Hospital Number:
Date of Birth:
Telephone Number(s):
Next Endocrine OPA:
Diagnosis:
Drugs:
Dose
pamidronate given:
Calcium
3 days later: