Adjustment of THR during Pregnancy
One particularly challenging situation is thyroid hormone replacement in pregnancy, where dose adjustments are usually required. During pregnancy, the production of T4 and T3 is increased by 50%, and the daily iodine requirement is increased by 50%. The TSH normal reference range in pregnancy is influenced by high T4-binding globulin, estrogens, human chorionic gonadotropin levels, increased iodine clearance, and enhanced type 3 deiodinase activity of the placenta. Recent guidelines state that the upper limit of normal of TSH should be 2.5 mU/L in the first trimester of pregnancy and 3 mU/L in the second and third trimesters.37
In women receiving L-T4 for replacement alone, the dose should be increased by 30% as soon as pregnancy is confirmed. In women receiving suppressive therapy, hormone levels should be checked every month during pregnancy, and the LT4 dose is increased if serum TSH level increases. It is not well established in current guidelines whether the TSH level goal should be lowered in women with history of thyroid cancer during pregnancy. Each physician needs to make an individualized clinical judgment taking into consideration the recurrence risk of the patient. The pre-pregnancy dose of L-T4 should be immediately resumed after delivery.14,38
THR in Pediatric Patients with Thyroid Cancer
Thyroid hormone replacement in children presents its own unique set of challenges. While children are not likely to complain of decreased energy, concerned parents may tend to transfer their perception of what thyroid hormone should do to the child’s activity level. The discussion of TSH suppression following thyroidectomy for thyroid cancer in adults also applies to children. Nevertheless, the ability to achieve consistent TSH suppression in children is difficult mainly due to higher non-compliance rates with the medication. When the home environment is not conducive to compliance, other measures may need to be taken. Anecdotally for one particularly non-compliant child, we have had the medication administered to the patient by the school nurse (and during the summer vacation a visiting nurse). It was given as a single weekly dose, and serum TSH levels were consistently kept below 0.5 mU/L. In general, weight-based requirements for thyroid hormone are increased in children and adolescents compared to adults,39
and for this reason TSH should be checked more frequently.
No data are available to compare the outcomes, risks, and benefits of different TSH suppression levels in children with thyroid cancer. Recognizing the limited data available, the ATA has submitted guidelines based on risk level and current disease status that recommend maintaining TSH suppression in children with known or suspected persistent disease. In children with no evidence of disease, the TSH can be normalized to the low normal range after an appropriate period of surveillance. In pre-pubertal children bone maturation and pubertal development should be monitored. Extrapolating from patients with Graves’s disease, the potential risks of TSH suppression include growth acceleration, advanced bone age, early-onset puberty, reduced bone mineral content, poor academic performance, and tachyarrhythmia.40
THR in Non-thyroidal Illness Syndrome
Critically ill patients who were otherwise euthyroid prior to illness or those severely malnourished demonstrate suppressed serum T3 and often T4 and TSH, with an increase in reverse T3. This pattern is known as non-thyroidal illness syndrome or “euthyroid-sick syndrome.” It is likely due to a suppression of the hypothalamic–pituitary–thyroid axis, a downregulation of type 2 deiodinase resulting in decreased T4-to-T3 conversion, and an increase in reverse T3 production. Whether this is a physiologic adaptation or a pathologic response is a question of great controversy.41,42
The thyroid hormone status of the tissues in a critically ill patient is unknown and may not correlate with serum levels. Nevertheless in athyreotic patients who are critically ill the rational approach is to treat with T3 until the patient recovers, monitoring T3 and TSH serum levels. Once the critical illness is corrected, return to T4 replacement should occur. It should be noted that there is no clinical or experimental evidence to support the preferential use of T3 over T4 in athyreotic patients who are critically ill.
Patients with Persistent Hypothyroid Symptoms despite a Suppressed TSH
L-T4 is the standard of care for thyroidectomized patients, is very efficient at achieving the desired TSH suppression in thyroid cancer cases, and in most patients it results in resolution of the signs and symptoms of hypothyroidism. However, a small proportion of patients (although ones that seem to find their way to multiple endocrinologists) being treated with L-T4 feel that this medication is not efficacious in restoring optimum health. One possible explanation for this phenomenon may be genetic variations in the expression of peripheral 5′-deiodinases, which are selenoprotein enzymes that catalyze the conversion of T4 to active T3 in the peripheral tissue.43
Patients with low 5′-deiodinase activity may be unable to metabolize T4 to T3 in adequate amounts and may therefore respond better to combined replacement therapy than to T4 alone.44
There is, however, no routinely available clinical biochemical or genetic test to determine whether this is the case,18
and each treating physician needs to weigh the unlikely occurrence of this rare possibility versus gaining the confidence of the patient that their physician is listening to them and concerned for their care. Most often a detailed discussion with the patient will reveal that they were not completely satisfied with their weight or health prior to the thyroidectomy. The presence of anti-thyroid antibodies may somehow be involved in these symptoms.
Patients Unable to Tolerate a Suppressed TSH
Patients with a history of thyroid cancer are encouraged to keep their serum TSH at least below 0.5 mU/L (see discussion above). However, there will be those patients in whom any slight decrease in the serum TSH results in palpitations and apparent increased sensitivity to TH.8
Such individuals may have had pre-thyroidectomy serum TSH values at the higher part of the normal range and, due to as yet undefined molecular pathways, are unable to tolerate a higher dose of thyroid hormone. In such instances the clinician will need to weigh the risks and benefits of suppressive therapy.
Patients Unable to Achieve a Suppressed TSH despite Proper Thyroid Hormone Therapy
There are some patients on adequate or even high doses of thyroid hormone therapy who are unable to achieve TSH suppression. The differential diagnoses include malabsorption, non-compliance, factors increasing the medication’s metabolism, or increased serum levels of T4-binding globulin. In addition, when the TSH cannot be suppressed in spite of adequate doses of thyroid hormone, the physician should consider the presence of heterophile antibodies and interference with the laboratory measurement including anti-mouse antibodies, rheumatoid factor, and autoimmune anti-TSH antibodies. Finally one could consider the coexistence of adrenal insufficiency, which may induce TSH elevation reversible with glucocorticoid replacement.12
Defects in thyroid hormone absorption are rare without a history of previous gut surgery, celiac disease, lactose intolerance, autoimmune gastritis, or Helicobacter pylori infection. A serum free T4 peak at 2 hours rising above the upper limit of normal after the administration of 100 μg of L-T4 suggests proper absorption, but unfortunately there are no well-established standards for this test.45 A radioisotope-labeled L-T4 tracer technique may be used to test absorption more accurately, but this technique is not readily available. Prior studies looking into this matter have shown that oftentimes patients suspected to have absorption problems actually exhibit a factitious disorder and have compliance issues.45
One daily dose of L-T4 accounts for 14% of the total weekly dose. Therefore a missed dose of L-T4 may affect free T4 and TSH levels over several weeks due to the long half-life of L-T4. The prevalence of non-compliant hypothyroid patients has been reported between 30% and 80% despite the simplicity of once-daily dosage of the medication.46 There are many possible causes for patient non-compliance, and special attention should be paid to try to address common psychosocial causes such as barriers to accessing the medication, difficulties with insurance coverage, literacy issues, and lack of understanding regarding the benefits of taking L-T4 as a medication.
If efforts to encourage regular daily consumption of L-T4 are unsuccessful, alternative options for medication delivery include twice weekly or once weekly dosage.11,47 However, only three crossover trials of such oral therapy have been conducted, and none of them were long-term or conducted in a patient group reported as non-adherent.48–50 The once-weekly or twice-weekly dosage approach should be avoided in patients with underlying heart disease because of the potential exacerbation of congestive heart failure and arrhythmias due to transient supraphysiological hormone concentrations achieved in the first 1 or 2 days of therapy.12
For patients with proven malabsorption issues, a weekly intramuscular injection of L-T4 may be a useful therapeutic approach in obtaining biochemical and clinical euthyroidism. Intravenous thyroid hormone therapy is another alternative, but it is not universally available.51 Because about 70% of an orally administered dose of T4 is absorbed, individuals unable to ingest L-T4 should initially receive 70% or less of their usual oral those when the medication is given intravenously. Crushed L-T4 tablets suspended in water should be given through a naso-gastric tube to patients receiving enteral feeding.
One possible rare cause of inability to achieve a suppressed TSH despite high doses of L-T4 is thyroid hormone resistance, also referred to as impaired sensitivity to thyroid hormone. This is a rare syndrome in which the thyroid hormone levels are elevated but the TSH level is not suppressed, or not completely suppressed as would be expected.52 However, it is very unlikely that this scenario would present de novo after thyroidectomy for thyroid cancer, and assessing pre-thyroidectomy thyroid function tests is of vital importance to establish normal function of the hypothalamic–pituitary–thyroid axis.