Abstract
Signs and Symptoms of Hypothyroidism
Both of the earlier articles (2,3) emphasize the symptoms and signs of hypothyroidism. These are also considered in detail by Garber et al. (1). Additionally, however, these new guidelines stress the fact that the clinical features of hypothyroidism are not specific and each varies widely in severity. This is revealed by Recommendation 5 which states “Clinical scoring systems should not be used to diagnose hypothyroidism,” Recommendation 29 which states “Thyroid hormones should not be used to treat symptoms suggestive of hypothyroidism without biochemical confirmation of the diagnosis,” Recommendation 6 indicating that “Tests such as clinical assessment of reflex relaxation time, cholesterol, and muscle enzymes should not be used to diagnose hypothyroidism,” and companion Recommendations 30 and 31, which proscribe thyroid hormone treatment for obesity and depression (1). Only when there is biochemical evidence of hypothyroidism (1) can symptoms be weighed to decide if thyroid hormone should be administered (Recommendation 16) or its dose adjusted (Recommendation 22.8).
Diagnosis of Hypothyroidism
All three guideline articles emphasize the importance of serum thyrotropin (TSH) and free thyroxine (T4) determinations or estimates for the diagnosis of hypothyroidism, but the earlier articles do not actually offer diagnostic criteria for hypothyroidism (1 –3). Surprisingly, although the new guidelines (1) have more than 50 recommendations, none of them state diagnostic criteria. Rather, the following statement is provided in the main text: “An elevated TSH, usually above 10 mIU/L, in combination with a subnormal free T4 characterizes overt hypothyroidism” (1).
Primary Versus Central Hypothyroidism
In the above sentence, “overt hypothyroidism” rather than “overt primary hypothyroidism” reflects the widespread custom in the literature whereby “overt hypothyroidism” and “subclinical hypothyroidism” are unspoken phrases referring to primary rather than central (hypothalamic–pituitary) hypothyroidism. This is unfortunate because central hypothyroidism, although uncommon, may be manifestly overt, even fatal, particularly when there is concomitant panhypopituitarism. Regarding “subclinical central hypothyroidism,” this expression has hardly entered the lexicon. However, acknowledging the need to avoid undertreatment of any degree of central hypothyroidism, the new guidelines state in the accompanying text, “The goal of therapy is generally to attain [serum free T4] values above the mean for assays being employed” (1).
Ordering a TSH to screen for hypothyroidism or guide thyroid hormone therapy has become an entrenched habit. So much so that, although it has long been recognized that serum TSH concentrations are generally normal or low in patients with central hypothyroidism, this exception to the rule is sometimes forgotten in clinical practice. Hopefully readers will recognize the importance of Recommendation 12, which states that “serum TSH determinations should not be used to diagnose or guide treatment of patients with central hypothyroidism.” If not, there will still be the occasional patient with central hypothyroidism whose dose of L-thyroxine is inappropriately reduced, as if by reflex, when the serum TSH is reported to be low.
The “rule” that serum TSH concentrations are normal or low in patients with central hypothyroidism also has exceptions. The new guidelines (1) are to be commended for indicating that serum TSH levels may be mildly elevated in patients with central hypothyroidism due to secretion of bioactive forms of TSH, although there are still rarer exceptions of patients with central hypothyroidism who have serum TSH concentrations even higher than “not above 6 or 7 mU/L”.
TSH and Circulating Thyroid Hormones in Hypothyroidism
Measurement of serum TSH and free triiodothyronine (T3) has a critical role not only in the diagnosis of hypothyroidism but also in determining the optimal dose of thyroid hormone for treatment of hypothyroidism. In contrast, as noted in Recommendation 10, “Serum total T3 or assessment of serum free T3 should not be done to diagnose hypothyroidism” (1). This is a rule for which, possibly, there are no exceptions.
The dialog regarding circulating TSH and thyroid hormones in the new guidelines (1) is far more extensive than in earlier ones (2,3). Thus, there are detailed discussions of the exceptions to the rules regarding serum TSH, T4, and free T4 values in the diagnosis and management of primary hypothyroidism. Nonthyroidal illness, adrenal insufficiency, pregnancy, obesity, aging, drug effects, resistance to thyroid hormone, etc. are all covered. Another potentially misleading entity, autonomous TSH-secreting tumors, could be added to the list.
L-Thyroxine for Treatment of Hypothyroidism
The 1995 ATA guidelines (2), the 2002 AACE guidelines (3), and the new guidelines (1) all specify L-thyroxine as the treatment of choice for hypothyroidism. The most emphatic recommendation is made by the new guidelines. Garber et al. (1) provide cogent reasons for not using dessicated thyroid hormone to treat hypothyroidism, strictly avoiding T3 to treat pregnant women with hypothyroidism, and avoiding off-label substances that contain thyromimetic ingredients or are purported to offer “thyroid support.” Regarding this, the sections on dietary supplements, nutraceuticals, thyroid hormone analogs, and so called thyroid-enhancing and thyromimetic preparations, are outstanding. A case report, also in this issue, complements the new guidelines. Jha et al. (4) describe a patient with thyroid storm due to administration of a compounded thyroid hormone preparation—always an inappropriate oral treatment for hypothyroidism. It was estimated that, due to errors in formulation, the patient received 720,000 μg of T3 and 30,000 μg of T4 during a 6-day period, far above the production rate for T3 or T4. This dramatic case emphasizes the rule to avoid nonstandard thyroid hormone preparations in outpatients with hypothyroidism. It has few, if any, exceptions.
Timing of L-Thyroxine Therapy for Hypothyroidism
Garber et al. (1) also extend previous guidelines by considering when and how patients with hypothyroidism should take their daily dose of thyroxine. Recommendation 23 states “L-thyroxine should be taken with water consistently 30–60 minutes before breakfast or at bedtime 4 hours after the last meal.” The recommendation is solid insofar as it utilizes the available studies but, complicating as it does the lifestyle of patients, will be difficult to implement. As far as this recommendation is concerned the provision in the new guidelines (1) to “use information in conjunction with best clinical judgment” is worth remembering. The overriding goal is to arrive at a dose schedule that ensures daily compliance with thyroid hormone therapy; compromises in implementing this recommendation may be needed.
One of the features of the new guidelines (1) is a comprehensive discussion of areas for future research. Among the topics are cardiac and cognitive benefits of treating subclinical hypothyroidism, further consideration of combination T4 and T3 therapy, interpretation of thyroid function tests, and screening for hypothyroidism in pregnancy. To this list might be added the need for additional research to identify additional “best times” that hypothyroid patients can take, perhaps more reliably, their thyroid medication.
Aspects of Hypothyroidism Not Addressed in the New Guidelines
The 2012 clinical practice guidelines in adults (1) are far more extensive than the above outline would indicate. Even so, as the authors stipulate, topics relating to hypothyroidism are even more numerous than those presented within the new guidelines (1). Three deserve comment. First, as indicated in the introduction to the new guidelines (1), myxedema coma is not considered. This deserves comment not only because of the serious nature of myxedema coma, but also because its management differs in some respects from the recommendations for outpatients with hypothyroidism. For example, in myxedema coma clinical signs and symptoms have a major role in diagnosis and initial management. When myxedema coma is suspected it is essential to obtain thyroid function tests and confirm that the patient is hypothyroid. However, treatment with thyroid hormone must often be started before this, based on a presumptive diagnosis of myxedema coma and the urgent need to reverse the deteriorating clinical course. Initial dosing with thyroid hormone is also more aggressive in myxedema coma than in some patients with hypothyroidism (See Recommendations 22.6, 22.7.1, 22.7.2, and 22.8). Second, although the new guidelines (1) emphasize the difficulties with thyroid function testing in severely ill patients, their preface stresses that they “principally address the management of ambulatory patients.” Therefore the guidelines do not cover parenteral administration of thyroid hormone. This is sometimes essential not only in patients with myxedema coma, but also in some severely ill patients who develop malabsorption of thyroid hormone and require intravenous L-thyroxine. Finally, as the title specifies, the new guidelines are intended for the management of hypothyroidism in adults, not children and infants. However, the guidelines do list “children and infants” in the category of patients who should be seen in consultation with an endocrinologist. Most would agree that endocrinologists should manage thyroid hormone treatment in infants with hypothyroidism. Endocrinologists should also be involved, though not always as frequently, in the management of children with hypothyroidism.
Thyroid Hormone Receptor Alpha Resistance: Selective Hypothyroidism, Not Panhypothyroidism?
The year 2012 is noteworthy not only for the publication of the first comprehensive guidelines dealing solely with hypothyroidism, but also for the first three reported human cases (5,6) of resistance to thyroid hormone (RTH) due to mutations of the thyroid hormone receptor alpha (TRα) gene (RTHα). Patients with RTHα have many of the classical features of hypothyroidism including growth retardation, skeletal dysplasia, severe constipation, macroglossia, and gait disturbances. This syndrome contrasts with RTH due to mutations of the TRβ gene (RTHβ). Patients with RTHβ, unlike those with RTHα, have few of the features of overt hypothyroidism and some tissues or organs even exhibit characteristics of mild thyrotoxicosis. As a gross simplification, the phenotypic differences between patients with RTHα compared with those with RTHβ are most probably related to differences between the cell functions regulated by TRα and TRβ. In addition, however, as TRβ but not TRα mediates thyroid hormone feedback on TSH secretion, there is an increase in serum TSH in patients with RTHβ, but not in those with RTHα. This probably has a compensating effect.
Finally, the relationship between phenotype and the degree of dominate negativity of the mutated TR genes in syndromes of RTH needs to be considered. In the patient reported by Bochukova et al. (5), the RTHα was a potent dominant negative inhibitor of the wild-type receptor in vitro. This was also noted by van Mullem et al. in their patient (6). Despite this, thyroid hormone treatment was partially successful in relieving constipation in the patient of van Mullem et al. (6) and her affected father. Much more information regarding the efficacy of thyroid hormone treatment to relieve the different signs, symptoms, and metabolic features of this new syndrome is eagerly awaited.
The description of RTHα opens a new chapter in our understanding of the pathogenesis of the features of hypothyroidism and gives theoretical credence to the concept of selective hypothyroidism as opposed to what might be call panhypothyroidism. At present the concept of selective hypothyroidism is only valid for RTHα. Future studies will indicate how common RTHα is and help decide if there are analogous conditions in which thyroid hormone insufficiency is limited to certain cells or tissues.
In RTHα, serum T4 and free T4 concentrations are low normal or subnormal, serum TSH levels are normal, and serum T3 and free T3 concentrations are high-normal or elevated (5,6). The last finding is interesting as it brings to mind the recommendation in the new guidelines for hypothyroidism (1). In RTHα, as in “panhypothyroidism”, serum T3 determinations can be misleading in judging thyroid hormone sufficiency.
The new guidelines for hypothyroidism of Garber et al. (1) are a major document and will undoubtedly be a foundation for forthcoming editions. It will be interesting to see if and how these will be influenced by recent and future discoveries relating to thyroid hormone action.