The thyroid gland is an endocrine organ that secretes the hormones triiodothyronine (T3) and thyroxine (T4), which is in turn under the influence of the TSH and the TRH. Though hyper- and hypothyroidism remain the common clinically manifesting condition of the thyroid, in some cases, the patient remains symptomless with either excess thyroxine levels or a decrease, with that of the normal TSH levels. This is termed as euthyroid hyperthyroxinemia and euthyroid hypothyroxinemia respectively. The cause is altogether different from the thyroid and are inappropriately managed as hyperthyroid and hypothyroid states, which should not be the case.

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thyroid hormone synthesis

Image: “Synthesis of thyroid hormones.” by Mikael Häggström – Mainly Own work Source image for nucleus derivative: (Public Domain license). License: CC0


Thyroid Hormones

As stated earlier, there are two thyroid hormones, which are thyroxine (T4) and triiodothyronine (T3). Thyroxine is the primary hormone secreted by the thyroid gland with triiodothyronine being secreted in lesser amounts. T3, however, has much greater biological activity compared to T4 and is generated at its site of action peripherally by deiodination of T4.

Biochemical characteristics

triiodothyronine structural formula

Image: “2D structure of thyroid hormone triiodothyronine.” by Harbin – Own work. License: Public Domain

The normal total serum T4 levels are approximately 103 nmol/L and the total serum T3 levels are approximately 2.3 nmol/L.

T4 and T3 are relatively lipophilic; thus, their free forms in plasma are in equilibrium with a much larger pool of protein-bound thyroid hormones in plasma and within tissues. Free thyroid hormones are added to the circulating pool by the thyroid gland. It is the free thyroid hormones that are physiologically active and that is implicated in the feedback to inhibit pituitary secretion of TSH. The function of protein-binding appears to be maintenance of a large pool of hormone that can readily be mobilized as needed.

Features of the bound protein

thyroxine structural formula

Image: “2D structure of thyroid hormone thyroxine.” by Harbin – Own work. License: Public Domain

The plasma proteins that bind thyroid hormones are albumin, a prealbumin known as transthyretin (formerly known as thyroxine-binding prealbumin) and a globulin known as thyroxine-binding globulin (TBG). The affinities of the thyroid hormone binding proteins are such that most of the circulating T4 is bound to TBG, with lesser amounts being bound to transthyretin and albumin.

Normally, 99.98% of the total serum T4 is bound to proteins, with very little excretion of T4 in urine. 99.8% of T3 is bound. TBG binds approximately 75% of the circulating T4 and T3, because of its high affinity. Thyroxine-binding prealbumin binds to only about 15% of the hormones, and albumin binds to the remaining 10%. Despite having the largest binding capacity, the thyroid hormones bind least avidly to albumin.

Outcomes of an alteration in the thyroid binding proteins

When a sudden, sustained increase in the concentration of thyroid-binding proteins in the plasma takes place, the concentration of the free thyroid hormones falls. This change is only transient.

However, the decrease in the levels of free thyroid hormones in serum stimulates TSH secretion, which in turn normalizes thyroid hormone levels by stimulating an increase in the production of free thyroid hormones. Therefore, patients with increased or decreased levels of thyroid hormone binding proteins, particularly TBG, are typically neither hyperthyroid nor hypothyroid but rather euthyroid.

Causes for the change in the thyroid binding protein level

Changes in the plasma concentrations of the thyroid hormones binding hormones mentioned above, particularly TBG because of its high affinity, can lead to changes in the total plasma T4 and T3 levels.

Variations in the concentration of TBG can either be congenital or acquired. TBG levels can be raised in the following settings: pregnancy, estrogen-treated patients, and some drugs. TBG levels can be lowered by: excesses of hormones such as glucocorticoids or androgens, some drugs such as dazanol and L-asparaginase (a cancer chemotherapeutic agent).

Other drugs such as salicylates, phenytoin (an anti-convulsant), mitotane and 5-fluorouracil (cancer chemotherapeutic agents) inhibit the binding of the thyroid hormones to TBG and consequently produce changes similar to those produced by a decrease in the concentration of TBG.

Euthyroid Hyperthyroxinemia

Definition of euthyroid hyperthyroxinemia

Euthyroid hyperthyroxinemia is defined as a condition in which there is an increase in the serum total thyroxine and triiodothyronine levels, with concomitant normal thyroid stimulating hormone serum levels and no signs and symptoms of thyroid pathology.

Etiology of euthyroid hyperthyroxinemia

Euthyroid hyperthyroxinemia follows abnormalities of the binding proteins and is usually as a result of an increase in the binding proteins. As much as any of the binding proteins can be affected, TBG is usually the one commonly affected, with TBG excess being the commonest binding protein abnormality.

Some of the causes of euthyroid hyperthyroxinemia include:

  • Hereditary: Familial dysalbuminemichyperthyroxinemia is a hereditary condition which usually results from mutations in TBG, TTR or albumin leading to an increase in their binding affinity for T4 and/or T3. The affected patients therefore have increased serum total T4 levels but are euthyroid (unbound hormone levels are normal) with normal serum TSH levels.
  • Estrogen: Estrogen increases serum TBG levels by slowing down its clearance. It does this by causing glycosylation of TBG, which in turn reduces the rate of clearance of TBG resulting in increased serum concentration. Therefore, serum TBG levels are usually increased in pregnant women, women using oral contraceptives, women on post-menopausal estrogen therapy, and patients with estrogen-secreting tumors.
  • Hepatitis: acute and sub-acute hepatitis cause a rise in the serum levels of TBG.
  • Drugs: A number of drugs cause a rise in the serum levels of TBG. These drugs include methadone and zanoxifen.
  • Acute intermittent porphyria: serum TBG levels may be raised in acute intermittent porphyria.
  • Reduced thyroxine deiodination: As mentioned earlier, thyroxine is usually deiodinated peripherally to form triiodothyronine. Some drugs, however, inhibit this process resulting in hyperthyroxinemia with normal serum thyroid-stimulating hormone (TSH) levels. These drugs include amiodarone, propanolol, and iodinated contrast agents such as ipodate and iopanoic acid.

Euthyroid Hypothyroxinemia

Definition of euthyroid hypothyroxinemia

Euthyroid hypothyroxinemia is defined as a condition in which there is a decrease in the serum total thyroxine and triiodothyronine levels, with concomitant normal thyroid stimulating hormone serum levels and no signs and symptoms of thyroid pathology.

Etiology of euthyroid hypothyroxinemia

Euthyroid hypothyroxinemia also follows abnormalities of the binding proteins and is usually as a result of a decrease in the binding proteins.

Some of the causes of euthyroid hyperthyroxinemia include:

  • Displacement of T4 from binding proteins: Some drugs displace T4 from their binding proteins resulting in reduced total T4 levels, but with normal serum free T4 levels. These drugs occupy the binding sites that would normally be bound by T4 therefore causing a fall in the total T4 levels. Examples of such drugs include: salicylates, high-dose furosemide in chronic kidney disease patients, NSAIDs, Mefenamic acid.

  • Hereditary: Hereditary TBG deficiency is an X-linked disorder characterized by very low levels of total T4 and T3. However, because unbound hormone levels are normal, patients are euthyroid and TSH levels are normal. It is important to recognize this disorder to avoid inappropriate efforts in trying to normalize total T4 levels, as it may lead to thyrotoxicosis and is usually futile due to the rapid clearance of the unbound thyroid hormone in the absence of TBG.

  • Hormonal excess: Hormonal excess such as androgens in high doses, glucorticoids, or the hormonal excesses observed in acromegaly and Cushings syndrome may cause a fall in the serum TBG levels resulting in reduced total serum T4 levels.

  • Nephrotic syndrome: Nephrotic syndrome which is characterized by urinary loss of proteins causes urinary loss of TBG, which in turn can result in hypothyroxinemia. Usually the patients are euthyroid, hence euthyroid hypothyroxinemia, but hypothyroidism may occur in some patients.

  • Medication: Some drugs lower serum TBG levels presumably by decreasing production of TBG. These drugs include: L-asparaginase, danazol, niacin.

Laboratory Investigations

A thyroid profile measures serum TSH, thyroxine and triiodothyronine levels. Total T4 and T3 can both be measured by radioimmuinoassay.

There are also direct assays that specifically measure only the free forms of these hormones. The latter are more clinically relevant measures given that these are the active forms, and also due to both acquired and congenital variations in the concentrations of binding proteins between individuals.

Depending on these thyroid hormone levels and clinical presentation, different diagnoses can be made. The following table summarizes the same:

Diagnosis

TSH

Free T4

Signs and symptoms

Primary hyperthyroidism

Decreased

Increased

Hyperthyroidism

Secondary hyperthyroidism;

TSH secreting tumor

Increased

Increased

Hyperthyroidism

Primary hypothyroidism

Increased

Decreased

Hypothyroidism

Secondary hypothyroidism;

Hypopituitarism

Decreased

Decreased

Hypothyroidism

Subclinical hyperthyroidism

Decreased

Normal

None

Subclinical hypothyroidism

Increased

Normal

None

Euthyroid hyperthyroxinemia

Normal

Increased

None

Euthyroid hypothyroxinemia

Normal

Decreased

None

Special Test – Aiding in the Distinguishing

Triiodothyronine(T3)-resin uptake test

The triiodothyronine(T3)-resin uptake test was designed in part to detect abnormalities in serum TBG which would in turn aid in diagnosing euthyroid hyperthyroxinemia and hypothyroxinemia, which, as mentioned above, are usually a result of abnormalities of the thyroid hormones binding proteins.

The test measures the number of unoccupied T4-binding sites and is performed by incubating the patient’s serum with radio-labeled T3. A resin is added afterwards. The radio-labeled T3 will bind the serum proteins (such as TBG), and any excess radio-labeled T3 will bind the resin that has been added subsequently.

Interpretation of the triiodothyronine(T3)-resin uptake test

Therefore, in body states where there is excess TBG, more radio-labeled T3 will bind TBG and less will bind the resin resulting in a low T3-resin uptake. As expected, these results are reversed in body states where there is reduced TBG. In TBG deficiency, less radio-labeled T3 will bind TBG causing more of it to bind resin and hence a high T3-resin uptake.

Expected outcome in the triiodothyronine(T3)-resin uptake test

The expected changes in serum free T4 index, serum total T4 and T3-resin uptake in hyperthyroidism, hypothyroidism, TBG excess and TBG deficiency can be summarized as follows:

Diagnosis

Serum Free T4 Index

Serum Total T4

T3-Resin uptake/ THBR

Hyperthyroidism

Increased

Increased

Increased

Hypothyroidism

Decreased

Decreased

Decreased

TBG excess

Normal

Increased

Decreased

TBG deficiency

Normal

Decreased

increased

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