Thyroid Function Tests Case Study B

1. Thyroid Function TestsCase Study B Presented by: Owen Naidoo Abdullah Osman Christine Tanzil Ayse Togac

2. Ms MA (a middle-aged woman) presents to A&E with: • History of abdominal pain • Vomiting • Features of sepsis.

3. Investigations resulted in the diagnosis of: • Ruptured appendix (surgically removed) • Peritonitis

4. Her post-op recovery was complicated by: • Transient oliguric renal failure • Pneumonia

5. Her TFT results 6 days post-op were as follows:

6. She did not have clinical symptoms of thyroid dysfunction or a goitre and so throxine treatment was not commenced. Thyroxine

7. Two weeks post-op her TFT results were as follows and still she displayed no clinical signs of thyroid disorder:

8. After a further three weeks, her TFT results were as follows: She also had a strongly positive peroxidase antibody  thyroxine treatment was commenced.

9. Some definitions… • Thyroid Stimulating Hormone (TSH) • The levels of TSH are controlled by the pituitary gland depending on the circulating levels of thyroxine • Synthesises thyroid hormones from iodide and tyrosine residues • Thyroid hormones: • These hormones are released into the peripheral circulation when required through a negative feedback system • T4: is broken down in the peripheral circulation into T3 and r-T3 • T3 and r-T3 should be found in the same proportions

10. What is hypothyroidism? • Hypothyroidism occurs in patients where there are insufficient levels of thyroid hormones • There are two types: • Congenital hypothyroidism • Acquired hypothyroidism

11. Congenital hypothyroidism • Primary hypothyroidism • This is the most common cause of congenital hypothyroidism • Secondary hypothyroidism • This occurs when the pituitary gland produces insufficient amounts of TSH (thyroid stimulating hormone)

12. Acquired hypothyroidism • Acquired hypothyroidism is caused by the thyroid gland being damaged (e.g. cancer therapy etc) • Primary hypothyroidism • The most common cause is Hashimoto’s disease • Secondary hypothyroidism • Is caused by a pituitary tumour • Tertiary hypothyroidism • Is caused by a hypothalmic tumour

13. Signs & Symptoms… • Weakness/ Lethargy/ Slowness • Cold intolerance • Memory loss • Weight gain • Dry skin • Change in voice (deepening) • Mild anaemia/pernicious anaemia • Effusions: pericardial, pleural, peritoneal & joint spaces

14. PART 2 • TASKS • ANALYSE MA’S RESULTS • ARE THEY CONSISTENT WITH HYPOTHYROIDISM?

15. TFT 6 DAYS POST OPP 14 DAYS POST OPP 35 DAYS POST OPP REFERENCE FT3 <1 3-8 pmol/L FT4 5 8 11 10-25 pmol/L TSH 6 11 7 0.4-4 mU/L MRS MA’S TFT RESULTS At 35 days tested strongly positive peroxidase antibody  thyroxine commenced

16. SUMMARY OF MA’S TFT’S POST OP • DAY 6 • Decreased FT4, elevated TSH • Day 14 • Decreased FT4, elevated TSH • Day 35 • Normal FT4, elevated TSH

17. GRAPH SHOWING RELATIONSHIP OF MA’S TSH TO FT4

18. DIAGNOSING MRS MA • WHAT DO WE KNOW: • MA does have elevated TSH suggests hypothyroidism • Most common cause of HT in the US is Hashimoto’s Disease. • MA is middle aged female  likely candidate for Hashimoto’s • Strongly positive peroxidase antibody (an autoantibody) • Positive autoantibodies in 95% of cases of Hashimoto’s • Advanced Hashimoto’s: low FT4, high TSH • MA low FT4, elevated TSH BUT later normal FT4.

19. GRAPH SHOWING RELATIONSHIP OF MA’S TSH TO FT4

20. READING TIME TFT RESULTS POSSIBLE DISEASE STATE Possibly initially Low FT4, low TSH NTI (sepsis etc.) (aka euthyroid sick syndrome) 6 DAYS PO Low FT4, high TSH Recovery phase of NTI, advanced Hashimoto’s 12 DAYS PO Low FT4, high TSH Recovery phase of NTI, advanced Hashimoto’s 35 DAYS PO Normal FT4, high TSH Subclinical hypothyroidism, recovery phase of NTI, POSSIBLITIES FOR MRS MA

21. CONCLUSION • +ve antibody strongly suggests Hashimoto’s • But why the drastic changes in TFT’s? • ?MA has a subclinical hypothyroidism disorder (typical of early Hashimoto’s disease) • Unknown to patient since asymptomatic. • During her illness she suffered from NTI which decreased her FSH and T4 • On recovering, levels return to her regular levels of subclinical hypothyroidism.

22. TO TREAT OR NOT TO TREAT • During stay at hospital (NTI)  controversial • Are patients TSH values decreasing and T4 values increasing? • If yes  no need to treat. • If no  controversial but guidelines recommend: • treat if TSH>10mU/L or • if TSH 5-10 mU/L and +ve peroxidase Ab &/ goitre (AACE, 2002).

23. WHY DO WE TREAT EVEN IF ASYMPTOMATIC • Avoid progression to overt hypothyroidism (3-20%, increased if +ve Ab) • Decrease • CV effects, • dyslipidemia, • neuropsychiatric events

24. The Results…

25. What are the likely explanations for this series of TFT results? • Hashimoto’s Thyroiditis • Subclinical Hypothyroidism • Euthyroid Sick Syndrome (aka NTI)

26. 1. Hashimoto’s Thyroiditis • Refers to autoimmune disorders of the thyroid gland. • Antibodies and WBC’s damage the thyroid gland • Due to excess WBC’s and fluid in the thyroid gland a ‘goitre’ is produced, leading to destruction of thyroid cells  & HYPOTHYROIDISM • Destruction of thyroid gland decreases T4 production and as a results TSH increases which makes the goiter even larger. • In this condition thyroid antibodies and usually low; however this is not the case for Ms MA (‘…..strongly positive peroxidase antibody’)

27. 2. Subclinical Hypothyroidism • Scenario characterised by a normal serum T4 and moderately high TSH levels. (N.B T3 levels are usually normal and thus don’t provide much extra in terms of diagnosis) • Serum antithyroid antibodies against peroxidase are usually, but not always, positive (as witnessed by Ms MA)

28. 3. Euthyroid Sick Syndrome • Situation whereby patients with other non-thyroidal illnesses may have abnormal TFTs, mainly because of decreased peripheral conversion of T4 to T3 and decreased binding to TBG. • Clinical features of Euthyroid Sick Syndrome include low T3; normal or low T4 and variable TSH.

29. Describe analytical principles behind free T4 measurement…

30. What is free T4? • Free T4 or thyroxine is unbound and hence biologically active and responsible for the regulation of thyroid function through the pituitary feedback mechanism. Besides being a more specific indicator of thyroid function than total T4, free T4 is not subject to the spontaneous fluctuations or drug-induced changes that occur with total T4.

31. Principles of free T4 measurement… • Principle methods for measuring free T4 is as follows: • Equilibrium Dialysis (ED) • Equilibrium Dialysis:-FT4 measured directly by a sensitive RIA in the dialysate • Ultrafiltration • Direct Immunoassays • Free T4 index method

32. Free T4 determination by Equilibrium Dialysis • The serum is put inside the cylinder where bound is separated from free hormone. • The gold standard for measuring free T4 is overnight equilibrium dialysis of serum containing 125I-T4. -The percentage of free T4 is calculated by determining the total counts in the dialysate divided by the total 125I-T4 added to the serum multiplied by the total T4 concentration

33. Free T4 determination by Ultrafiltration • Ultrafiltration has almost the same principle as ED. • The serum has labelled T4 and this is filtered against a protein free buffer. • Free T4 concentration is worked out as: radiolabelled iodine is inversely proportional to free T4 concentration.

34. Free T4 determination by Immunoassays • There is a one step and two step method for calculating free T4 concentration by immunoassay (IAS). • Step 1 method: This method is based on the assumption that structurally modified and labelled analogues of T4 will not bind to serum thyroid hormone binding proteins but will compete with free T4 for binding to the T4 antibody introduced in the assay.

35. Free T4 determination by Immunoassays (cont) • Radio-labelled T4 analogue is added to anti-T4 antibody. • The serum is added to the anti-T4 antibody simultaneously. • Competition occurs and both T4 is removed. • Then you measure proportion of labelled T4 that became antibody bound.

36. Step 2 method: • Free T4 in patient serum is removed by binding to T4 antibody, which is attached to a solid phase. • The serum is then removed. • Next, Radio-labelled 125I-T4 is incubated with the solid phase that has unbound sites available. • Radio-labelled 125I-T4 is removed and activity is quantified.

37. Free T4 determination by Index method • The index method requires two independent tests. • One measuring total serum T4 and the other measuring thyroid hormone-binding ratio or T3 resin uptake. • The free T4 index is then calculated using the total T4 and the TBG level, the thyroid binding ratio, or T3 resin uptake. • The index is directly proportional to the free T4 level.

38. Advantages and Disadvantages • Equilibrium Dialysis: • Advantages: Gold standard, accurate • Disadvantages: Time consuming, expensive, technically demanding • Immunoassay: • Advantages: quick compared to ED, higher accuracy than ED, regularly available • Disadvantages: expensive, procedure has to be carried out precisely

39. What factors can effect T4? • Age • Infection • Stress • Pregnancy

40. What Drugs can effect T4? • Amiodarone: structurally resembles thyroxine molecule. Decreases serum T4 levels • Phenytoin and Carbamazepine: accelerate clearance of T4 and depress FT4 • Propranolol: elevation of serum free T4 levels • Lithium: inhibits T4 release. • Glucocorticoids: suppress T4 levels