1. 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
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2. Q 1. A 26 year Pakistani female has lethargy and bradycardia
Q 1. A 26 year Pakistani female has lethargy and bradycardia. Screening of thyroid dysfunction should be carried out by:
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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3. 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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4. 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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5. 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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6. Q 2: Serum T4 of a patient decreased from 3. 0 pg/ml to 1. 5 pg/ml
Q 2: Serum T4 of a patient decreased from 3.0 pg/ml to 1.5 pg/ml. The expected change in TSH is:
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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7. 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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8. e. Sub-Clinical Hypothyroidism1
Q 3: A 65 year old female has following thyroid profile: Serum fT pg/ml ( ) Serum fT ng/ml ( ) Serum TSH mIU/L ( ) The most probable diagnosis in this patient 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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9. 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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10. 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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11. 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 70-80% are SHO.
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12. 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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13. Secondary Hyperthyroidism Secondary Hypothyroidism
Q 4: A 68 year old male admitted with pneumonia and sepsis has following thyroid profile. Serum fT pg/ml ( ) Serum TSH mIU/L ( )
Secondary Hyperthyroidism
Secondary Hypothyroidism
Sick Euthyroid Syndrome
Sub-Clinical Hyperthyroidism
Thyroid crisis
c. Sick Euthyroid Syndrome1
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14. (sick euthyroid syndrome)
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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15. Low T3 is common in critical illness
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17. Thyroid function in non-thyroidal 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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18. Critically ill patients with low serum T3 and low T4 SHOULD NOT BE TREATED with thyroid hormone
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19. 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:
Serum Free T > nmol/L
Serum Free T > pmol/L
Serum TSH mIU/L
Serum TSH < mIU/L
Serum Thyroglobulin > mg/L
d. Serum TSH < mIU/L1,3
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20. 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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21. 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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22. 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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23. 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.
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24. a. Gestational Hyperthyroidism1
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 T ng/ml ( ) Serum T pg/ml ( ) Serum TSH mIU/L ( ) Most probable diagnosis in this patient is:
Gestational Hyperthyroidism
Grave`s Disease
Overt Hyperthyroidism (requiring immediate treatment)
Sick Euthyroid Syndrome
Sub-clinical Hyperthyroidism
a. Gestational Hyperthyroidism1
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26. 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
↑ Basal metabolic rate; ↑ cardiac output
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27. 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. Hypothalamic Hypothyroidism b. Normal Axis c. Pituitary Hypothyroidism d. Primary Hyperthyroidism e. Primary Hypothyroidism
b. Normal Axis2
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29. 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:
Give THREE advantages of replacing RIA with this Chemiluminescence –based system.
Running test cost is a big issue in Chemiluminescence –based systems. How will you justify this additional expenditure?
What thyroid-testing strategy you will formulate to reduce the workload to a rationalized level?
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30. 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
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31. 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.
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32. Suggested answer of Q.81,2
Chemiluminescence has following advantages over RIA:
Can perform highly sensitive TSH assay to clearly differentiate Hyperthyroidism from normal
Random access autoanalysis is available. So no need to wait for batch analysis as in RIA.
No hazards of radioactivity and disposal is not a problem.
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33. Suggested answer of Q.8 (cont)
b. Justification of higher running cost
No down payment and good maintenance service due to Reagent Rental System.
Better patient satisfaction as they can get reports within hours instead of weeks.
Decision making by physicians can be quickened and hospital stays will be reduced.
Better clinical correlation due to highly sensitive assay.
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34. Suggested answer of Q.8 (cont)
c. Strategy to rationalize work load
TSH should be done as the first test
Since 70-80% patients have normal tests, they will not require T3 or T4
Patients with higher TSH may undergo T4 as a reflex testing.
T3 and T4 may be done in patients with low TSH.
Clinical colleagues can be persuaded by an awareness campaign.
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35. 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?
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36. 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.

37. Clinical Features of CH (Cont)
Constipation
Lethargy
Prolonged jaundice
Hypotonia
Umbilical hernia
Large fontanels
Slow movement
Hoarse cry
Feeding problems
Macroglossia
Dry skin
Hypothermia

38. Cut off limits for TSH Normal < 15 IU/L Borderline 15 – 30 IU/L
Hypothyroidism >30 IU/L

39. 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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40. 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.

41. 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.

42. Suggested answer of Q.91 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
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43. 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.
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44. What is the most probable diagnosis in this case?
Q 10: A 72 years female has following thyroid profile: Serum fT pg/ml ( ) Serum TSH mIU/L ( ) Your Physician colleague has referred the case to you with following queries:
What is the most probable diagnosis in this case?
Should anti-thyroid treatment be started in this patient?
What are the dangers if this patient is not given anti-thyroid treatment for some time?
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45. 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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46. 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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47. Adverse effects in SHE Dementia
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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48. Incidence of Atrial Fibrillation over age 60 based on TSH Level
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49. 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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50. 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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51. 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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52. Suggested answer of Q.101,3,4 Diagnosis Subclinical Hyperthyroidism
Since the patient is >65 years treatment should be considered if following co-morbidities are present:
Presence of heart disease
Osteoprosis
Symptoms of hyperthyroidism
Otherwise just monitor by repeating tests after an appropriate interval.
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53. 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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54. a. Hormonal Diagnosis of the patient.
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 ( ) • FSH: mIU/mL • LH: mIU/mL • Prolactin: ng/ml (7-26) • Testosterone: 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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55. Suggested answer of Q.111 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)
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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56. 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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57. References
UpToDate. (online) Cited on 22 Mar Available at:
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
UK guidelines for the Use of Thyroid Function - British Thyroid Association (online) Cited on 22 Mar Available at:
Cooper DS. Approach to the Patient with Subclinical
Hyperthyroidism. J Clin Endocrinol Metab.2007;92:3–9.
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58. Thank You
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