Question 25

College Answer

a)

• Low serum total T3 is most commonly observed-mean values are 40% of normal.
• Free T3 is also reduced but less so.
• Reverse T3 (rT3) is increased. Low T3 is caused by a reduced peripheral conversion of T4 to T3 secondary to inhibition of type 1 5’-deiodinase.
• Serum T4 and TSH may transiently rise then return to normal.
• On recovery T3 and rT3 return to normal.

b)

i. Amiodarone 
Inhibition of peripheral conversion T4 to T3

ii. Propranolol 
Inhibition of peripheral conversion T4 to T3

iii. Glucocorticoids

Inhibition of peripheral conversion T4 to T3

Suppression of TSH secretion

iv. Opiates 
Suppression of TSH secretion

c)

A sequential, multidrug approach is vital and the order of therapy is important. Three pathways need consideration-halting synthesis, preventing release of stored hormone and blockade of peripheral effects including blocking conversion of T4 toT3 as well as control of adrenergic symptoms.

Halting synthesis:

First line therapy with Thionamides- thiouracils (Propylthiouracil or PTU) and or imidazoles (methimazole and carbimazole) may be used. Both block thyroperoxidase coupling of idotyrosine residues in formation of T4 and T3.PTU (not imidazoles) will also block peripheral conversion of T4 to T3. 
Both given gastrically/PO/retention enema.

Halting release:

Thionamides block synthesis only but not secretion of preformed glandular stores of hormone. Separate treatment is needed to inhibit proteolysis of colloid and continuing release of T3 and 4. Inorganic iodine therapy either with orally administered Lugol solution or potassium iodide should be used. Iodine should only be used 30 -60 minutes

AFTER administration of Thionamides since hormone synthesis may be stimulated. 
Alternatives include Li Carbonate and some of the older radiographic contrast agents.

Blocking peripheral action: 
B blockade is essential to control peripheral actions of thyroid hormone.

Propranolol is commonly used either gastrically or IV. A drop in T3 levels may be seen with its use (decreases T3-T4 conversion). Glucocorticoids have a role in that they also block conversion of T4 to T3 and may treat any relative adrenal or vasomotor insufficiency that occurs.

Discussion

The sick euthyroid syndrome is discussed in greater detail elsewhere.

In brief, the TFT abnormalities are:

• T3: low
• rT3: high
• T3/rT3 ratio: low
• T4: high ...or normal
• TSH: high ...or normal

The drugs which affect thyroid metabolism are also discussed in another chapter("The influence of drugs on thyroid function")

In short:

• Amiodarone decreases the peripheral conversion of T4 to T3. It can either inhibit thyroid gland synthetic function, or it can stimulate them (particularly when it causes a thyroiditis). It can also decrease the clearance of T4.
• Propanolol merely inhibits the peripheral conversion of T4 to T3
• Corticosteroids decrease the secretion of TSH, and inhibit the peripheral conversion of T4 to T3
• Opiates merely inhibit the secretion of TSH.

In not so short:

Drugs Which Affect Thyroid Function
~Organised by Their Effect on Thyroid Hormones~

TSH	Inhibition of release	Dopamine Dobutamine Corticosteroids Octreotide Opiates
	Stimulation of release	Metaclopromide Antipsychotics, especially amisulpiride
T3 and T4 synthesis	Inhibition of thyroid synthetic function	Thiouracils (eg. propylthiouracil) Imidazoles (eg. carbimazole) Lithium carbonate Amiodarone Thalidomide
	Stimulation of thyroid synthetic function	Inorganic iodine (eg. potassium iodide) - if you have a normal thyroid gland Iodinated contrast agents (high iodine content) Amiodarone
T3 and T4 release from the thyroid gland	Inhibition of release	Inorganic Iodine (eg. potassium iodide) Iodinated contrast agents (high iodine content)
	Stimulation of release	Amiodarone (by thyroiditis)
Conversion of T4 into T3	Inhibition of conversion	Amiodarone Propanolol Corticosteroids Thiouracils (eg. propylthiouracil)
	Stimulation of conversion	Sorafenib Selenium (a cofactor in T4-T3 conversion; selenium supplementation will not result in a supranormal T3 level - merely a return to normal)
Transport of thyroid hormones by binding to thyroid-binding globulin (TBG)	Increased TBG levels (thus decreased free T3)	Oestrogens Tamoxifen 5-fluorouracil (5-FU) Heroin Methadone
	Decreased TBG levels (thus increased free T3)	Androgen hormones Corticosteroids Niacin (nicotinic acid)
	Increased binding of T4 to TBG	Estrogens, particularly in the setting of pregnancy
	Decreased binding of T4 to TBG (by displacement)	Aspirin and salicylates in general Frusemide (and ethacrynic acid) Heparin
Clearance of T4	Increased clearance	Phenytoin Carbamazepine Rifampicin Phenobarbital
	Decreased clearance	Amiodarone Glycosylflavones in millet-rich diets of the poor in the developing world, or in the weird hippies who think it is healthy to emulate them.

The management of thyrotoxic crisis is well summarised by the college answer, but could be whittled down to point-form to improve the cerebral dwell-time among time-poor exam candidates:

• Prevent synthesis of T3 and T4:
  • Thiouracils: propylthiouracil - blocks synthesis of T3 and T4 as well as peripheral T4-T3 conversion
  • Imidazoles: carbimazole - block synthesis of T3 and T4
• Prevent T3 and T4 release:
  • Inorganic iodine therapy, eg. potassium iodide (given after synthesis is blocked)
• Block peripheral T3 and T4 activity:
  • β-blockade: propanolol (which also decreases T4-T3 conversion)
  • Corticosteroids: also decrease T4-T3 conversion

For those uncomfortable with the austere minimalism of point-form, an extensive rambling digression is also available.

UpToDate has an excellent entry on this topic, for the paying customer.

Alternatively, one can attempt to piece things together from free-full-text articles, and from this Life In The Fast Lane summary.

Zargar, A. H., et al. "Prevalence and pattern of sick euthyroid syndrome in acute and chronic non-thyroidal illness-its relationship with severity and outcome of the disorder." JOURNAL-ASSOCIATION OF PHYSICIANS OF INDIA 52 (2004): 27-32.

Peeters, Robin P., et al. "Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients." Journal of Clinical Endocrinology & Metabolism 88.7 (2003): 3202-3211.

Baruah, M. P., and R. J. Singh. "Effects of drugs on thyroid function." Thyroid Research and Practice 9.1 (2012): 3.