This document discusses thyroid function tests (TFTs) and provides guidance on their interpretation. There are three main patterns of abnormal TFT results: 1) TSH and T4 abnormal in opposite directions, indicating true thyroid disease. 2) TSH and T4 abnormal in the same direction, which could indicate central disease, spurious results, or recent medication adherence issues. 3) T4 alone is abnormal, which may be due to binding globulin issues. The document reviews the four thyroid hormones, their regulation and production. It provides tips on when to order free T4/T3 tests and discusses various causes of abnormal TFT results, including non-thyroidal illness, medication effects, and binding globulin disorders

1. TFT Interpretation
Dr Raseena vattamkandathil
MEM Resident

2. Reasons Why TFTs Can Be A Confusing Topic
❏ The interpretation of TFTs seems like it should be easy, and mostly it is.
❏ However a minority of TFTs won't conform to what logic suggests
❏ Confusing terminology
● “Thyroid hormone”- generally refers to T3 and T4
● There are a total of 4 hormones directly involved in the regulation of
thyroid gland activity

3. Thyroid hormone regulation
❏ Thyroid releasing hormone
from hypothalamus stimulate
anterior pituitary to release
TSH
❏ TSH
1) Increase the release of
preformed thyroid
hormone
2) Increases formation of
thyroid hormone

4. 1. Iodine trapping
2. Synthesis and secretion of
thyroglobulin
3. Oxidation of iodides
4. Organification of thyroglobulin
5. Coupling reaction
6. Storage

5. Thyroid hormone biosynthesis and storage
1. Iodine trapping
2. Synthesis and secretion of
thyroglobulin
3. Oxidation of iodides
4. Organification of thyroglobulin
5. Coupling reaction
6. Storage

6.  Thyroid secrete predominantly T4 (~90%), and a small
amount of T3 (~10%)
 >99% of Thyroid hormones are plasma protein bound
in the circulation (mainly Thyroxine binding globulin)
 The biological activity of T3 is much greater than T4
 Peripheral tissues convert T4 to T3

7. Thyroid function tests
Common TFTs
1. TSH
2. Free T4 and T3
(FT4,FT3)
Rarely ordered TFTs:
1. Total T4 and T3
2. TRH
3. Thyroxine binding
globulin
4. Thyroglobulin

8. FT4
+/-
FT3
TSH
Low High
Low Central Hypothyroidism
(Primary pituitary failure)
Primary
Hypothyroidism
(Primary thyroid
failure)
High Primary Hyperthyroidism Secondary
Hyperthyroidism
(ie TSH producing
tumor)
Basic TFT Interpretation

10. Measuring T3/4 is not routinely necessary….
Not recommended for
● Routine screening
● Low probability of thyroid disease
● Routine monitoring in treated primary hypothyroidism
Why? Many factors can cause mild abnormalities of total and free T3/ T4 in
euthyroid patients..
Clinical connundrum→ Normal TSH, Abnormal T3/T4, Normal appearing patients

11. ……..But is important in some situations
1. Suspected or known central thyroid disease: Mainly central
hypothyroidism
2. High suspicion of overt thyroid disease
3. Recent change in thyroid status (< 4- 6 weeks)
 thyroid hormone started in severe hypothyroidism
 Recently post-thyroidectomy
 Recent methimazole/ PTU start for hyperthyroidism

12. Assays # Truth
There are limitations to every TSH, total hormone, and free
hormone assays that are unrelated to physiologic or pathologic
changes in the patient
Examples:
● Interfering antibodies
● Biotin high doses Interferes with TSH and T4 assays

13. Thyroid Antibodies
 Thyroid peroxidase antibody (TPO- Ab)
Thyroid peroxidase catalase production
of thyroid hormone
 Thyroglobulin antibody (Tg- Ab)
Thyroglobulin + Iodine = hormones
 Thyroid stimulating immunoglobin (TSI)
 TSH Receptor Antibody Stimulatory antibodies that
bind to thyroid cells

14.  There is a very high background
prevalence of TPO and
thyroglobulin antibodies
 So don’t check routinely
 Up to 25% positivity in some
populations
 As you get older up to 20% can
have high TPO antibodies

15. Clinical use of Thyroid Antibodies
 TPO Antibodies are useful in predicting eventual hypothyroidism in patients
at risk
 Borderline high TSH or euthyroid goiter
 Positive family history
 Before starting high-risk meds ( Amiodarone, Lithium, IFN )
 Thyroglobulin- Antibodies
 Not predictive of thyroid dysfunction
 Thyroglobulin is a cancer marker so  Monitoring thyroid cancer
patients

16.  Not common in the general population
 Identifying cause of hyperthyroidism in equivocal cases,
especially when a thyroid scan is not feasible (eg
Breastfeeding)
 +ve TSI  Graves disease
*Do not treat antibodies
*Do not follow antibody trends in hypo or hyperthyroidism
TSI and TSH - R Ab

17. Overt and Subclinical Thyroid Dysfunction*
1. TSH and T4 are abnormal in the opposite direction
2. TSH is abnormal with normal T4- Subclinical

18. Overt Hypothyroidism
 Autoimmune/ Hashimoto’s
 Surgery or I-131 Ablation
 Iodine deficiency
 Medications
○ Amiodarone
○ Lithium
○ IFN
○ TKIs (Sumatinib), Radiation
TSH
Total or Free T4
Treatment→ Levothyroxine adjusted
every 6-12 weeks based on TSH

19. Subclinical Hypothyroidism
❏ Aka “mild hypothyroidism”
❏ Same possible causes as overt hypothyroidism
❏ Mostly early autoimmune or medications
 Normal in elderly to have mild elevation in TSH
 Always consider other causes of isolated elevated TSH besides thyroid disease
❏ May or may not be symptomatic
TSH
Total or Free T4 Normal

20. To treat or not to treat….?
❏ Treat if TSH > 10
● Cardiovascular parameters like lipids improve with
treatment
● Most get overt disease in a few years
❏ If TSH : 4.5 - 10: Observe or treat based on other factors

21. Refractory hypothyroidism on levothyroxine
Common:
 Adherence issues
 Addition of oestrogen
 Absorption interference
 Fe, Ca, MVI, Fibre
 PPI
 GI Disease
LT4 Loading test may help
differentiate between the two

22. Overt Hyperthyroidism
❏ Graves disease
❏ Toxic multinodular goiter
❏ Toxic uninodular adenoma
❏ Iodine load in susceptible
gland
❏ Thyroiditis
❏ Exogenous thyroid hormone
Mx→ Methimazole/PTU, I-131, Sx Mx→ Beta blockers, NSAIDS and steroids
for subacute
TSH
Total or Free T4 *
(Sometimes normal, but then will have increased total/ Free T3)

23. Subclinical Hyperthyroidism
❏ Same possible causes as overt hyperthyroidism
❏ Mostly early Graves or hyperfunctioning nodules
 May be physiologic in some african american women
to have low TSH
 Should always consider other causes of isolated low
TSH besides thyroid disease
❏ May or may not be symptomatic
Treat if TSH < 0.1 - 0.2 in patients > 60yrs or with CV risks Observe or
treat others based on CVS and bone risks
TSH
Total or Free T4 Normal
Make sure total or free T3 is normal if the patient appears symptomatic before labelling
“Subclinical”

24. “Always think drugs when TFTs don’t make sense”

25. Case
❏ 58 year old man admitted to ICU with pneumonia and
respiratory distress requiring intubation
❏ Improves with antibiotics and supportive care and is
extubated on day 3
❏ Mental status does not return to base line
❏ TSH - .05 (Team is concerned about central
hyperthyroidism)
❏ Further labs: T4- 5.1 (5.5 - 11.0), T3- 0.8 (1.0- 1.7)
❏ Vitals stable, Ambulating and eating, moderately
confused
What underlying
thyroid condition is
likely

26. Abnormal TFTs in Non thyroidal
illness
❏ Abnormal thyroid function tests in critically ill patients in
absence of any underlying thyroid problem
❏ Multiple reasons: Cytokines, Inhibitors of deiodinase, Altered
TBG
❏ Main pattern “looks like ” central hypothyroidism: Low TSH,
T4, and T3 (Free T4 may be normal or high)
❏ Pattern is transient and improves as the patient recovers

27. Case 2
❏ 66-year-old woman with long standing hypothyroidism
pn stable dose of levothyroxine 112 mcg/day x 3 years
❏ k/c/o HTN/HLD/Sellar meningioma
❏ Examination normal except for BMI- 32
❏ TSH .01, Dose reduced : 100→ 75→ 50→ off, but TSH
remains low
❏ Referred for evaluation of hyperthyroidism
❏ Exam now with HR-52, BP -136/98, periorbital edema,
thick voice, delayed reflexes and non-pitting edema ie
She looks hypothyroid
What happened?

28. Central or Secondary Hypothyroidism
Causes
❏ Tumour
❏ Infarction, apoplexy, TBI
❏ Surgery
❏ Infiltrative diseases
(Sarcoid, Lymphoma, mets)
❏ Hypophysitis (Autoimmune,
ipilimumab)
Clues
❏ Mass effect symptoms
❏ Symptoms or signs of other
pituitary deficiencies
● Amenorrhea
● Hypogonadism
● Adrenal insufficiency

29. Central or Secondary Hypothyroidism
Differentiating from primary
hypothyroidism is important
❏ Address underlying cause
❏ Replace other pituitary
hormone deficits if needed,
especially cortisol
Management:
❏ LT4 is adjusted to keep FT4 or
total T4 in the upper end of
normal and patient is clinically
euthyroid

30. TSH low + T4 low
1. Non thyroidal illness*
2. Central hypothyroidism
3. Overtreatment with regimen that includes T3
Free T4 may be low, normal or high in non-thyroidal illness

31. TSH High + Total/Free T4 high
❏ Recent compliance with LT4 therapy
❏ Drugs that impair conversion of T4 to T3(eg Amiodarone)
❏ Central hyperthyroidism, ie TSH secreting pituitary
adenoma

32. Abnormal total T4/T3
❏ High total T4/T3 alone
● Exogenous estrogens, SERMS (Tamoxifen),
pregnancy
● Congenital high TBG
❏ Low total T4/T3 alone
● TBG loss
● Congenital low TBG

33. Abnormal Free T4/T3
High free T4/T3 alone
❏ Drugs that increase dissociation
of T4 from TBG
● Heparin
● Furosemide
● Salicylates
❏ Sometimes mildly high with
TBG deficiency states
Low free T4/T3 alone
❏ Phenytoin, Carbamazepine
❏ Pregnancy 3rd trimester
❏ Sometimes mildly low with TBG
deficiency states

34. SUMMARY
❏ TSH is the best screening test for suspected primary thyroid dysfunction
❏ Order T4/Free T4 if you:
1. Suspect central thyroid dysfunction
2. Have high suspicion for primary thyroid dysfunction
3. Need to assess thyroid function after recent (< 4-6 week prior)
change in thyroid status

35. 3 Basic patterns of Abnormal TFTs……
T4 alone is
abnormal
03 ● Binding globulin issue
TSH and T4 abnormal in
same direction
02
● True central disease
● Spurious result from meds
● Recent adherence
TSH and T4 abnormal in
opposite direction
01
True disease
(If TSH alone is abnormal→Subclinical
thyroid disease)

36. TSH Total T4 Free T4 Diagnosis
Overt hypothyroidism
Normal Normal Subclinical hypothyroidism + Other causes of TSH
Overt hyperthyroidism
Normal Normal Subclinical hyperthyroidism + Other causes of TSH
/ Normal NTI, Central hypothyroidism, Armour/ T3 treatment
/ Normal Recent adherence to LT4, Amiodarone, TSH resist,
TSH secreting Pituitary tumor
Normal Normal High TBG states, esp high estrogen states
Normal Normal Low TBG states, central hypothyroidism
Normal Normal Heparin, furosemide
Normal Normal Pregnancy 3rd trimester

37. THANK YOU!!