Transcript Presentation - Pakistan Society Of Chemical Pathology

Pakistan Society of Chemical Pathologists
Distance Learning Programme in Chemical Pathology
Lesson No 2
Thyroid Functional Disorders
By
Surg Commodore Aamir Ijaz
MCPS, FCPS, FRCP (Edin)
Professor of Pathology / Consultant Chemical Pathologist
Bahria University Medical & Dental College /
PNS SHIFA Karachi
and
Dr Lena Jafri
FCPS (Chem Path)
Instructor Chemical Pathology
Department of Pathology and Microbiology; Extension 1931
Aga Khan University
02/04/2016 13:20
1
Q 1. A 26 year Pakistani female has lethargy
and bradycardia. Screening of thyroid
dysfunction should be carried out by:
a.
b.
c.
d.
e.
T3 and T4 estimation only
TSH and Free T4
TSH and T4
TSH only
TSH, T3 and T4 estimation
d. TSH only1
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2
TSH Only Strategy for Thyroid Screening
• The measurement of TSH in a basal blood
sample by a sensitive immunoassay
provides the single most sensitive,
specific and reliable test of thyroid status
in thyroid disorders.
• Thyroid dysfunctional disorders with
normal TSH are very rare.
• So in many countries ‘TSH only’ strategy
is adopted for the diagnosis.
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3
Reflexive testing for
Thyroid Dysfunction
Serum TSH normal — no further testing
performed
 Serum TSH high — free T4 added to
determine the degree of hypothyroidism
 Serum TSH low — free T4 and T3 added
to determine the degree of
hyperthyroidism

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Some exceptions to TSH only Strategy
Measure serum TSH with Thyroid hormones:
 In a young woman with amenorrhea (e.g.
Sheehan`s Syndrome).
 If the patient has convincing symptoms of
hyper- or hypothyroidism despite a normal
TSH result.
 In critical ill patients with strong suspicion
of a thyroid disorder
 Some other rare situations
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Q 2: Serum T4 of a patient decreased
from 3.0 pg/ml to 1.5 pg/ml. The
expected change in TSH is:
a.
b.
c.
d.
e.
Fifty fold increase in TSH
One hundred fold increase in TSH
Ten fold increase in TSH
Two fold decrease in TSH
Two fold increase in TSH
b. One hundred fold increase in TSH2
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Sensitivity of TSH
(Hormone from Mother Gland)
If
T4 halves, TSH increases by
100 fold or even more
If T4 doubles, TSH decreases
by 100 fold or even less
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Q 3: A 65 year old female has following thyroid profile:
Serum fT3
2.16 pg/ml
Serum fT4
1.34 ng/ml
Serum TSH
5.62 mIU/L
The most probable diagnosis in this patient
a.
b.
c.
d.
e.
(1.60-4.20)
(0.70-1.68)
(0.30-4.0)
is:
Normal thyroid profile for the age
Primary Hypothyroidism
Secondary Hypothyroidism
Sick Euthyroid Syndrome
Sub-Clinical Hypothyroidism
e. Sub-Clinical Hypothyroidism1
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Subclinical Hypothyroidism
(SHO)
• Subclinical hypothyroidism is defined
biochemically as a normal T4
concentration in the presence of an
elevated TSH.
• Clinical symptoms may or may not be
present
• So it can only be diagnosed on the basis
of laboratory test results.
• It is also called ‘Mild Hypothyroid Disease’
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What is Elevated TSH?





Upper limit of TSH is important in defining SHO.
Many surveys have recommended upper limit to
be 2.5 mU/L.
But consensus is on 4.0 to 4.5 mU/L.
A higher upper limit is suggested in very
advance age (e.g.> 80 y) but without any
agreement.
So we use 4.0 mIU/L as upper limit.
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Causes of SHO
Causes of SHO are the same as of Overt
Hypothyroidism (High TSH, Low T4).
 SHO is far more common than overt
disease e.g. among all hypothyroid 7080% are SHO.

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Treatment of SHO
Patients with TSH > 8-10 mU/L should be
treated.
 Controversy over treatment in patients with
TSH 4-8 mU/L (in both children and adults).
 In patients with TSH 4-8 mU/L treatment
should be considered in pregnancy and in
patients with hyperlipidaemia and heart
disease, etc.

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Q 4: A 68 year old male admitted with pneumonia
and sepsis has following thyroid profile.
Serum fT3
Serum TSH
0.16 pg/ml
0.22 mIU/L
(1.60-4.20)
(0.30-4.0)
a. Secondary Hyperthyroidism
b. Secondary Hypothyroidism
c. Sick Euthyroid Syndrome
d. Sub-Clinical Hyperthyroidism
e. Thyroid crisis
c. Sick Euthyroid Syndrome1
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Non Thyroidal Illness
(sick euthyroid syndrome)


Non Thyroidal Illness (sick euthyrodism) is
characterized by Normal / low TSH and
low T3 and/ or T4.
It is a protective response of body in
chronic illness to reduce metabolism
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Low T3 is common in critical illness
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Thyroid function in nonthyroidal illness

Thyroid function should not be assessed in
seriously ill patients unless there is a
strong suspicion of thyroid dysfunction.

If you suspect thyroid dysfunction in a
critical patient then TSH assay may be
accompanied by T4.
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
Critically ill patients with low serum T3
and low T4 SHOULD NOT BE TREATED
with thyroid hormone
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Q 5: A 22 years female had undergone total
thyroidectomy after a diagnosis of thyroid
carcinoma. She is on thyroid replacement therapy.
Which of the following values constitutes an
important part of the treatment goals in this
patient:
a.
b.
c.
d.
e.
Serum
Serum
Serum
Serum
Serum
Free T3
Free T4
TSH
TSH
Thyroglobulin
d. Serum TSH
02/04/2016 13:20
<
>
>
3 nmol/L
22 pmol/L
2- 3 mIU/L
< 0.2 mIU/L
> 40
mg/L
0.2 mIU/L1,3
19
Thyroid Function Testing
in Thyroid Cancer






TSH has to be kept very much suppressed after
surgery for thyroid cancer
This is done by giving exogenous thyroid
hormone.
British Thyroid Association has recommended
TSH level suppressed to <0.10mU/L3
The serum FT4 should be elevated
So in these patients TSH and FT4 do not need to
be within the ‘reference range’;
However, clinical features of over treatment
should be noted.
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Target TSH value in Patients with
Thyroid Malignancy
 TSH may provide stimulation of
any remnant thyroid secondaries
 A higher dose of thyroxin is given
to the patient to suppress TSH.
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Serum Thyroglobulin (Tg) and
Thyroglobulin Antibodies (TgAb)
It is an excellent marker for monitoring
treatment of thyroid cancers but only in patients
with total thyroidectomy or 131iodine ablation.
 In such patients detectable serum Tg (>2ug/L)
is highly suggestive of residual or recurrent
tumour. So the treatment goal is < 2ug/L (and
not in the ref range).
 TgAb is recommended to be measured at the
same time as Tg to exclude interference of
endogenous TgAb in Tg assays
 Tg has no rule in diagnosis of thyroid cancer.

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Monitoring of Hypoparathyroidism
in patients with Thyroid Cancer
 In
patients with total thyroidectomy
or 131iodine ablation,
hypoparathyroidism will be present
 So Ca, P and Mg has to be monitored
and kept within reference range.
02/04/2016 13:20
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Q 6:
A 24 years female is pregnant for 10 weeks. She has severe nausea,
excessive vomiting, electrolyte disturbances, and weight loss of more than 5%
of body weight. She has no goitre or exophthalmos. Her Thyroid profile shows:
Serum Free
Serum T4
Serum TSH
T3
3.26
ng/ml
1.80 pg/ml
0.12 mIU/L
(1.60-4.20)
(0.70-1.68)
(0.30-4.0)
Most probable diagnosis in this patient is:
a.
b.
c.
d.
e.
Gestational Hyperthyroidism
Grave`s Disease
Overt Hyperthyroidism (requiring immediate treatment)
Sick Euthyroid Syndrome
Sub-clinical Hyperthyroidism
a. Gestational Hyperthyroidism1
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Effects of Pregnancy on
Thyroid Biochemistry
Physiologic Change
Thyroid-Related Consequences
↑ Serum thyroxine-binding globulin
↑ Total T4 and T3; ↑ T4 production
↑ Plasma volume
↑ T4 and T3 pool size; ↑ T4
production; ↑ cardiac output
D3 expression in placenta and (?) uterus
↑ T4 production
First trimester ↑ in hCG
↑ Free T4; ↓ basal thyrotropin; ↑ T4
production
↑ Renal I- clearance
↑ Iodine requirements
↑ T4 production; fetal T4 synthesis during
second and third trimesters
↑ Oxygen consumption by fetoplacental
unit, gravid uterus, and mother
02/04/2016 13:20
↑ Basal metabolic rate; ↑ cardiac
output
26
Q 7: A 34 year female underwent TRH stimulation
test which showed a peak of TSH at 30 minutes
which comes to baseline by 60 minutes.
The patient is most probably having:
a.
b.
c.
d.
e.
Hypothalamic Hypothyroidism
Normal Axis
Pituitary Hypothyroidism
Primary Hyperthyroidism
Primary Hypothyroidism
b. Normal Axis2
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Q 8: You are a newly appointed Consultant Chemical
Pathologist in a Public Sector Hospital. You find that
Thyroid profile (TSH, T3 and T4) are carried out in a
nearby Government Nuclear Medical Centre on a
Radioimmuno- Assay (RIA). The patients get reports after
2-3 weeks and there are problems in clinical correlation,
too. Several commercial firms are ready to provide you
Hormone Autoanalysers based on Chemiluminescence
methodology on Reagent Rental basis.
Considering the above mentioned scenario please answer
following queries:
a. Give THREE advantages of replacing RIA with this
Chemiluminescence –based system.
b. Running test cost is a big issue in Chemiluminescence –based
systems. How will you justify this additional expenditure?
c. What thyroid-testing strategy you will formulate to reduce the
workload to a rationalized level?
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Radioimmunoassay (RIA)
and Chemiluminescence


RIA (Antigen labeled classical Radioimmunoassay) is a
First Generation TSH Assay. It has detection limits of
about 1 mU/L. It is not sufficiently sensitive to
distinguish between normal serum TSH concentrations
and the low serum TSH concentrations present in most
patients with hyperthyroidism.
IRMA (Antibody labeled immunometric assay) is a
Second Generation TSH assay having detection limit of
about 0.1 mU/L. Again these assays are not good
enough to evaluate TSH levels in Hyperthyroidism
02/04/2016 13:20
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Radioimmunoassay (RIA) and
Chemiluminescence (Cont)



Chemiluminescence assay (Third generation TSH assay)
has detection limit of about 0.01 mU/L. This can,
therefore, provide detectable TSH measurement even in
mild hyperthyroidism.
In order to reliably detect values of serum TSH in the
hyperthyroid range, one needs a Third Generation assay
with a functional sensitivity of at least ≤0.05 mU/L.
Chemiluminescence assay can easily differentiate serum
TSH values in patients with hyperthyroidism from those
in euthyroid patients because of the considerably lower
detection limit, even with poor quality control.
02/04/2016 13:20
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Suggested answer of
a.
1,2
Q.8
Chemiluminescence has following
advantages over RIA:
i.
Can perform highly sensitive TSH assay to
clearly differentiate Hyperthyroidism from
normal
ii. Random access autoanalysis is available. So
no need to wait for batch analysis as in RIA.
iii. No hazards of radioactivity and disposal is
not a problem.
02/04/2016 13:20
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Suggested answer of Q.8 (cont)
b. Justification of higher running cost
i.
No down payment and good maintenance
service due to Reagent Rental System.
ii. Better patient satisfaction as they can get
reports within hours instead of weeks.
iii. Decision making by physicians can be
quickened and hospital stays will be
reduced.
iv. Better clinical correlation due to highly
sensitive assay.
02/04/2016 13:20
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Suggested answer of Q.8 (cont)
c. Strategy to rationalize work load
i. TSH should be done as the first test
ii. Since 70-80% patients have normal tests,
they will not require T3 or T4
iii. Patients with higher TSH may undergo T4 as
a reflex testing.
iv. T3 and T4 may be done in patients with low
TSH.
v. Clinical colleagues can be persuaded by an
awareness campaign.
02/04/2016 13:20
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Q 9: During mandatory screening on 4th day of life,
a neonate had following TSH result:
TSH: 33.2 mIU/mL
a. What is the most probable diagnosis in this
baby?
b. Write THREE clinical features you will like to see
in this patient for confirmation of the diagnosis?
c. If no signs or symptoms are found would you
still strict to your diagnosis?
d. What immediate actions you will like to take to
prevent the child from adverse effect of the
disease?
02/04/2016 13:20
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Clinical Features of
Congenital Hypothyroidism (CH)
 The
vast majority (more than 95
percent) of infants with congenital
hypothyroidism have few if any
clinical manifestations of
hypothyroidism at birth
 The signs and symptoms may be so
subtle that they can be easily missed.
Clinical Features of CH (Cont)












Constipation
Lethargy
Prolonged jaundice
Hypotonia
Umbilical hernia
Large fontanels
Slow movement
Hoarse cry
Feeding problems
Macroglossia
Dry skin
Hypothermia
Cut off limits for TSH
 Normal
< 15 IU/L
 Borderline 15 – 30 IU/L
 Hypothyroidism >30 IU/L
Exclusion of Transient CH
It is important to perform TFT on the
mother in cases with abnormal results
 History of anti-thyroid medication
ingestion during the pregnancy should be
obtained
 Exclude the possibility of placental transfer
of maternal antibodies that block the
action of TSH.

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Treatment of CH
Ideally treatment should be initiated in an infant
with a clearly positive screening test as soon as
confirmatory blood samples have been drawn,
pending results.
 In cases in which screening tests are borderline,
a treatment decision can be made after results
of the confirmatory tests return
 Treatment should NEVER be delayed beyond 18
days of life.

Treatment of CH (Cont)
Immediate diagnosis and treatment of
congenital hypothyroidism in the neonatal
period is critical to normal brain
development and physical growth
 There is an inverse relationship between
age at clinical diagnosis and treatment
initiation and intelligence quotient (IQ)
later in life, so that the longer the
condition goes undetected, the lower the
IQ
 Treatment for CH is lifelong.

Suggested answer of
a.
1
Q.9
Most probable diagnosis
Congenital Hypothyroidism
Most Common Clinical features
The most common neonatal symptoms are
constipation, lethargy, and prolonged
jaundice while the most common physical
signs are hypotonia, umbilical hernia, and
large fontanels
b.
02/04/2016 13:20
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Suggested answer of Q.9 (Contd)
c. Yes. In many babies the change may be so
subtle that it may be missed clinically.
d. This baby requires urgent thyroxin replacement.
The
paediatrician
should
be
informed
immediately. Venous serum sample should be
drawn for TSH and T4 by chemiluminescence
(usually neonatal screening is not done on
immunoassays). The paediatrician will start
thyroxin after sending the sample. Mother
should also undergo Thyroid Function Tests
and TgAb to rule out Transient CH.
02/04/2016 13:20
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Q 10: A 72 years female has following thyroid profile:
Serum fT3
2.26 pg/ml
(1.60-4.20)
Serum TSH
0.11 mIU/L
(0.30-4.0)
Your Physician colleague has referred the case to you with
following queries:
a. What is the most probable diagnosis in this
case?
b. Should anti-thyroid treatment be started in this
patient?
c. What are the dangers if this patient is not
given anti-thyroid treatment for some time?
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Sub-Clinical Hyperthyroidism (SHE)



Low serum TSH concentrations (<0.5 mU/mL) but
normal free T4 and fT3 concentrations, a constellation of
biochemical findings defined as subclinical
hyperthyroidism.
The term overt hyperthyroidism refers to patients with
elevated levels of free T4, T3, or both, and a subnormal
TSH concentration.
Both subclinical and overt hyperthyroidism are
biochemical definitions since hyperthyroid symptoms are
non-specific and may be present in patients with
subclinical disease, and absent in those with overt
disease, especially the elderly
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Types of SHE

Exogenous SHE: is the term used to describe
hyperthyroidism caused by ingestion of
excessive amounts of thyroid hormone.

Endogenous SHE: Autonomously functioning
thyroid adenomas and multi-nodular goiters are
the most common causes of endogenous SHE.
Nearly 57% patients with multi-nodular goiters
have SHE.
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Adverse effects in SHE
Increased Bone Resorption: i.e. Osteoprosis
and susceptibility to fractures
 Cardiovascular Effects: e.g.

– Atrial Fibrillation
– Coronary Artery Disease
– Heart Failure etc.

Poor Quality of Life: e.g. Disturbances in
sleep and decreases in some physical
functions
 Dementia
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Incidence of Atrial Fibrillation over
age 60 based on TSH Level
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Patients of SHE with Higher Risk
Elderly patients >65 years
 Patients with risk factors for cardiac
arrhythmias
 Postmenopausal women with or at risk for
osteoporosis

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Consideration for treatment of SHE
Patients at high risk for complications
In patients at high risk use the following approach:
 If the serum TSH value is <0.1 mU/L, treat the patient.
 If the serum TSH is 0.1 to 0.5 mU/L, treatment if there is:
– underlying cardiovascular disease
– the bone density is low.
– one or more focal areas of high uptake (ie, evidence of
autonomy. Subclinical hyperthyroidism due to autonomous
nodule(s) is more likely to progress to overt hyperthyroidism
than is subclinical hyperthyroidism due to Graves' disease).
 Measure TSH, free T4, and T3 every six months if the above
mentioned features are not present.
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Consideration for treatment of SHE (Contd)
Patients at low risk for complications
In patients at low risk for complications of
hyperthyroidism (young individuals,
premenopausal women), use the following
approach:
– If the serum TSH value is <0.1 mU/mL, treat if the patient has
symptoms suggestive of hyperthyroidism and/or if a thyroid
radionuclide scan shows one or more focal areas of increased
uptake.
– If the TSH is between 0.1 to 0.5 mU/mL, observation alone is
appropriate i.e. measure TSH, free T4, and T3 every six months.
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Suggested answer of
1,3,4
Q.10
Diagnosis
Subclinical Hyperthyroidism
b. Since the patient is >65 years treatment should
be considered if following co-morbidities are
present:
a.
• Presence of heart disease
• Osteoprosis
• Symptoms of hyperthyroidism
Otherwise just monitor by repeating tests after an appropriate
interval.
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Suggested answer of Q.10 (cont)
c. If treatment is delayed in spite of
presence of above mentioned features she
may develop cardiac arrhythmias or
fractures and poor quality of life.
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Q 11: A 24 year female has menstrual irregularities and has
not conceived one year after marriage. Her hormonal
profile is as following:
•
Serum TSH:
> 100 mIU/L
(0.30-4.0)
•
FSH:
9 mIU/mL
•
LH:
34 mIU/mL
•
Prolactin:
41 ng/ml
(7-26)
•
Testosterone:
3.4 nmol/L
Consultant Gynaecologist has referred the patient to you
for your opinion regarding:
a. Hormonal Diagnosis of the patient.
b. Most probable cause(s) of increased Prolactin.
c. Should anti-prolactin treatment given to her
alongwithThyroxin?
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Suggested answer of Q.111
a.
Hormonal Diagnosis
– Primary Hypothyroidism
– Hyperprolactinaemia
– Hormonal Features of PCOS i.e. Increased LH:FSH ratio,
Hyperandrogenaemia and Hyperprolactinaemia
(Plz note that in Secondary and Tertiary Hyperthyroidism TSH is not
that high and they are extremely rare conditions)
b.
Increased prolactin may be secreted due to:
– High TRH as a result of Primary Hypothyroidism may cause
stimulation of pituitary to release prolactin.
– Hyperprolactinaemia is also a known feature of PCOS
– Prolactin may be secreted from a microadenoma in pituitary.
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Suggested answer of Q.11 (cont)
c.
Patient should be treated for :
– Primary Hypothyroidism i.e. Tab Thyroxin
after confirmation of diagnosis by repeating
TSH with T4.
– PCOS e.g. Metformin.
– Hyperprolactinaemia with specific medicines if
prolactin levels remains high when TSH
decreases markedly.
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References
1.
2.
3.
4.
UpToDate. (online) Cited on 22 Mar 2013. Available at:
https://www.uptodate.com
Demers LM and Spencer C. The Thyroid:
Pathophysiology and Thyroid Function Testing. In
Burtis CA, Ashwoods ER and Bruns DE, (edi) Teitz
Textbook oF Clinical Chemistry. 4th ed. W. B. Saunders
Company; 2006;pp 2053-2095.
UK guidelines for the Use of Thyroid Function British Thyroid Association (online) Cited on 22 Mar
2013. Available at: www.british-thyroidassociation.org/Guidelines/
Cooper DS. Approach to the Patient with Subclinical
Hyperthyroidism. J Clin Endocrinol Metab.2007;92:3–9.
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Thank You
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