Primary hypothyroidism and quality of life

Abstract

In the 1970s, treatment with thyroid extract was superseded by levothyroxine, a synthetic L form of tetraiodothyronine. Since then, no major innovation has emerged for the treatment of hypothyroidism. The biochemical definition of subclinical hypothyroidism is a matter of debate. Indiscriminate screening for hypothyroidism has led to overdiagnosis and treatment initiation at lower serum levels of thyroid-stimulating hormone (TSH) than previously. Adverse health effects have been documented in individuals with hypothyroidism or hyperthyroidism, and these adverse effects can affect health-related quality of life (QOL). Levothyroxine substitution improves, but does not always normalize, QOL, especially for individuals with mild hypothyroidism. However, neither studies combining levothyroxine and liothyronine (the synthetic form of tri-iodothyronine) nor the use of desiccated thyroid extract have shown robust improvements in patient satisfaction. Future studies should focus not only on a better understanding of an individual's TSH set point (the innate narrow physiological range of serum concentration of TSH in an individual, before the onset of hypothyroidism) and alternative thyroid hormone combinations and formulations, but also on autoimmunity and comorbidities unrelated to hypothyroidism as drivers of patient dissatisfaction. Attention to the long-term health consequences of hypothyroidism, beyond QOL, and the risks of overtreatment is imperative.

Fig. 1 |. Roles of the DIO1 and DIO2 pathways in the TSH feedback mechanism during treatment with levothyroxine.

Levothyroxine is converted into triiodothyronine (T₃) by the action of type 1 deiodinase (DIO1) and type 2 diodinase (DIO2). T₃ produced in DIO1-expressing tissues (such as the liver) rapidly returns to the circulation, whereas T₃ produced in DIO2-expressing tissues (such as the brain, pituitary and adipose tissue) remains in the tissue longer and stimulates local thyroid hormone signalling. Conversion of levothyroxine or thyroxine (T₄) to T₃ triggers the ubiquitination of DIO2 and its destruction by the proteasome. Serum levels of T₄ are detected by the medial basal hypothalamus (MBH)–pituitary unit. Tanycytes within the MBH express high levels of DIO2, allowing them to convert T₄ into T₃, which then suppresses thyroid-stimulating hormone (TSH) secretion from the thyroid and thyrotropin releasing hormone (TRH) secretion from TRH neurons. ER, endoplasmic reticulum; Ub, ubiquitin. WSB1 is a subunit of ubiquitin ligase. FIGURE 1 adapted with permission from REF., Mary Ann Liebert Inc.

Fig. 2 |. Proportion of dissatisfaction expressed by patients with self-reported hypothyroidism by type of treatment for hypothyroidism.

a | Percentage of dissatisfied responders across four categories: weight, fatigue, mood and memory. Responders received one of three treatments: levothyroxine (n = 6,949); levothyroxine and liothyronine combination therapy (n = 978) or desiccated thyroid extract (DTE) (n = 3,239). An asterisk denotes that the values for DTE were statistically significantly different (P < 0.05) to other treatments. b | Percentage of dissatisfied responders (left) receiving either levothyroxine (n = 677), levothyroxine and liothyronine combination therapy (n = 124), liothyronine (n = 45) or DTE (n = 123). Quality of life (QOL) scores (right) for the same patient groups. A score of 100 represents the best possible QOL while a score of 0 represents the worst. Asterisks denote statistically significant differences between levothyroxine compared with levothyroxine and liothyronine combination (**P = 0.001), and levothyroxine compared with DTE (*P = 0.010). These graphs show that the differences between different treatments are minor and that a substantial proportion of patients are dissatisfied and have a suboptimal QOL regardless of type of treatment, which suggests that combination treatment with levothyroxine and liothyronine or DTE often fails to restore health-related QOL. Panel a is derived from data from Peterson et al.; panel b is derived from data from Mitchell et al..

Fig. 3 |. Changes in components of QOL before and after treatment of hypothyroidism.

Radar plot showing patient-related outcome using ThyPRO, at baseline (red) and six months after starting levothyroxine treatment for autoimmune hypothyroidism (green), compared with normative data (yellow). FIGURE 3 is adapted from REF., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).