Transcript Endocrinology- Thyroid Function Tests.

Endocrinology- Thyroid
Function Tests.
GROUP C:
Wedyan Meshreky
Helen Naguib
Sharon Naguib
Ms MS, aged 40 years, has been taking Lithium carbonate
therapy (1000mg/d) for the last 6 weeks as a mood stabiliser.
She also takes the following medications on a regular basis:
Hydrochlorothiazide 50mg d
Verapamil 240mg d
What effect does lithium have on thyroid function? What clinical
chemistry tests should be performed and why? Explain any
concerns you might have. Describe analytical protocols for
evaluation of the hypothalamic and pituitary control of the
thyroid gland. Describe the clinical application of the results of
these investigations.
Lithium - Background
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DOC in the treatment of bipolar manic-depressive
disorder.
Low therapeutic index
Recommended therapeutic plasma lithium
concentration is 1.0-1.5mmol/L1 in acute mania and
0.6 to 1.2 mmol/L1 during long term control.
Serum levels should not exceed 2mmol/L
Lithium is highly concentrated in the thyroid gland,
probably by active transport
Lithium inhibits the secretion of T4 and T3 by poorly
understood mechanisms. This results in an increase in
pituitary secretion of TSH.
Lithium and Thyroid Function
Lithium can cause:
– Goiter
– Hypothyroidism
– Chronic autoimmune thyroiditis
- Hyperthyroidism
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Goiter
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Generally it presents as a smooth enlargement of
the thyroid gland and requires no further
intervention.
Can occur within several weeks of initiation of
lithium therapy; although, in most cases, it may
take months to several years for a goiter to occur.
Euthyroid goiter occurs in 4-12% of patients.
Hypothyroidism
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Occurs in Approximately 10% of Lithium – treated
patients, predominantly female.
Can be with or without goiter.
Usually sub clinical
Responds to treatment with thyroxine; generally not
necessary to stop lithium treatment.
Observed more frequently in patients with prior history of
a damaged thyroid gland.
Few patients may have overt hypothyroidism with all of its
usual signs and symptoms.
Chronic Autoimmune
Thyroiditis
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Inflammation of the Thyroid.
Rare - occurs in approximately 0.7%.
Cause is not clear. Some authors have speculated that
lithium may directly stimulate autoimmune reactions.
Possibility that these patients have underlying chronic
autoimmune thyroiditis.
Hyperthyroidism
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In a recent retrospective analysis, the incidence of
hyperthyroidism in patients treated with lithium was more
than three times greater than the incidence of
thyrotoxicosis in the general population.
However, there have been suggestions that this
hyperthyroidism is random and not due to lithium.2
What clinical chemistry tests
should be performed and why
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Thyroid function tests should be run
routinely whenever a person is suspected of
having bipolar disorder, since a
misbehaving thyroid gland can produce
symptoms of mania or depression.
…cont
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Before starting Lithium, patients should have a careful
thyroid physical examination and TFT’s including T4, T3
test, TSH, free T4 index and antithyroid antibodies.
If a patient is hypothyroid before Lithium treatment,
Thyroxine may be started.
Patients with normal thyroid function, need to have TFT’s
every 3-6 months. If there are changes in thyroid function,
there is a possibility that thyroid function tests may
normalize over 6 months to 2 years with continuous
lithium treatment.
Other tests…
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Renal function tests. (dose must be reduced)
Complete blood counts periodically.
Periodic electrocardiograms.
Lithium serum levels (greater than 2 mmol/L, although
toxic symptoms may occur at levels greater than 1.5
mmol/L).
Explain any concerns you might
have…
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DRUG INTERACTIONS:
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Lithium & HCT: concurrent use can lead to d Li
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conc.  Li toxicity (weakness, tremor, excessive
thirst, confusion..)
Mechanism: reabsorption of Na and Li ions at
proximal renal tubule  Li retention
Concomitant use should be avoided
Li levels should be monitored within the first week:
lower Li doses may be needed
Concerns..
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Li & Verapamil: concurrent use can result in
decreases in Li conc, leading to exacerbation
of manic psychosis
Serum Li levels should be monitored
periodically
Px’s should be followed closely for signs of
manic psychosis, & any symptoms of
neurotoxicity (ataxia, tremors, tinnitus,
nausea, vomiting or diarrhoea)
TSH
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1st generation assays using RIA had
poor sensitivity (limit of 1mU/L)
Disadv: cross reactivity with
gonadotrophins (eg LH, FSH, hCG)
sharing with TSH a common ‘a’ subunit
Newer TSH assays using immunometric
assay more sensitive and accurate
TSH immunometric assay
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One Ab directed against the ‘a’ subunit serves
to anchor the TSH molecule
Another Ab usually a monoclonal Ab directed
at the ‘b’ subunit is either
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Radioiodinated: Immunoradiometric assay (IRMA)
Conjugated: with – an enzyme :
Immunoenzymometric assay (IEMA)
- a chemiluminescent compound:
Chemiluminescent assay (ICMA)
Principle
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TSH serves as the link between an
immobilised Ab binding TSH at one epitope &
a monoclonal Ab directed at a 2nd part of the
molecule
Eg. IEMA: one Ab is attached to magnetic
particles and the other is labelled with
Alkaline Phosphastase. There are 4 stages to
the assay,  uses spectrophometry and abs
measured at 550nm or 492nm
Principle..
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Signal is directly related to amount TSH
Greater sensitivity and decreased
interference from related compounds
2nd, 3rd and 4th generation assays have
higher sensitivity (~0.005-0.01mU/L)
TRH
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TRH test: administering 500mcg IV
synthetic TRH to measure the increase
of pituitary TSH in serum
Normally: rapid rise in TSH levels, peaks
in 30min, decreasing to normal by
120min
In primary hypothyroidism: rise is
exaggerated
TRH..
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Useful in distinguishing pituitary from
hypothalamic hypothyroidism
20 to pituitary deficiency: absent/impaired
TSH response to TRH
Hypothalamic disorder: normal amounts of
TSH..delayed peak and prolonged elevation
Hyperthyroidism: TSH release remains
suppressed
TRH test rarely used now to diagnose thyroid
dysfunction due to the availability of newer
TSH assays
Thyroid Gland
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Secretes thyroid hormones (TH) which
control our metabolic rate in 2 ways:
Stimulates every tissue in body to produce
proteins
Increases amount of O2 that cells use.
Thyroid Hormones
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Gland requires Iodine to produce thyroid hormones.
TH affect heart rate, resp. rate, growth, heat
production, fertility, digestion, rate at which we
burn calories etc.
The two hormones are:
T4- Thyroxine
T3- Triiodothyronine
T4 is the major hormone produced but it is
converted to T3 in the liver and other tissues.
T3 is the more active hormone.
Controlling the level of TH
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Firstly the hypothalamus secretes TRH which causes
the pituitary gland to produce TSH.
TSH then goes on to stimulate the gland to produce
TH.
What is the clinical application of
these investigations?
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By measuring TSH and the level of TH,
thyroid dysfunction (hyperthyroidism or
hypothyroidism) and the cause can be
determined.
Hyperthyroidism
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Excessive thyroid hormone activity.
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Causes:
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Grave’s disease
Toxic multinodular goiter or adenoma
Silent thyroiditis
Iodine induced hyperthyroidism (eg amiodarone,
lithium)
Excessive pituitary TSH
Excessive ingestion of thyroid hormone
Signs & Symptoms
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Nervousness & Irritability
Palpitations & tachycardia
Heat intolerance & increased sweating
Tremor
Frequent bowel movements (diarrhoea)
Weight loss (or gain)
Fatigue or muscle weakness
Diagnosis of Hyperthyroidism
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Hyperthyroidism of any cause results in a low
levels of TSH and high levels of free T4.
If TSH is low and FT4 is normal, serum T3 should
be measured. If elevated this condition is called
T3 toxicosis.
If TSH, T3 and T4 are elevated, then diagnosis
for a TSH-secreting tumour is confirmed.
During severe illness, TSH, T4, & T3 levels often
fall outside normal ref. Ranges so, clinical
assessment should be made in conjunction with
laboratory assessment.
Treatment of Hyperthyroidism
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Surgical intervention
Antithyroid drugs
Radioactive iodine
Hypothyroidism
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Results from under-secretion of TH from the
thyroid gland.
Most common causes:
Hashimoto’s disease (chronic autoimmune
thyroiditis)
Surgical removal of thyroid gland, thyroid
gland ablation with radioactive iodine etc
Secondary causes: pituitary or hypothalamic
disease.
Sign & Symptoms
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Fatigue
Weight gain from fluid retention
Dry skin and cold intolerance
Coarseness or loss of hair
Goitre
Constipation
Depression
Hyperlipidaemia
Bradycardia
Hypothermia
Diagnosis of 1o
hypothyroidism
Elevated TSH levels with low to normal FT4.
 Presence of antithyroid peroxidase antibodies
are present in almost all patients with
Hashimoto’s.
 2o Hypothyroidism: due to dysfunction of
hypothalamic-pituitary axis:
Eg. low TSH and T4 may be due to deficient
secretion of TRH from the hypothalamus or
secretion of TSH from the pituitary.
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Additional testing
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May be necessary in rare cases in which a doctor
cannot determine whether the problem lies in the
thyroid or in the pituitary gland.
One of these tests involves injecting TRH IV and
then measuring the level of TSH in the blood to
determine the pituitary gland's response.
If cancer of the thyroid gland is suspected, a
biopsy is performed.
When medullary thyroid cancer is suspected,
blood levels of calcitonin are checked, because
these cancers always secrete calcitonin.
Cont…
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Ultrasound scan uses sound waves to measure
the size of the gland and to determine whether
the growth is solid or filled with fluid (cystic).
Uses radioactive iodine or technetium and a
device to produce a picture of the thyroid gland
that will show any physical abnormalities.
Thyroid scanning can also help determine
whether the functioning of a specific area of the
thyroid is normal, overactive, or underactive
compared with the rest of the gland.
Summary
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Hyperthyroidism:
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PRIMARY:  T4 and TSH
SECONDARY: T4 and  TSH
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Hypothyroidism:
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PRIMARY:  T4 and  TSH
SECONDARY:  TSH and  T4