Week 3: Thyroid physiology and thyroid function tests

Question 1

Thyroid hormone biosynthesis

Answer 1

1. Iodide metabolism: need ~150ug iodide from diet daily. Large reserve in colloid
2. Iodide transport: by Na/I symporter on basolateral membrane of follicular cell
   - TSH and Iodide deficiency augments uptake
3. Thyroglobulin biosynthesis
   - Tg made on rER/golgi, transported to apical side for iodination and transfer to colloid for storage
4. Iodination of Tg: catalyzed by thyroid peroxidase (TPO) on apical membrane.
   - forms DIT and MIT, which combine to form T3 (DIT+MIT) and T4 (DIT+DIT)
5. thyroid hormone release: Tg from colloid resorbed via micropinocytosis and fuses with lysosomes. Transported to basolateral side. hydrolysis frees T4 and T3.

Question 2

thyroxine binding globulin (TBG)

Answer 2

• most of thyroid hormone bound to TBG, which has 10x affinity for T4 than T3
  1. Causes of elevated TBG levels
• high estrogen stages in pregnancy and with OCPs
• drugs: heroin, methadone, clofibrate, 5-FU, nicotinic acid
• diseases: liver disease
  2. causes of reductions in circulating TBGs
• acute and chronic non thyroidal illness
• nephrotic syndrome due to tubular leak
• glucocorticoid, androgen abuse, anabolic steroids
• congenital deficiency

Question 3

T3 and rT3

Answer 3

• T3 has much lower serum concentration than T4. TBG has lower affinity to T3, so most of body’s stores of T3 are in intracellular compartment
• rT3: produced in peripheral tissues. Primarily a disposal pathway in peripheral metabolism of T4

Question 4

Iodothyronine deiodinases

Answer 4

1. Type 1: 5” deiodinase
   - located in liver, kidney, thyroid gland
   - inhibited by propylthiouracil (PTU)
   - prefers rT3 substrate, can convert T4 to T3
   - converts rT3 to T2
2. Type 2 5’-deiodinase
   - CNS, placenta, heart, thyroid, pituitary gland
   - prefers T4 as substrate
   - responsible for most of circulating T3
3. Type 3 5-Deiodinase
   - CNS, skin, placenta
   - T4 and T3 preferred substrates
   - responsible for generation of rT3 from T4

Question 5

mechanism of action of Thyroid hormone

Answer 5

• hormones enter target cell via MCT8 protein (transporter)
• effects of T3 mediated by T3 receptors in nucleus of the cell
• act in dominant negative manner: when receptor has no ligand bound, it represses that particular transcription. When ligand binds, transcription occurs.
• beta2 receptor: inhibitory and provides negative feedback regulation of TSH. Transcription is active when no T3 bound

Question 6

Changes in thyroid hormone metabolism with illness

Answer 6

• initial: fall in serum T3->low T3 state
• rise in rT3 values
• may result from inhibition of Type 1 and Type 3 enzyme activity
• low T3-low T4 state: decline in serum T4, due to change in affinity of TBG for T4

Question 7

Free T4/TSH relationship

Answer 7

• TSH levels regulated by balance between TRH stimulation and negative feedback by T4 (sensed by conversion locally to T3)
• senses small changes in free T4 levels and alters TSH synthesis accordingly
  1. amplification: a 2fold change in free T4 produces a 100 fold change in TSH
  2. individual Set point

Question 8

Three conditions in which TSH does not accurately reflect thyroid status of patient

Answer 8

1. presence of hypothalamic or pituitary disease
2. treatment of chronic thyroid hormone excess or deficiency
   - there is a lag of TSH because thyroid becomes hypo/hyperplastic and needs time to respond to therapies
3. the superimposition of non thyroidal illness

Question 9

Summary of thyroid function tests

Answer 9

• serum T4 level: function of thyroid gland
• serum T3 level: metabolic status of patient
• TU and T3U: serum binding proteins
• Free T4 estimate: T4/TU or T4xT3U; free T4 levels
• Serum TSH level: readout of the endogenous free T4 value
• anti-TPO titer: immune state of the thyroid gland