Approaah to Interpretation of Thyroid Function Tests

1. Approach to
Thyroid Function Tests
Indications for TFT
• Clinical suspicion of thyroid disease.
• Newborn: heel prick test for TSH for early detection of neonatal
hypothyroidism.
• Woman:
o Pregnant.
o Planning to be pregnant.
o Post-partum: 4 – 8 weeks.
• Elderly.
• Drug exposure: Amiodarone, Lithium.
• History of neck irradiation.
• Autoimmune diseases as T1DM.

2. Hypothalamic Pituitary Thyroid
(HPT) Axis
Primary Disorder
(Hypo or Hyperthyroidism)
Secondary Disorder
(Pituitary)
Tertiary Disorder
(Hypothalamic)
Central

3. T4 T3
Plasma
Concentration
• Total
• Free
70 times more
7 times more
Free Fraction 0.03 % 0.3 %
Relative Potency Mainly
a prohormone
Nearly 10 times
more potent
T ½ 6 – 7 days 1 – 2 days
Source 100 % thyroid 20% thyroid
80% peripheral
deiodination of T4
(largely in the liver)

4. T2
Idothyronine Deiodinases
D2
D2D3
D3

5. Binding Proteins
• TBG (Thyroxine Binding Globulin).
• TBPA (Thyroxine Binding Prealbumin) (Transthyretin).
• Albumin (non- specific binder).
↑ Bininding Proteins (mainly TBG) → ↑ TTH, but usually fTH
adjusts
• Hyperestrogenaemia:
o Pregnancy
o Oestrogens
o Contraceptive pills
o Gonadotrophins, eg, for IVF
o Clomiphine (↑ gonadotrophins)
o SERM (selective estrogen receptor modulators) as Raloxifene
• Other drugs: Opiates, Fibrates, Nicotinic Acid
• Congenital hyperthyroglobulinaemia (euthyroid hyperthyroxinaemia)

6. ↓ Bininding Proteins (mainly TBG) → ↓ TTH, but usually fTH
adjusts
• Acute, chronic illness (-ve acute phase reactants)
• Fasting, starvation
• Liver disease
• Kidney disease (nephrotic syndrome)
• Drugs:
o Androgens
o Corticosteroids
o Anticonvulsants as phenytoin, primidone
• Congenital hypothyroglobulinaemia (euthyroid hypothyroxinaemia)
Familial Dysalbuminaemic Hyperthyroxinaemia
Albumin has increased affinity for TH binding
↑ TTH but usually fTH adjusts

7. Displacement of Thyroid Hormones
from Plasma Protein Binding Sites
• Hereditary disorders producing lower affinity binding proteins
• Drugs competing for the binding sites
o Heparin (unfractionated or low molecular wt.) → Stim of
lipoprotein lipase → liberation of FFA which compete with TH for
plasma protein binding sites → artefactual hyperthyroxinaemia if
fTH are assed in patients on heparin therapy, eg, HD patients
(Sample should be taken 10 hh after last heparin injection)
o Frusemide
o Salicylates
o NSAIDs
o Phenytoin
↓ TTH but usually fTH adjusts

8. TSH
• TSH remains the most commonly used endocrine test in clinical
practice.
• TSH stimulates cellular growth and vascularity of thyroid gland.
• It stimulates several follicular cell functions:
• Iodide trapping
• Iodide organification
• Thyroid hormone release
• The negative feedback control of TSH by TH generates a log linear
relationship between TSH and TH so that small changes in TH lead to
much amplified counter-regulatory TSH changes. So, TSH is usually
the 1st
TFT to fall out of the reference interval (though it is relatively
wide). So, TSH is regarded as the best initial screening test for thyroid
disorders in most circumstances.

9. • TSH is the most sensitive and specific test for investigation and
management of 1ry thyroid dysfunction (but may be misleading alone
in the rare central thyroid dysfunction).
•A TSH value within the reference range excludes most cases of 1ry
overt thyroid disease.
• TSH shows a diurnal variation of up to + 50% with peak after
midnight and nadir in afternoon.
• This variation has minimal effect on serum T4, bec hourly T4
secretion rate (3 – 5 ug) represents a very small fraction of the
extrathyroidal T4 pool (500 – 600 ug).
• In pregnancy, TSH ↓ during 1st
trimester then gradually returns to
pre-pregnancy value
• TH (conversely) ↑ during 1st
trimester then gradually return to pre-
pregnancy value (or even ↓ below the reference range in 3rd
trimester)
• Some labs report trimester specific reference ranges.

11. 0.3 - 5 > 105 - 10< 0.03 0.03 – 0.3
Normal
(0.4 – 4.5)
Requires
treatment
Requires
treatment
Requires
follow up
for confirmation
and assessment of
other indicators for
treatment
Requires
follow up
for confirmation
and assessment of
other indicators for
treatment
0.1 was the boundary
between these 2 categories
in older references when
TSH values below 0.1 were
difficult to measure
Interpretation of TSH values if TH values are normal:
Subclinical
Hyperthyroidism
Subclinical
Hypothyroidism

12. • The distribution of TSH values within the refernce range is not
normal, with the median values (also depending on population iodine
intake) usually between 1 – 1.5 mU/L
• This signifies that values in the range of 2.5 – 4.5 mU/L may
(particularly in younger persons) indicate subtle hypothyroidisn
(though these values do not justify for the definition of subclinical
hypothyroidism).

13. Thyroid Hormones
• T4 utilization rate ↓ progressively with age after birth from
10 ug/kg/day in 1st
few days of life to 1- 2 ug/kg/day in adult life.
This last figure is used to guide thyroxine replacement therapy
(Eltroxine or Euthyrox tablets, 50, 100 ug)
• Total and free T3, T4 ↓ more modestly with age.
• rT3 ↑ with age
• There is little or no change due to puberty, gender or racial variation.
• Specific normal reference ranges are advocated for age groups,
pregnancy trimesters and puerperium.

14. 1ry Thyroid Disorders
• Defined by either ↓ (hypo) or ↑ (hyper) TH with reciprocal
(and actually earlier and more evident) changes in TSH.
• Considered subclinical if TSH abnormal while TH still within normal.
• Subclinical thyroid disorders are relatively common:
o Subclinical hypothyroidism: 4 – 8% (up to 20% in women > 60Y)
o Subclinical hyperthyroidism: 2%

15. Etiology of 1ry Thyroid Disorders
1ry Hypothyroidism 1ry Hyperthyroidism
• Congenital
• Iodine deficiency (endemic
goitre)
• Iodine induced (Wolff Chaikoff
effect)_transient
• Autoimmunity
• Post thyroiditis
– Subacute: transient
– Chronic: persistent
• Post thyroid ablation:
– Thyroidectomy
– Radio-Iodine
• Graves` disease
• Toxic multinodular goitre
The 2 commonest causes
• Toxic nodule
• Iodine induced (Jod Basedow
effect)_transient
• Early thyroiditis (subacute or
chronic) (transient)
• Ectopic TH, eg, struma ovarii
• Excess thyroxine (factitious
thyrotoxicosis)

16. Subclinical
Hypothyroidism
Subclinical
Hyperthyroidism
• Progression to frank
hypothyroidism.
• Menstrual irregularities,
subfertility.
• Adverse pregnancy outcome
(abortion, neonatal
hypothyroidism).
• Dyslipidaemia.
• Atherosclerotic CVD (CAD, MI,
PAD).
• ↑ All cause, cardiovascular
mortality.
• Progression to frank
hyperthyroidism.
• Menstrual irregularities,
subfertility.
• Adverse pregnancy outcome
(abortion, neonatal
hyperthyroidism).
• Atrial fibrillation
• Osteoporosis
• Cardiac dysfunction
• ↑ All cause, cardiovascular
mortality.
Health Risks of Subclinical 1ry Thyroid Disorders

17. Indicators for Need for Treatment
in Subclinical 1ry Thyroid Disorders
Subclinical Hypothyroidism Subclinical Hyperthyroidism
• TSH > 10 mU/L
• Follow up TSH (after 3 months)
progressively increasing.
• Clinical features possibly
attributed to hypothyroidism.
• Therapeutic trial → favourable
clinical and/or TSH response.
• History of prior thyroid
dysfunction.
• Other autoimmune disorders, eg
T1DM.
• Woman with family history of
thyroid disease.
• Woman who is pregnant or
planning to be pregnant.
• +ve Anti TPO Ab / Dyslipidaemia
•TSH < 0.1 (0.03) mU/L
• Follow up TSH (after 3 months)
progressively decreasing.
• Clinical features possibly
attributed to hyperthyroidism.
• Therapeutic trial → favourable
clinical and/or TSH response.
• History of prior thyroid
dysfunction.
• Other autoimmune disorders, eg
T1DM.
• Woman with family history of
thyroid disease.
• Elderly.

18. Non-Thyroidal Illness (NTI) (Syndrome)
Euthyroid Sick Syndrome
Low T3 Syndrome
• The most common biochemical abnormality of endocrine function
among medical inpatients.
• Abnormal TFT (mainly low TT3) are present in > 70% of ICU patients,
with 50% having low TT4.
• Non- Thyroidal Illness: the most widely adopted name nowadays.
It implies an illness that manifests as abnormal TFT in absence of
intrinsic thyroid disease.
• Euthyroid sick syndrome: was based on the observation that,
despite TFT abnormalities, there is no clinical features of thyroid
dysfunction and no conclusive benefit from treatment.
• Low T3 syndrome: describes the earliest and most common and
characteristic abnormality, present even in the mildest forms.

19. Mechanisms of NTI
Central Hypothyroidism
• Malnutrition → ↓ leptin → ↓ TRH
• Inhibition of TRH, TSH secretion by increased local T3 dt stim of dopamine
(D2) receptors by
o Sepsis, inflammation
o Dopamine, dopaminergic drugs
↓ Plasma Protein Binding Capacity for Thyroid Hormones (↓TH)
These proteins are –ve acute phase reactants. They ↓ dt:
• ↓ Synthesis
• ↑ Breakdown
• Movement out of plasma space
• ↓ Binding affinity
↑Thyroid Hormone Degradation and/or Excretion
This may be the most important factor responsible for acute drop in T3

20. Changes in Deiodinase Activity
These changes are triggered by:
• Hormonal changes: ↑ glucocorticoids, glucagon
• ↑ Proinflammatory cytokines as IL-1, IL-6, TNF-α
• ↑ Free radicals, heavy metals
• ↓ Vit B12, zinc
Although change in deiodinase activity is a plausible mechanism, it does not
play a major role in the acute drop of T3 and it may be a consecuence rather
than a cause for this.
Contrary to other
deiodinases, D2 is
retained in the
endoplasmic reticulum,
so it is particularly adept
at supplying T3 for local
use in hypothalamus,
pituitary, brown adipose
tissues and muscles.
Tissues w express D1 as
liver, kidney export
much of the T3
produced to plasma

21. Patterns of NTI
• Changes involve mainly the total hormone levels; changes in free fractions are
only modest.
• T3 ↓, and T4 ↓ to a lesser extent → ↓ BMR, ↓ protein and fat catabolism.
• Whether these changes are adaptive or maladaptive remains controversial.
• Different patterns were described:
Low T3 Syndrome (70%)
• Commonest and present to some degree in other patterns
• T3 falls rapidly and progressively within ½ - 24hh of onset of causative illness
• rT3 is increased
Low T3, T4 Syndrome (30%)
• Observed in severely ill patients admitted to ICU
• T4 falls over a period of 1 – 2 days
High T4 Syndrome (1%)
• Acute psychiatric illness
• Hepatitis (↑ binding protein production)
• Iodine exposure

23. Other Abnormalities
↓ Nocturnal TSH surge, unrelated to ambient circulating T4, T3 levels, but
probably related to hypothalamic dysregulation
Changes during Recovery
A transient rise in TSH consistently precedes restoration of T3, T4 levels.
Neither the fall of TH during NTI nor the rise in TSH during recovery justify
thyroid hormone treatment.
Importance of NTI
• Diagnosis to be able to differentiate between TFT abnormalities
indicative of NTI and those indicative of intrinsic thyroid disease.
• Prognosis
Thyroid function disturbances correlate with disease severity.
Low TH predict poor prognosis.
• Treatment
In order not to give unnecessary or even harmful treatment

24. Patterns of Abnormal TFT
TSH
TH
• 1ry hyperthyroidism
• NTI (esp acute
psychiatric illness)
• THR
• Early thyroiditis
• NTI (esp acute
psychiatric illness)
• Central
hyperthyroidism
• THR
• NTI (esp acute
psychiatric illness)
• Recovery from NTI
•Subclinical
hyperthyroidism
• 1ry hyperthyroidism
early on treatment
• Thyroxine overdose
• NTI
• Normal
• Properly treated
hypo or
hyperthyroidism
• Subclinical
hypothyroidism
• 1ry hypothyroidism
early on treatment
• AntiThyroid overdose
• NTI (recovery)
• Central
hypothyroidism
• NTI
• NTI (main
presentation)
• Late thyroiditis
1ry hypothyroidism
N↓ ↑
N
↓
↑

25. Auto Antibodies in Thyroid Disease
• Most thyroid disorders are autoimmune in nature.
• Look for thyroid disorders in patients with autoimmune diseases
and look for autoimmune diseases in patients with thyroid disorders.
• 3 AutoAntibodies are the most important:
TPOAb (Thyroid Peroxidase Ab)
• Previously called antimicrosomal Ab (AMA)
• Associated with 1ry hypothyroidism
TRAb (Thyrotropin Receptor Ab)
• Previously called LATS (long acting thyroid stimulator) or
TSI (thyroid stimulating Ig).
• Associated with Graves` disease
• Correlates with activity and severity of thyroid associated ophthalmopathy
Anti TBG
* Associated with Hashimoto thyroiditis

26. Thyroglobulin Level
• Differentiates between Graves` disease (elevated) and factitious
thyrotoxicosis (decreased).
• Useful for detection of recurrence of differentiated thyroid cancer

27. Approach for Discordant TFT
• Re-evaluate the clinical history.
• Age: neonatal period / elderly
• Pregnancy.
• NTI.
• Underlying iodine deficiency →
Wolff Chaikoff effect / Jod Basedow effect
• Thyroxine therapy.
• Medications.
• Exclude TH, TSH assay interference.
• Investigate for rare disorders of HPT function.