Alison Wong Meme Phung Zhi Yuan Quek

CASE Mr. AR, aged 55 years Recently been prescribed amiodarone as treatment for atrial tachyarrhythmia Medications on a regular basis: - Digoxin 62.5 mcg 3 mane - Warfarin 4 mg d as directed

AMIODARONE Remarkable structural resemblance to thyroid hormones Iodine-rich benzofuran derivative 37% by weight is organic iodine

EFFECTS OF AMIODARONE ON THYROID FUNCTION 1.Effects on thyroid physiology  peripheral 5’-deiodination of thyroxine (T 4 ) to triiodothyronine (T 3 )  in the serum levels of T 4 and rT 3 and a  in the serum levels of T 3 entry of T 4 and T 3 into peripheral tissue inhibited

early phase of treatment, thyroid- stimulating hormone (TSH) levels also  in response to the  T 3 levels as treatment continues, the serum TSH levels often fall back to normal as the total T 4 concentration rises

Changes in thyroid function test results with development of hyperthyroidism and hypothyroidism

2.Amiodarone-induced thyrotoxicosis excessive synthesis of thyroid hormone induced by iodine excessive  in T 4 level alone may not be diagnostic diagnosis straightforward if T 3 or FT 3  and TSH suppressed onset of thyrotoxicosis   in T 4 levels,  in T 3 levels and a dramatic  in TSH levels

suppression of TSH levels possible in subclinical episodes single abnormal TSH insufficient subclinical episodes represented by suppressed TSH, T 3 & FT 3 at lower end of reference range,  T 4 or FT 4

3.Amiodarone-induced hypothyroidism iodide released by amiodarone metabolism inhibits thyroid hormone biosynthesis and release subclinical hypothyroidism  moderately  TSH levels additional tests needed diagnosis confirmed by  TSH with low T 4 or FT 4 low T 3 or FT 3 unreliable indicator

CONCERNS Digoxin and Amiodarone - digoxin toxicity Warfarin and Amiodarone - increased risk of bleeding

THYROID BINDING GLOBULIN (TBG) Analytical protocols for measurement of TBG Clinical applications of measuring TBG in evaluating thyroid function.

T 3 and T 4 Poorly soluble in plasma Transported primarily by TBG TBG = a plasma protein that carries % of circulating T 4 and T 3. Remaining 25-30% of T 4  transported by albumin and prealbumin. T 3  no affinity for prealbumin and circulates only with TBG and albumin.

Thyroid Hormone Transport Serum Cell Bound T 3 and T 4 Equilibrium between bound and free hormone exists Thyroid binding Globulin Less than 1%

Bound T 3  inactive Free T 3  active Bound and free hormone exist in equilibrium

T 4  higher affinity for TBG in plasma than T 3.  99.95% bound, ~0.05% free Total T 4 is a direct measure of T 4 Estimate of total T 4  approximated by amount of bound thyroxine Under conditions with normal TBG concentrations, the total T 4 level reflects the functional state of the thyroid.

PROBLEMS WITH TBG MEASUREMENTS Changes in TBG levels :  will dramatically alter the total T 4 concentration, without affecting the unbound free T 4 level.  do not reflect a change in thyroid status  equilibrium between the free and bound hormones is maintained remain euthyroid by the normal free thyroid hormone and TSH concentrations patient may be physiologically normal but have an abnormal total serum T 4 level

There are several conditions that can affect (  or  ) TBG levels.

CONDITIONS ASSOCIATED WITH INCREASED TBG SYNTHESIS AND PLASMA LEVELS 1.Oestrogen effects – pregnancy, oral contraceptives 2.Infectious Hepatitis 3.Biliary cirrhosis 4.Genetic determination - increased genetically by an X-linked abnormality

CONDITIONS ASSOCIATED WITH DECREASED TBG SYNTHESIS AND PLASMA LEVELS 1.Severe liver disease 2.Androgens and anabolic steroids 3.High doses of glucocorticoids 4.Large doses of phenytoin, aspirin and their derivatives 5.Nephrotic syndrome 6.Genetic determination

T 3 RESIN UPTAKE (T 3 RU) Measures the amount of unsaturated binding sites on the thyroid hormone transport proteins Provides an indirect estimate of the binding capacity of the plasma thyroid- binding proteins

Proportion of labelled T 3 will bind to available sites on the serum TBG; excess will bind to the resin resin uptake is inversely proportional to the total TBG 80% sensitivity for hyperthyroidism 50-60% sensitivity for hypothyroidism

METHODOLOGY OF THE T 3 UPTAKE TEST

T 3 U VALUES %T 3 U = camp/cpm R X %T 3 U R Typical values for %T 3 U are 25-30% Increased Values = Hyperthyroidism Decreased Values = Hypothyroidism

FREE THYROXINE INDEX (FTI) Is a reflection of the amount of free T 4 A calculated value correct for changes in TBG concentrations FTI = (Total T 4 ) X (T 3 Resin Uptake) (T 4 RU Control)

FTI Normal FTI: euthyroid subjects, pregnancy, women taking estrogens, patient with nephrosis or hepatitis and persons taking drugs that elevate T 3 U Increased FTI: hyperthyroidism Decreased FTI: hypothyroidism