Reverse T3 or perverse T3? Still puzzling after 40 years
REVERSE T3 AND SYSTEMIC ILLNESS
D3 is the main physiologic inactivator of thyroid hormones. This enzyme plays a central role in protecting tissues from an excess of thyroid hormone.23,24 This mechanism is crucial for fetal development and explains the high expression of D3 in the human placenta and fetal tissues.
In adult tissues, the importance of D3 in the regulation of thyroid hormone homeostasis becomes apparent under certain pathophysiologic conditions, such as nonthyroidal illness and malnutrition.
Whenever a reduction in metabolism is homeostatically desirable, such as in critically ill patients or during starvation, conversion to T3 is reduced and, alternatively, conversion to reverse T3 is increased. This pathway represents a metabolic adaptation that may protect the tissues from the catabolic effects of thyroid hormone that could otherwise worsen the patient’s basic clinical condition.
Euthyroid sick syndrome or hypothyroid?
In a variety of systemic illnesses, some patients with low T3, low or normal T4, and normal thyroid-stimulating hormone (TSH) levels could in fact be “sick euthyroid” rather than hypothyroid. The first reports of the euthyroid sick syndrome or low T3 syndrome date back to about 1976, and even though assays for reverse T3 were not widely available, some authors linked the syndrome to high levels of reverse T3.15,16 The syndrome is also known as nonthyroidal illness syndrome.
Advances in techniques for measuring T3, reverse T3, and other iodothyronines filled a gap in the understanding of the alterations that occur in thyroid hormone economy during severe nonthyroidal diseases. In 1982, Wartofsky and Burman25 reviewed the alterations in thyroid function in patients with systemic illness and discussed other factors that may alter thyroid economy, such as age, stress, and diverse drugs.
More recently, the low-T3 syndrome was revisited with a generalized concept regarding the role of D3 in the syndrome.26 D3, normally undetectable in mature tissues, is reactivated in diverse cell types in response to injury and is responsible for a fall in serum T3 levels. Hypoxia induces D3 activity and mRNA in vitro and in vivo.27 Recent studies have focused on the role of cytokines in the low T3 syndrome. For instance, interleukin 6 reduces D1 and D2 activity and increases D3 activity in vitro.28
In the outpatient setting, diverse conditions may affect thyroid hormone homeostasis, compatible with mild or atypical forms of low-T3 syndrome, including caloric deprivation, heart failure, and human immunodeficiency virus infection.29
POSSIBLE CLINICAL UTILITY OF MEASURING REVERSE T3
In inpatients
Unfortunately, measuring serum reverse T3 levels has not, in general, proven clinically useful for the diagnosis of hypothyroidism in systemically ill patients. Burmeister30 demonstrated, in a retrospective study, that when illness complicates the interpretation of thyroid function tests, serum reverse T3 measurements do not reliably distinguish the hypothyroid sick patient from the euthyroid sick patient. The best way to make the diagnosis, Burmeister suggested, is by clinical assessment, combined use of free T4 and TSH measurements, and patient follow-up.
In the outpatient setting, the utility of reverse T3 measurements is controversial. In intensive care units, the differential diagnosis between hypothyroidism and nonthyroidal illness syndrome can sometimes be difficult. Reverse T3 levels can be low, normal, or high regardless of the thyroidal state of the patient.30 Moreover, endogenous changes in the hypothalamic-pituitary-thyroid axis may be further complicated by medications commonly used in intensive care units, such as dopamine and glucocorticoids. Changes in thyroid function should be evaluated in the context of the patient’s clinical condition (Table 1).20 But regardless of the T3 level, treatment with T3 or T4 should not be started without taking into consideration the patient’s general clinical context; controlled trials have not shown such therapy to be beneficial.20
In outpatients
In noncritical conditions that may be associated with mild forms of low T3 syndrome, patients generally present with low T3 concentrations concurrently with low or normal TSH. Not infrequently, however, patients present with a serum reverse T3 measurement and impute their symptoms of hypothyroidism to “abnormal” reverse T3 levels, in spite of normal TSH levels.
There is no rationale for measuring reverse T3 to initiate or to adjust levothyroxine therapy—the single test relevant for these purposes is the TSH measurement. The risks of basing treatment decisions on reverse T3 levels include the use of excessive doses of levothyroxine that may lead to a state of subclinical or even clinical hyperthyroidism.
TAKE-HOME MESSAGE
The existence of an inactivating pathway of thyroid hormones represents a homeostatic mechanism, and in selected circumstances measuring serum reverse T3 may be useful, such as in euthyroid sick patients. The discovery of the molecular mechanisms that lead to the reactivation of D3 in illness is an important field of research.
