**Fig. 2** Neuropsychological outcomes in children with congenital hypothyroidism (CH) treated early and continuously with levothyroxine (LT4). (**a**) *Study 1*: global intelligence quotient measured at 5.75 years of age in children with CH of varying severity, and in euthyroid control children. Children with CH received LT4 at a median dose of 12 μg/kg from a median age of 14 days. Bars show range of measurements. Differences between groups were described as being not statistically signifcant (the source did not provide *p* values). (Drawn from data presented in Ref. [56]). (**b**) *Study 2*: IQ measurements at 5.9 years of age in children with CH according to whether they had received a low or high dose of LT4. LT4 treatment started between 13 and 60 days after birth (mean 27 days). Low-dose LT4 = 6–<10 μg/kg/day; high-dose LT4 = 10–16 μg/kg/day). Bars are SD. There were no signifcant differences between low- and high-dose groups for any measure of IQ (*p* = 0.16–0.78). (Drawn from data presented in Ref. [57])

mild-to-moderate developmental delay at age 2–3 years in early-diagnosed and treated children with congenital hypothyroidism [61]. Ten-year old children with congenital hypothyroidism who were diagnosed via neonatal screening have been shown to be at risk of reduced health-related quality of life (HRQoL), and adverse perception of self-worth, compared with their euthyroid peers [62]. These defcits in QoL were independent of cognitive or neuropsychological functioning.

#### *3.2 Subclinical Hypothyroidism*

Individual studies have demonstrated that LT4 treatment reduced hypothyroidlike symptoms in children with subclinical hypothyroidism [63], or the mean antithyroglobulin titre in children with Hashimoto's thyroiditis [64]. Treatment of children with mild, subclinical hypothyroidism with LT4 was not disease modifying, in that it did not decrease the likelihood of an increase in TSH after treatment withdrawal [65]. There is little evidence to support improved neuropsychological outcomes with LT4 treatment in this population, however [34]. One prospective study found signifcantly reduced scores for verbal memory and verbal recall in 20 children with TSH 5–10 μIU/L, compared with a control group [36]. Treatment for 6 months with LT4 restored the test performance in the children with subclinical hypothyroidism to the level of controls.

Obesity is associated with hypothyroidism (especially the subclinical form) in children, as described above. A 6-month, randomised trial in 51 obese children with TSH 4–10 mIU/L (with or without abnormalities of other thyroid hormones) showed that administration of LT4 vs. no additional treatment, alongside weight loss interventions, had no signifcant effect on BMI or lipid abnormalities [66]. A similar study, where LT4 was or was not added to a behavioural intervention for obesity, reported similar results [67]. These data suggest there is no place for LT4 in the general management of obesity in children with TSH levels consistent with subclinical hypothyroidism. Correlations of higher TSH levels with higher BMI in hypothyroid children controlled on LT4 have been observed [68], but this association is probably not independently causative for obesity [1, 69].

Administration of LT4 to 30 children with subclinical hypothyroidism (mean age 7 years, mean TSH 8.7 mIU/L) for 6 months increased measures of left ventricular systolic performance (myocardial performance index, fraction shortening, and ejection fraction), but did not affect diastolic function (*E*/*E*′ ratio) [70]. This study was uncontrolled, and these parameters were not overtly decreased before treatment, so that the clinical relevance of these fndings is diffcult to assess. Migraine may be a symptom of subclinical hypothyroidism, which responds to treatment with LT4 [71].

Box 1 summarises guideline recommendations for the management of subclinical hypothyroidism in children [43, 53, 69]. The majority of this population will not need active treatment, as long as thyroid hormones are within range and thyroid function is not deteriorating. The European guidance differs from the guidelines from Latin America and from the USA since it was specifcally addressed for hypothyroidism in children, and it identifes the frst 3 years of life as the crucial period for optimising thyroid function with LT4 (this is the time when thyroid hormones have their greatest infuence on development of the brain). Monotherapy with LT4 is used exclusively: there is no role for the therapeutic use of T3 currently, as in other populations. A recent expert opinion recommends reserving LT4-based management of subclinical hypothyroidism to children with autoimmune (Hashimoto) disease, children whose thyroid function is deteriorating over time, or for children with goitre, other congenital abnormalities associated with thyroid dysfunction (Turner Syndrome or Down Syndrome) [72].

#### **Box 1: Summary of Guidance Relating to the Use of Levothyroxine (LT4) in Children with Subclinical Hypothyroidism** [46, 53, 69]

	- *Especially beyond 1 month of age and who have signs and symptoms of hypothyroidism and/or risk factors for progression of thyroid dysfunction*

Guidance has been adapted and combined from Latin American [46], the USA [53], and European [69] guidelines and has been paraphrased for brevity. See the full guidelines for more details

#### *3.3 Biochemically Euthyroid Children*

A randomised trial in 59 biochemically euthyroid children with Hashimoto's thyroiditis showed that treatment with LT4 (mean dose 1.6 μg/kg/day, based individually on body weight) vs. no treatment reduced thyroid volume transiently, and did not affect either thyroid function or the level of thyroid autoantibodies [73]. Observational data from 330 children with autoimmune thyroiditis and type 1 diabetes showed a reduction in antibodies in the treated cohort, suggesting a possible role for LT4 therapy in this population [74].

#### **4 Conclusions**

Thyroid hormones are essential for the development of the central nervous system early in life. Early and continuous treatment with LT4 of children with overt hypothyroidism preserves near-normal neuropsychological development. Subclinical hypothyroidism often resolves spontaneously and most children will not need LT4 treatment. However, close observation is key since some children with this condition may require LT4 to manage symptoms, or they may develop overt hypothyroidism in the future.

#### **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

## **Levothyroxine in the Older Patient**

**Salman Razvi**

**Levels of the pituitary hormone thyrotropin (thyroid-stimulating hormone, TSH) tend to run higher in older individuals than in younger adults. As TSH is used to guide replacement with levothyroxine (LT4), older patients may be at risk of over treatment if TSH levels towards the lower part of the standard adult reference range are aimed for. Recent randomised clinical trials have not demonstrated clinical beneft from the use of LT4 in older patients with subclinical hypothyroidism (diagnosed and treated according to standard, adult TSH reference ranges). The results of the recent Study of Optimal Replacement of Thyroxine in the Elderly (SORTED 1) feasibility trial suggest that older hypothyroid patients can be treated using a higher than usual target range for TSH with no apparent adverse effects, at least over the short term.**

#### **1 Thyroid Homeostasis in Older Individuals**

#### *1.1 Thyroid Homeostasis*

Hypothyroidism is diagnosed when serum thyrotropin (thyroid-stimulating hormone or TSH) is elevated and thyroid hormones are low. The incidence of hypothyroidism increases with age. The reference range limits for serum TSH and thyroid hormones are calculated from measurements obtained from all age groups. However, both the median and 97.5th centile values for TSH increase with age (Fig. 1) [1]. Several studies from various parts of the world have confrmed the increase in serum TSH concentrations with ageing [2–6].

S. Razvi (\*)

Translational and Clinical Research Institute, University of Newcastle, Newcastle-upon-Tyne, UK e-mail<EMAIL_ADDRESS>
**Fig. 1** Medians and 2.5th–97.5th percentile reference ranges for thyrotropin (TSH) according to age in healthy subjects from a large (*n* = 13,344) population-based study in the USA. Subjects with risk factors for thyroid dysfunction such as pregnancy, oestrogens, androgens, lithium, antithyroid antibodies, and treated thyroid disease were excluded. (Drawn from data presented in Ref. [1])

A study of ambulatory older individuals found that 1 in 40 people had low levels of circulating free thyroxine (FT4) index although thyrotropin levels were normal [7]. A comparison of six of these subjects (mean age 69 years) with six age- and gender-matched subjects with normal FT4 index (also with a normal thyrotropin level) showed that pituitary or hypothalamic dysfunction, pituitary thyrotropin reserve, thyroid reserve, and the biological actions of secreted thyrotropin, did not differ between these groups [7]. Accordingly, the authors concluded that this functional hypothyroidism in some older patients was due to a resetting of the hypothalamic-pituitary-thyroid feedback axis. The mechanisms underlying the increase in TSH with age remain to be elucidated. It does appear, however, that TSH secretion in older people is increased without any change in its bioactivity [8].

#### *1.2 Thyroid Hormone Levels and Clinical Outcomes*

Lower TSH or higher FT4 levels, including variations of these hormones within the normal range, have been associated with increased risk of mortality [9–12], major adverse cardiovascular events (including myocardial infarction) [13], heart failure [14], frailty [15], and dementia [16, 17] in older populations. Conversely, low-normal FT4 was associated with better mobility and less fatigue, compared with higher levels of FT4, in a study of 602 older euthyroid individuals [18].

Not all studies have associated higher FT4 levels within the normal range with adverse outcomes in older patients, however. Higher thyrotropin and lower FT4 in hospitalised older patients was associated with an increased risk of a composite of morbidity/mortality outcomes (death, admission to the intensive care unit, or hospital stay >18 days) in a retrospective study [19]. Another study found a higher rate of cognitive decline over time in older women with low-normal vs. high-normal, FT4 [20]. A population-based study demonstrated no association between FT4 levels and cognitive decline in a cohort born in 1912–1914 [10].

Some of these studies suggested little or no signifcant effect of modest increases in TSH (consistent with subclinical hypothyroidism) on outcomes in this population, even where higher FT4 was associated with an adverse prognosis [12, 14, 17]. Higher TSH in 85 year-old individuals was associated with reduced mortality in the Leiden 85+ study though the authors emphasised the need for further data to corroborate this fnding [10]. Another study of a larger number of 85-year-old individuals followed up for a longer period of time than the Leiden study did not confrm the protective association of high TSH with mortality in this age group but nevertheless confrmed that a slightly raised serum TSH was not associated with adverse outcomes [4]. Elsewhere, the risk of heart failure was only increased if TSH was unequivocally abnormal (<0.1 or >10 mIU/L) [14]. A meta-analysis concluded that the excess risk of adverse cardiovascular outcomes in older patients with subclinical hypothyroidism was small, with minimal increased risk in studies of higher quality (relative risks 1.2–1.8 vs. euthyroid individuals) [21]. A second meta-analysis found no association between subclinical hypothyroidism and adverse cardiovascular outcomes in older patients [22].

#### **2 Therapeutic Use of Levothyroxine in Older Patients with Hypothyroidism**

#### *2.1 Analyses from Randomised, Placebo-Controlled Trials*

The Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial (TRUST) randomised 737 adults aged ≥65 years with thyrotropin 4.6–<20 mIU/L and normal FT4 to double-blind treatment with levothyroxine (LT4) or placebo for 1 year [23, 24]. As expected, mean thyrotropin was lower in the LT4 group (3.6 mIU/L) compared with the placebo group (5.5 mIU/L) at study end. However, there was no effect on the co-primary endpoints in this study (change from baseline in two validated questionnaires specifc to thyroid dysfunction: Hypothyroid Symptoms and Tiredness, and the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire), or on other secondary outcomes. The TRUST trial has been criticised for recruiting participants with mostly low symptom burden [25]. Therefore, it is interesting that a *post hoc* analysis in subjects with more pronounced symptoms of hypothyroidism at baseline produced a similar lack of clinical beneft of LT4 treatment [26]. Additional sub-analysis from TRUST found no effect of LT4 treatment on cardiac function [27] or bone metabolism [28] in this population.

Pooling the data from two randomised trials, including a subgroup from TRUST, involving a total of 251 patients with subclinical hypothyroidism aged ≥80 years also found no signifcant effect of LT4 on thyroid symptoms or fatigue, relative to placebo [29]. Administration of LT4 for 1 year to patients aged ≥65 years in the primary care setting had no signifcant effect on cognitive function [30]. A randomised trial in outpatients aged 55 years or over reported a nominally signifcant effect of LT4 treatment on a composite memory score though there were no benefts of treatments relating to other endpoints, or to health-related quality of life [31]. A metaanalysis published in 2018, which included two studies in patients aged >65 years with subclinical hypothyroidism also found no evidence of clinical beneft arising from intervention with LT4 [32].

Hypothyroidism has been associated with an adverse cardiovascular prognosis in some studies (see chapter, "Levothyroxine and the Heart"). Randomisation of 185 patients with subclinical hypothyroidism in a nested subgroup of participants within the TRUST trial aged ≥65 years to LT4 vs. placebo for an average of 18 months had no signifcant effect on carotid intima-media thickness (a measure of the overall burden of atherosclerosis), however [33].

#### *2.2 Observational Studies of Levothyroxine in Older Patients with Hypothyroidism*

Observational data in subjects with subclinical hypothyroidism (diagnosed using a cut-off for thyrotropin of 8 mIU/L) showed that a similar overall improvement from baseline in health-related quality of life occurred following LT4 treatment in younger (<40 years) and older (>60 years) patients [34]. Both age groups beneftted from improvements in "Emotional Susceptibility" and "Impaired Daily Life" domains; older patients additionally improved their score for "Tiredness" and younger patients improved their score for "Cognitive Complaints". A recent study that included 24 patients with hypothyroidism who were aged ≥65 years and already receiving stable doses of LT4 involved increasing the dose of LT4 by 12.5 mg/day (irrespective of the previous dose) in a single-blind manner for 3 months [35]. This change was suffcient to reduce mean thyrotropin from 1.95 to 0.47 mIU/L. The period of administration of the higher LT4 dose was accompanied by a signifcant improvement in the Geriatric Depression Scale score, including in patients with a score consistent with clinical depression at baseline, without inducing symptoms of hyperthyroidism. However, the impact of higher doses of LT4 in this age group on long-term outcomes, particularly the risk of atrial fbrillation and osteoporosis, is unknown.

Any severity of hyperthyroidism increases the risk of bone fractures [36], which is a particular concern for the elderly who may be already at risk of age-related osteoporosis [37]. Treatment of women aged ≥65 years with LT4 at a daily dose >150 μg/day was associated with increased fracture risk in an observational study, with the highest risk in women already receiving treatment for osteoporosis [38]. A case-control study in subjects aged ≥70 years also found a dose-related increase in the risk of fractures associated with LT4 treatment [39]. One potential mechanism for the observed adverse events may be due to the risk of inadvertent over-treatment with LT4. In a community-based cohort study, iatrogenic thyrotoxicosis accounted for approximately half of low TSH events, with the highest rates among older women, who are vulnerable to atrial fbrillation and osteoporosis [40]. No evidence of any differences in long-term health outcomes are observed when thyrotropin concentrations are maintained within the reference range [41]. Chapter "Levothyroxine and Bone" provides a fuller account of the effects of LT4 on bone health.

#### *2.3 Managing Elderly Patients with Hypothyroidism: Implications of the SORTED 1 Trial*

The studies reviewed above suggest that the clinical sequelae of hypothyroidism, particularly the subclinical form, appear to be less severe in older vs. younger patients. The randomised evaluations of LT4 have not provided unequivocal evidence for beneft of intervention with LT4 in older patients, especially those with subclinical hypothyroidism [23, 24, 26–29]. It is important to remember that the diagnosis of hypothyroidism and the titration of the LT4 dose were guided in these studies by standard reference ranges for thyrotropin in adults. Given the shift towards higher levels of thyrotropin in elderly populations, the population of TRUST and similar studies probably included individuals who had high TSH relative to the standard adult reference range, who would have been classifed as euthyroid using a more age-appropriate reference range [32].

The Study of Optimal Replacement of Thyroxine in the Elderly (SORTED1) study evaluated the clinical consequences of using LT4 to control the level of thyrotropin within a higher range than the usual reference range used to guide LT4 therapy in adults [42–44]. This trial was conducted in 48 elderly (≥80 years) patients with pre-existing hypothyroidism whose thyrotropin was well controlled as per the usual local adult reference range (0.4–4.0 mIU/L). The patients were randomised in a single-blind manner to continuing treatment guided by the standard reference range, or by a higher range (4.1–8.0 mIU/L) for 6 months.

As expected, the mean thyrotropin level (±SD) was higher at 6 months in the higher range group (6.6 ± 2.9 mIU/L) than in the standard range group (1.4 ± 1.0 mIU/L); corresponding mean values of other hormones were 16.0 ± 2.5 and 19.4 ± 3.5 pmol/L, respectively, for FT4 and 3.5 ± 0.5 and 3.9 ± 0.4 pmol/L, respectively, for FT3. The mean FT3/FT4 ratio was similar in the higher range (0.23 ± 0.04) and standard range (0.21 ± 0.05) groups.

There were no clinically signifcant differences between groups for mean values of lipid parameters, blood pressures, weight, pulse rate, and a bone resorption marker at study end (Fig. 2). In addition, small and similar changes in group occurred in scores on questionnaires that measured generic and thyroid dysfunction-specifc quality of life (EQ-5D and ThyDQoL), or on the risk of falling (falls risk assessment test) or mobility (timed up and go test). The most common allcause adverse events (AE) in the standard and higher range groups were "Feeling more tired" (38% and 50%, respectively) and "Problems with balance or mobility" (17% in each group). No other AE occurred in more than two patients in either group.

**Fig. 2** Effects of randomisation of elderly subjects with subclinical hypothyroidism to a higher or lower target range for thyrotropin on cardiovascular risk factors and a marker of bone resorption in the SORTED 1 Trial. Formal statistical testing was not carried out in this trial, but differences may be considered to be not statistically signifcant as 95%CI for mean differences between groups overlap zero for every parameter. *HDL* high density lipoprotein. See text for defnitions of higher and lower range groups. (Drawn from data presented in Ref. [44])

#### **3 Conclusions**

Thyrotropin levels shift towards higher concentrations in older individuals but current reference ranges are applied uniformly across all age groups. Hence, a signifcant number of people, particularly in the older age group, are diagnosed with subclinical hypothyroidism and a proportion of these are treated with LT4. The long-term health outcomes and cost-effectiveness of treatment in this particular group of patients is unknown. Furthermore, it also remains unclear whether a higher thyrotropin reference range should be aimed for in older patients on LT4 therapy.

The SORTED 1 trial demonstrated that titrating LT4 therapy to a higher than usual reference range in elderly patients may not adversely affect symptoms of hypothyroidism, or impair quality of life. Moreover, this trial has shown that a suitably powered long-term study is feasible, in order to verify these fndings.

Current guidelines for the management of hypothyroidism in adults date back to 2014, or earlier [45, 46]. These guidelines acknowledge the shift towards higher levels of thyrotropin as people age (Box 1), as well as the possibility of accepting a higher target value for thyrotropin. There is no unequivocal recommendation to use age-specifc reference ranges for thyrotropin in elderly patients with hypothyroidism, however. There is growing recognition, though, that the TSH reference range does need to appropriately refect the age of the individual [47]. The results of recent randomised trials, including SORTED 1 and TRUST, will inform future guidance on the management of the elderly patient with hypothyroidism, probably leading to a less intensive application of LT4 and acceptance of a higher range of thyrotropin levels in elderly patients.

#### **Box 1: Key Recommendations from the USA** [45] **and European** [46] **Guidelines on the General Approach for the Management of Hypothyroidism in Elderly Patients**

#### **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

## **Levothyroxine and the Heart**

**Bernadette Biondi**

**Thyroid hormone defciency has been associated with multiple changes in cardiovascular structure and function in recent studies. A strong relationship has been reported between overt and subclinical hypothyroidism with serum TSH ≥10 mIU/L and adverse cardiovascular outcomes, suggesting the necessity of replacement doses of Levothyroxine. The potential benefts of replacement therapy remain an active area of research in euthyroid patients with heart failure.**

#### **1 Introduction**

Hypothyroidism is a common condition of thyroid hormone defciency which can lead to increased cardiovascular mortality when untreated. Overt hypothyroidism is defned by thyroxine concentrations below the reference range and a serum thyrotropin (thyroid-stimulating hormone, TSH) measurement that is outside an appropriate reference range (typically between 0.4 and 4.0–4.5 mIU/L, defned in a population of subjects without thyroid disease) [1, 2]. Subclinical hypothyroidism occurs where there is elevation of TSH despite the level of free thyroxine (FT4) being within the normal reference range. Patients with a serum TSH ≥10 mIU/L have a severe form of subclinical hypothyroidism, whereas patients with subclinical hypothyroidism and TSH <10 mIU/L are described as having a "mild" form of this condition, according to European guidance [1]. This chapter considers the effects of hypothyroidism and levothyroxine (LT4) replacement therapy on the heart and cardiovascular system.

B. Biondi (\*)

Professor of Endocrinology and Internal Medicine, University of Naples Federico II, Naples, Italy e-mail<EMAIL_ADDRESS>

**Table 1** Overview of observational studies of the associations between thyroid status and cardiovascular health that recruited at least 1000 subjects

#### **2 Overview of the Adverse Effects of Thyroid Dysfunction on the Heart**

Many observational studies have evaluated cardiovascular function in people with hypothyroidism and Table 1 summarises the results of some large, recent studies [3–19]. The fndings of these studies were variable, probably because of differences between populations in terms of the severity of hypothyroidism, the age of the patients, and the presence of comorbidities. Nevertheless, expert opinions reported a signifcant association between hypothyroidism with serum TSH ≥10 mIU/L and adverse cardiovascular outcomes [20, 21]. A systematic review demonstrated multiple effects of subclinical hypothyroidism on the heart that were consistent with reduced diastolic or systolic cardiac left ventricular performance, and some of its key fndings are summarised in Table 2 [21, 22]. In contrast, a meta-analysis found that the presence or absence of anti-thyroid peroxidase antibodies neither increases nor reduces the risk of adverse cardiovascular outcomes in people with subclinical hypothyroidism [23].

**Table 2** Overview of the effects of subclinical hypothyroidism and levothyroxine replacement therapy on the heart, from a systematic review

Changes in parameters refect those seen in most (not necessarily all) studies: ↑ = increased; ↓ = decreased; ↔ = variable effects

*E/A* early-to-late transmitral peak fow velocity ratio, *ET* ejection time, *IRT* isovolumic relaxation time, *LV* left ventricular, *PEP* pre-ejection period. Compiled from information presented in Refs. [21, 22]

a Usually increased when measured using Doppler ultrasound (usually no effect when measured using Weissler's method)

Results of studies that evaluated the relationships between thyroid status and the lipid profle have also been variable although there is some evidence that more severe increases in TSH are associated with a more adverse change in the lipid profle [22]. Effects of the hypothyroid state on "non-traditional" cardiovascular risk factors (e.g. markers of haemostasis or systemic infammation) were variable although there was some support for a possible action of hypothyroidism in exacerbating atherosclerosis [22].

The association of hypothyroidism with adverse cardiovascular outcomes appears to be stronger and most consistent for people with heart failure [24–26]. A recent (2019) meta-analysis of 14 studies (21,221 patients) found a signifcant association between hypothyroidism (including the subclinical form) and major prognostic outcomes associated with heart failure, such as cardiac death and/or hospitalisation [27]. A pooled analysis of prospective cohort studies showed that the risk of heart failure events (any physician-diagnosed acute heart failure event, or hospitalization or death related to heart failure) increased as the level of TSH increased above a euthyroid range defned as a TSH level of 0.45–4.49 mIU/L [28]. The hazard ratio (HR) for heart failure events for TSH 7–9.9 mIU/L vs. the euthyroid state was 1.65 (95%CI 0.84–3.23). TSH levels associated with hyperthyroidism also increased the risk of heart failure events in this analysis. Elsewhere, 12 years of prospective follow-up of 3,044 elderly (age ≥65 years) subjects with subclinical hypothyroidism showed that a TSH level >10 mIU/L was associated with an almost doubled risk of developing new heart failure HR 1.88; 95%CI 10.5–3.34) [18]. On the other hand, cardiovascular diseases such as heart failure may themselves lead to an altered thyroid function [29]. Low circulating T3 levels are a common fnding in patients with heart failure and contribute to adverse outcomes in this condition [25].

#### **3 Effects of Levothyroxine Replacement Therapy on the Cardiovascular System**

#### *3.1 Effects on ECG Parameters*

Hypothyroid patients have abnormal heart rate variability compared with euthyroid controls, which can be corrected by an adequate LT4 replacement therapy [30]. Ambulatory ECG recording showed that long-term LT4 replacement appears to avoid the bradyarrhythmias commonly associated with hypothyroidism [31]. Moreover, LT4 treatment may reduce QT interval dispersion in patients with subclinical hypothyroidism, reducing the risk of malignant cardiac arrhythmias [32].

#### *3.2 Effects of l-Thyroxine on Cardiovascular Structure and Function*

Subclinical hypothyroidism appears to represent a mild form of thyroid failure that displays early signs of the cardiovascular dysfunction associated with hypothyroidism [33, 34]. The impairment in systolic and/or diastolic performance observed in patients with subclinical hypothyroidism, compared with healthy controls, has been shown to reverse during treatment with LT4 for periods of up to 1 year (Table 2) [21]. Such effects have been observed in young adults but not in elderly subjects in some randomized trials [35–37].

An overview of these and other studies in populations with subclinical hypothyroidism are summarised in Table 3 [32, 35–51]. Markers of atherosclerosis or arterial stiffness improved in some studies [39, 52]. A further cross-sectional analysis demonstrated an improvement in atrial volume [53]. Another randomised trial showed that treatment with LT4 improved cholesterol levels in people with subclinical hypothyroidism [39]. In addition, patients with mild subclinical hypothyroidism without associated cardiovascular risk factors have a coronary endothelial dysfunction that appears in response to a physiological stimulus [54]. A metaanalysis found an improved lipid profle and reduced carotid intima-media thickness (a marker of the overall burden of atherosclerosis) in patients with subclinical hypothyroidism [38]. Finally, treatment with LT4 may reduce cardiovascular risk in patients with diabetes: increased prevalence of thyroid dysfunction in patients with diabetes (and *vice versa*) suggests that there may be pathogenetic links between these conditions [55].

Thus, clinical evidence has associated overt and severe subclinical hypothyroidism with indices of increased cardiovascular risk, including dyslipidaemia, impaired cardiac function (especially during diastole) and impaired vascular function [56]. Evidence of potentially benefcial cardiovascular effects of LT4 replacement therapy on these parameters has led some experts to propose intervention with LT4 in patients with mild subclinical hypothyroidism and elevated cardiovascular risk factors. However, until more reliable evidence is available from randomised,

(continued)

#### **Table 3** (continued)

Diagnoses of subclinical hypothyroidism are as described in source publications according to clinical guidance at the time and have not been reviewed against current guidance

Abbreviations for study designs: *DB* double blind, *MA* meta-analysis (individual studies included in this analysis are omitted here for conciseness), *O* observational/cohort study, *R* randomised, *RT* retrospective. Other abbreviations: *BMI* body mass index, *CHD* coronary heart disease, *HF* heart failure, *IHD* ischaemic heart disease, *IRR* incidence rate ratio, *LV* left ventricular, *MACE* major adverse cardiac events, *ACH* subclinical hypothyroidism, *TSH* thyroid-stimulating hormone (thyrotropin)

a Months with euthyroid function established on LT4 replacement therapy

controlled trials, intervention with LT4 should be considered on an individual, caseby-case basis, balancing the patient's potential for progressive thyroid failure with the need to protect the cardiovascular system [56].

An increase in left ventricular mass with a consequent diastolic dysfunction can be observed during long-term therapy with TSH-suppressive doses of LT4 [57, 58]. The addition of a β-blocker can ameliorate the potentially adverse effects of prolonged TSH suppression and be useful in patients with high-risk differentiated thyroid cancer [58]. The role of LT4 in the management of thyroid cancer is discussed in chapter, "Levothyroxine and Cancer" of this book.

#### *3.3 Effects of LT4 on Major Adverse Cardiovascular Events*

So far, only retrospective studies have evaluated the effects of LT4 treatment on cardiac endpoints in patients with subclinical hypothyroidism (Table 3c). The results of these studies, however, are variable. Two studies showed no signifcant effects of LT4 replacement on the risk of myocardial infarction, or on cardiovascular and all cause death [49, 50]. Intriguingly, there was a suggestion of a greater potential for cardiovascular beneft of LT4 therapy in younger than in older patients [51, 52]. A smaller study suggested some cardiovascular beneft for a longer rather than a shorter duration of LT4 treatment [47].

A large database analysis in a population with hypothyroidism, of whom 97% received LT4 during a median follow-up of 6 years, showed that treatment with LT4 *per se* was insuffcient to protect the cardiovascular system if TSH was not normalised [48]. Specifcally, under-treatment with LT4 (TSH >10 mIU/L) in this study was associated with increased risk of ischaemic heart disease (HR 1.18 [1.02–1.38], *p* = 0.03), heart failure (HR 1.42 [1.21–1.67], *p* < 0.001), or death (HR 2.21 [2.07–2.36], *p* < 0.001), compared with euthyroid subjects (TSH 2–2.5 mIU/L). A further, register-based study showed that every 6 months of elevated TSH was associated with increased risk of mortality in LT4-treated individuals, with identical risks (HR 1.05 [1.03–1.08], *p* < 0.0001) for TSH >4 IU/L or TSH >10 IU/L, compared with euthyroid controls (this study is not shown in Table 3, as it did not report cardiovascular outcomes) [59].

Treatment with LT4 for more than 1 year reduced the risk of developing CHD, compared with no LT4 treatment, in a large retrospective analysis from Taiwan [60]. The effect of LT4 therapy on clinical outcomes was also measured in a retrospective study on 12,283 patients with atrial fbrillation [61]. The adjusted risk of mortality was lower in women treated with LT4 (hazard ratio [HR] 0.78 [95%CI 0.68–0.91]), but not men (HR 0.87 [95%CI 0.69–1.10]) compared to those untreated. There was no signifcant effect of LT4 treatment on rates of myocardial infarction, stroke, or heart failure in this study. A large (*N* = 87,902) retrospective study saw no difference in cardiovascular outcomes between patients receiving a branded or generic preparation of LT4 [62].

#### *3.4 Effects of LT4 in Patients with Heart Failure*

A retrospective analysis of a large database of patients with heart failure from Denmark (*N* = 224,670) compared outcomes in non-users of LT4 and in 6,560 patients using LT4 at the start of the analysis, and in 9007 who subsequently received LT4 therapy [63]. Both groups of LT4 users were at increased risk of allcause death, cardiovascular death, or MACE, compared with non-users. However, the risk of myocardial infarction was increased in patients already taking LT4 at baseline but reduced in patients who started LT4 during the follow-up period.

Large, randomized clinical trials of LT4 replacement therapy powered for determination of effects on clinical outcomes are lacking in populations of euthyroid subjects with heart failure and hypothyroidism. A placebo-controlled evaluation of LT4 treatment in 20 subjects with cardiac insuffciency secondary to idiopathic dilated cardiomyopathy demonstrated improvements in multiple measures of cardiac function, including LV ejection fraction, cardiac output, LV diastolic dimensions, systemic vascular resistance, and functional capacity [64, 65]. Another small (*N* = 28) study involved randomization of patients with severe symptoms of heart failure (New York Heart Association class III–IV) to LT4 supplementation or to no treatment for 1 month [66]. Signifcant improvements were seen in LV ejection fraction and isovolumic relaxation time in the LT4 group. An uncontrolled evaluation of LT4 in 10 patients with severe LV systolic dysfunction and cardiogenic shock demonstrated signifcant improvements in cardiac index, pulmonary capillary wedge pressure, and mean arterial blood pressure at times up to 36 h after treatment [67]. LT4 treatment also contributed to stabilization of the condition of 9/10 of these patients, allowing for surgical intervention (heart transplant or insertion of a mechanical device to assist the heart).

Administration of T3 in patients with heart failure has also been demonstrated to improve cardiac performance in patients with severe heart failure, in some [68, 69] but not all [70] studies. Although current guidance for the management of thyroid dysfunction (see chapter, "Pharmacodynamic and Therapeutic Actions of Levothyroxine") does not support the therapeutic use of preparations of T3, these fndings are consistent with a role for thyroid dysfunction within the pathophysiology of heart failure, and with the importance of the low T3 syndrome in this setting [25]. The therapeutic use of T3 in patients with heart failure remains within the research domain, for now, and further clinical studies are needed in this area.

#### **4 Conclusions**

Hypothyroidism, including the severe form of subclinical hypothyroidism in which TSH is ≥10 mIU/L, has been associated with multiple negative changes in the structure and function of cardiovascular tissues and adverse cardiovascular outcomes. Some studies have shown that intervention with LT4 to correct hypothyroidism can result in a reduced risk of MACE although the results of studies are conficting. Randomized clinical trials are needed and yet problematic in patients with overt hypothyroidism because management guidelines clearly state that all patients with this condition must be treated with LT4.

A potential role for LT4 therapy remains an active area of research in patients with subclinical hypothyroidism. It is particularly important to correct hypothyroidism

and the more severe form of subclinical hypothyroidism in these patients [20, 21, 25]. Elderly patients with hypothyroidism may be especially challenging to manage, as they are more likely than younger patients to present with one or more cardiovascular comorbidities. For all patients, careful tailoring of the LT4 dose in hypothyroid patients should be performed to ovoid over-treatment and possible adverse effects on the cardiovascular system.

#### **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

## **Levothyroxine and Bone**

**Weiping Teng**

**Thyroid hormones play an important role in the development of the skeleton in children, and in maintaining bone mineral content in adults. Hyperthyroidism is associated with loss of bone mineral content, with increased risk of fractures. This has raised concerns that treatment (especially over treatment) with levothyroxine (LT4) might mimic these adverse effects on the skeleton. Clinical data on the effects of LT4 administration on bone are conficting. In general, the use of LT4 to maintain euthyroid levels of thyroid hormones in patients with hypothyroidism, or even the use of thyrotropin-suppressive therapy following removal of thyroid tumours, does not appear to carry a substantial risk of osteoporosis or fractures. Nevertheless, a cautious approach to avoid over treatment is recommended, especially in patients with or at risk of developing osteoporosis.**

#### **1 Overview of the Effects of Thyroid Hormones on the Skeleton**

Thyroid hormones (principally triiodothyronine, derived from naturally produced thyroxine or exogenously administered levothyroxine [LT4]) are essential for the normal development of the skeleton [1, 2]. Untreated congenital hypothyroidism, where there is a profound lack of thyroid function from birth, is associated with delayed development of the skeleton, impaired development of epiphyseal growth plates, short stature (dwarfsm), reduced mineralisation of bones, scoliosis and congenital hip displacement, among other complications [1, 2]. Reduced bone turnover

W. Teng (\*)

First Hospital of China Medical University, Shenyang, China

Institute of Endocrinology, China Medical University, Shenyang, China e-mail<EMAIL_ADDRESS>
in adults with hypothyroidism may result in increased bone mineralisation and mass, but such changes are slow to develop and this phenomenon has not been well studied clinically [2]. Hypothyroidism is not strongly associated with fractures [3, 4] although one meta-analysis described such a relationship that was apparently independently of changes in bone mineral density (BMD).

Hyperthyroidism increases the rate of turnover of bone, with a net loss of bone mineralisation; accordingly, suboptimally managed hyperthyroidism can be a cause of osteoporosis and increased fracture risk [1, 2]. Restoration of euthyroid status reverses the loss of bone mineral content and also ameliorates the excess fracture risk in patients with hyperthyroidism [5]. Meta-analyses of cohort studies have revealed an excess risk of fractures in people with subclinical hyperthyroidism [3, 4, 6], and even in populations with high-normal free thyroxine (FT4) and low-normal thyrotropin (thyroid-stimulating hormone, TSH), according to current reference ranges [7].

The association of even mild severities of hyperthyroidism with bone loss and increased fracture risk raises a question over the possibility of an adverse effect on the skeleton of either over treatment with LT4, or during receipt of the TSHsuppressive doses of LT4 administered following the surgical removal of thyroid tumours. This chapter reviews clinical studies of bone health in people receiving treatment with LT4 in these settings.

#### **2 Bone Health in Patients Receiving Treatment with Levothyroxine**

#### *2.1 Patients with Congenital Hypothyroidism*

Early and continuous treatment with LT4 has been shown to promote normal growth [8, 9] and BMD or other indices of bone health [10–12] in children with congenital hypothyroidism, relative to their euthyroid peers (Fig. 1), and normal BMD in adults [13]. Maintenance of a healthy weight and calcium intake appears to be an important determinant of bone health in these children, as in other populations [11].

#### *2.2 Adult Patients with Hypothyroidism*

#### **2.2.1 Subclinical Hypothyroidism**

Administration of LT4 to women with subclinical hypothyroidism increased the rate of bone turnover although whether this effect of LT4 *per se*, or a reversal of a previous hypothyroid-induced reduction in bone turnover was unclear [14]. A meta-analysis of studies in populations with subclinical hypothyroidism found no clinically signifcant reduction in bone loss during LT4 treatment in pre-menopausal women (2.7% after 8.5 years of treatment), but there was more signifcant bone loss in post-menopausal women (9.0% after 9.9 years of treatment) [15]. In contrast, a randomised, controlled trial found no effect of 14 months of LT4

vs. no treatment on BMD in 17 women with subclinical hypothyroidism [16]. Observational data over 3 years showed that the bone-preserving effect of hormone replacement therapy for post-menopausal women was blunted during administration of LT4 for subclinical hypothyroidism [17]. Finally, BMD in adolescent girls treated with LT4 for subclinical hypothyroidism for 2–5 years had similar BMD to a control group [18].

#### **2.2.2 Overt Hypothyroidism**

LT4 dosage >150 mg/day, vs. lower doses, was associated with increased risk of fractures in women aged ≥65 years with hypothyroidism and a prior history of osteoporosis (Fig. 2) [19]. There was no signifcant effect in women without prior osteoporosis in this study. Another cross-sectional, observational study in postmenopausal women found reduced BMD associated with a longer duration of LT4 treatment, with no signifcant relationship between LT4 dosage and BMD in these women [20]. Another observational study in post-menopausal women found no association between LT4 treatment and bone loss, irrespective of the degree of suppression of TSH [21].

**Fig. 2** Risk of fractures associated with different daily doses of levothyroxine in a large database population stratifed by osteoporosis status at baseline. a No prior diagnosis of osteoporosis and no prescriptions for bisphosphonates; b prior diagnosis of osteoporosis regardless of treatment; c prior diagnosis of osteoporosis without prescription of bisphosphonate or raloxifene; d prior diagnosis of osteoporosis with prescription of bisphosphonate or raloxifene; e for age, comorbidities, comedications, Charlson comorbidity score, health service usage. (Drawn from data presented in Ref. [19])

**Fig. 3** Risk of a composite outcome of osteoporotic fractures or death, according to the prevailing level of thyrotropin (TSH), in a population-based database study of individuals receiving treatment with levothyroxine from the UK. a Adjusted for age, gender, history of hyperthyroidism, history of osteoporotic fracture, presence or absence of diabetes. (Drawn from data presented in Ref. [22])

Large database studies have also evaluated the effect of LT4 treatment on bone in general populations of patients with hypothyroidism. In one study, patients receiving LT4 therapy were at increased risk of fractures if they had either a high TSH level (>4 mIU/L) or a suppressed TSH level (≤0.03 mIU/L), compared with patients with TSH within the reference range (Fig. 3) [22]. Patients with TSH 0.4–4.0 mIU/L were not at increased risk of fractures in this study. Another large database study of 162,369 people with hypothyroidism, of whom 97% received LT4 during followup, found increased fracture risk among those with TSH >10 mIU/L, compared with those well controlled to within the euthyroid range (HR 1.15 (95%CI 1.01–1.31, *p* = 0.03) [23]. These studies demonstrated the importance of optimisation of LT4 treatment, rather than LT4 treatment *per se*, for maintaining bone health.

A case-control study from Denmark, where all 124,655 patients with a fracture served as cases and 373,962 randomly selected age- and gender-matched people without fractures served as controls, found no association between LT4 treatment and risk of fracture [24]. An analysis of 23,183 LT4 users from the UK General Practice Research Database (i.e. managed in the primary care setting) also found no signifcant association between LT4 use and fracture risk overall although there was an apparent increased risk in males [25]. Other observational data also did not identify a signifcant effect of LT4 treatment on bone health [26].

The recent SORTED 1 trial found no difference in effects on bone health measured using circulating levels of C-terminal telopeptide (CTx) levels in very elderly patients (≥80 years) with hypothyroidism randomised to control of TSH in the standard reference range (0.4–4.0 mIU/L), or to a higher target range (4.1–8.0 mIU/L) [27]; see chapter, "Levothyroxine in the Older Patient" for a fuller account of this trial. CTx correlates inversely with TSH, including during treatment with LT4, and may provide a useful marker for following effects of LT4 on bone metabolism [28].

#### *2.3 Effects of Thyrotropin-Suppressive Doses of Levothyroxine*

Long-term treatment with high doses of LT4 may be administered to suppress the activity of residual thyroid tumour cells after total thyroidectomy for welldifferentiated thyroid carcinoma (see chapter, "Levothyroxine and Cancer"). This setting has been likened to a state of "subclinical hyperthyroidism" by some authors [29].

The application of TSH-suppressive doses of LT4 has raised concern over its effects on bone health, given the known association between hyperthyroidism, osteoporosis and increased risk of fractures, as described above. Indeed, many clinical studies have applied various measures of bone mineral density or other markers of skeletal function to post-surgical, athyroid patients receiving TSH-suppressive therapy. Conficting results of the effects of TSH suppression were reported in premenopausal women (adverse effect [30–41], or no clear adverse effect [42–47]), or post-menopausal women (adverse effect [40, 48, 49] or no clear adverse effect [31, 45, 47, 50–53]). Clear adverse safety signals for osteoporosis during TSH suppression did not emerge from several studies in populations that included female populations of mixed pre-/post-menopausal status [54–60], men [31, 45, 61–63] or a mixture of either gender [37, 64–67] (one small study in a mixed population demonstrated increased bone loss with TSH suppression in patients with thyroid cancer [68]). Trabecular bone score may be a more sensitive measure than bone mineral density of the effects of treatment with LT4 on bone structure this parameter has been used in patients who have [31, 32], or have not [69], received thyroidectomy and TSH suppression for thyroid cancer, although changes in this measure did not correlate with changes in BMD in LT4-treated patients in another study [70]. An absence of marked effects on bone health was also observed in studies in which pre-menopausal women [71–74], post-menopausal women [71, 74, 75] or mixed populations [76, 77] received less intensive TSH-suppressive therapy for benign thyroid nodules, or for goitre.

Several studies evaluated fracture risk. One study found that the 10-year fracture risk (assessed using FRAX, an online risk assessment tool) in women (mean age 52 years) did not correlate signifcantly with LT4 dose, the duration of LT4 therapy or FT4 [42]. Others found no marked increase in the risk of fractures associated with TSH-suppressive therapy [65, 78, 79]. One study found associations between the intensity of TSH suppression and fracture risk: the incidence of vertebral fractures was 45% for patients with TSH <0.5 mIU/L, compared with 24% for TSH 0.5–1.0 mIU/L and 4% for TSH >1.0 mIU/L [80]. Similarly, the risk of osteoporosis was increased in patients receiving a cumulative LT4 dose over time of >395 mg, but not in patients receiving a lower dose, among 9398 patients with new-onset thyroid cancer followed for an average of 6.6 years [81].

Determinants of bone health in patients receiving TSH-suppressive therapy appear to be complex and multifactorial. A family history of osteoporosis and oestrogen defciency have been identifed as risk factors for adverse effects on bone in this population [57, 58, 82]. TSH-suppressive therapy itself was shown not to affect levels of sex hormone-binding globulin [83]. More data on the relationship of TSHsuppressive therapy and bone health are required, relating to older subjects, and men, in particular, however [84].

#### **3 Clinical Perspectives**

Clinical data on the effects of LT4 administration on bone are conficting. The many studies reviewed above differed importantly in design, their populations, their durations and the indices of bone health measured, especially with regard to important clinical outcomes, such as fractures. In general, the use of LT4 to maintain euthyroid levels of thyroid hormones in patients with hypothyroidism, or even the use of TSH-suppressive therapy following removal of thyroid tumours, does not appear to carry a substantial risk of osteoporosis or fractures. Nevertheless, the associations between LT4 administration and loss of bone mineralisation of increased fracture risk in some studies suggests the use of a cautious approach to avoid over treatment, especially in patients with or at risk of developing osteoporosis, such as postmenopausal women, or the elderly.

#### **References**

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

## **Levothyroxine and Cancer**

**Tomasz Bednarczuk**

**Treatment with LT4 is used to suppress thyrotropin levels after the management of differentiated thyroid cancers after surgery, with doses and targets for thyrotropin (thyroid-stimulating hormone, TSH) determined by the risk of cancer recurrence determined in the individual patient. Moreover, the role of thyroid hormones and their receptors in the initiation—and, potentially, cure—of a range of cancer types is an active area of research.**

#### **1 Introduction**

#### *1.1 Overview of the Management of Differentiated Thyroid Cancer*

In general, the treatment of differentiated thyroid cancers (DTC) consists of surgery, post-operative/adjuvant radioactive iodine (RAI, 131I) treatment and hormonal therapy with levothyroxine (LT4) [1, 2]. Surgery is the standard intervention for the management of DTC (although the management of microcancers of the thyroid remains a matter of debate) [1, 2]. Where the patient receives a total thyroidectomy, the resulting athyroid state induces a severe hypothyroidism that causes thyrotropin (TSH) to rise to high levels, typically at least 30 IU/mL after several weeks (compared with the usual upper limit of the normal reference range of about 4 mIU/L) [3].

For papillary or follicular thyroid tumours, the high TSH level stimulates any remaining unresectable thyroid tissue or metastatic tumour cells that retain some

T. Bednarczuk (\*)

Department of Internal Diseases and Endocrinology, Medical University of Warsaw, Warsaw, Poland e-mail<EMAIL_ADDRESS>
endocrine activity to take up iodine from the circulation [3]. Treatment with RAI is then administered periodically over a period of years and the RAI is taken up avidly by these cells resulting in their irradiation and ablation: in this way, the majority of these cancers can be eradicated successfully [1, 3]. Injections of recombinant human TSH may also be used to increase RAI uptake of residual thyroid cancer cells [3, 4].

Patients may require lifelong substitution of LT4 after thyroid surgery for DTC, depending on the amount of thyroid tissue removed [3, 5]. Moreover, high-risk patients may receive TSH-suppressive therapy with LT4. The decision on whether to aim for full suppression of TSH (TSH < 0.1 mIU/L), or partial TSH suppression (TSH 0.1–0.4 mIU/L) should be personalised [2, 3].

#### *1.2 Scope of This Chapter*

This chapter reviews the benefts and risks associated with LT4-suppressive therapy in patients who have undergone surgery and RAI for DTC. The diagnosis of thyroid cancer, tumour staging, allocation of patients to different modalities of surgery and their outcomes, and the application, effectiveness of and development of refractoriness to RAI *per se* are beyond its scope and will not be discussed further here (we refer the reader to current guidelines in these areas [1, 3, 5, 6]). In addition, the consequences of long-term suppressive LT4 administration for bone homeostasis and health in these patients are considered in chapter "Levothyroxine and Bone" of this book, and are also not discussed in detail here. Chapter "Levothyroxine and the Heart" of this book reviews the effects of TSH-suppressive doses of LT4 on the heart. Finally, medullary thyroid tumours arise from calcitonin-secreting parafollicular cells (C-cells) that do not secrete thyroxine: these patients are not treated with RAI and LT4 and their management is also not addressed here [7].

#### **2 Application of Thyrotropin-Suppressive Doses of Levothyroxine After Surgery and Radioactive Iodine for Well-Differentiated Thyroid Tumours**

#### *2.1 Need for Suppression of Thyrotropin in Thyroid Cancer Survivors*

TSH promotes the growth of thyroid tumours, and levels of this hormone are suppressed in the initial period following surgery for many DTC. A meta-analysis supports the effectiveness of this approach in improving long-term clinical outcomes post-thyroidectomy, compared with patients who did not receive TSH-suppressive therapy [8]. However, it has become clear in recent years that stringent suppression of TSH does not improve long-term clinical outcomes in patients with other than high-risk presentations of well-differentiated thyroid cancer [9–13]. Accordingly, **a**

patients with thyroid cancer assessed as being at lower risk of disease recurrence do not require complete suppression of TSH. This approach is designed to optimise the balance between suppression of disease recurrence (beneft) and the potential for adverse effects on bone [9].

For adults, the level of thyroglobulin has been found to be strongly predictive of the risk of recurrent disease (see Fig. 1a) [14], and thus different targets for TSH suppression are provided in guidelines for low-risk patients according to their post-surgery thyroglobulin levels [1, 3]. A recent meta-analysis has confrmed the diagnostic and prognostic power of thyroglobulin measurement during post-thyroidectomy TSH suppression using LT4, with negative predictive value for ruling out evidence of structural thyroid carcinoma in excess of 99% [15]. The relationship between thyroglobulin and post-surgical outcome is less well understood in children, for whom targets for TSH suppression are accordingly not stratifed formally according to the thyroglobulin level [3].

**Fig. 1** Thyroid hormones homeostasis and the risk of thyroid cancer. (**a**) Case-control study from the EPIC cohort. A population of 357 individuals with differentiated thyroid cancer were matched with 2 (women) or 3 (men) cancer-free control subjects. Signifcance values shown are p for trend. Total thyroxine (T3) and total triiodothyronine (T3) did not signifcantly infuence cancer risk and have been omitted for clarity. Adjusted for study site, age, gender, time/data of blood draw. (Drawn from data presented in Ref. [14]). (**b**) Risk factors for malignancy within the thyroid nodules in a multivariable logistic regression analysis that included variation of thyrotropin (TSH) levels within the normal range. Adjusted for gender, age, nodule size, preoperative TSH in patients not on levothyroxine. (Drawn from data presented in Ref. [26])

**Fig. 1** (continued)

#### *2.2 Long-Term Consequences of Thyroidectomy and Thyrotropin Suppression*

TSH-suppressive LT4 therapy induces a thyroid hormone status that is broadly equivalent to subclinical hyperthyroidism [13]. Overt hyperthyroidism during LT4 suppressive therapy should be avoided. Accordingly, care must be taken to achieve a balance between the achievement of adequate suppression of TSH levels to optimise cancer-free survival, with the potential adverse effects associated with subclinical hyperthyroidism [16]. Clinical studies in patients who have received LT4-based TSH-suppressive therapy have revealed several areas of concern or beneft, which are described briefy below.

#### **2.2.1 Bone**

Untreated longstanding hyperthyroidism is associated with loss of bone mineralisation, osteoporosis and increased risk of fractures. Studies in TSH-suppressed populations have been conficting, but some studies have demonstrated increased osteoporosis and fracture risk associated with LT4 treatment (reviewed in chapter "Levothyroxine and Bone" of this book).

#### **2.2.2 The Cardiovascular System**

A retrospective study from the Korean National Health Insurance database, which covers 97% of people in that country, evaluated the risk of coronary heart disease (CHD) and ischemic stroke over a follow-up period of 4.3 years in 182,419 patients following thyroidectomy for differentiated thyroid cancer [17]. Higher hazard ratios for CHD and stroke were found for the thyroidectomised population, relative to propensity scorematched controls. The signal for adverse cardiovascular outcomes became stronger at doses of LT4 that were higher than 115–144 μg/day. Although atrial fbrillation was more common in patients receiving higher doses of LT4, this was associated with only 4% of strokes. As expected, cardiovascular risk factors increased the risk of CHD or stroke. Another chart review in thyroid cancer survivors found no association between up to 9 years of over-suppression of TSH with LT4 (according to guideline recommendations based on risk of thyroid cancer recurrence) and adverse cardiovascular outcomes, but this study only contained 14 subjects [18]. Chapter "Levothyroxine and the Heart" of this book reviews the effects of LT4 on the heart.

#### **2.2.3 Patient-Reported Outcomes**

Fatigue is often reported as a long-term complication of thyroidectomy and subsequent TSH suppression [19]. One study showed that the persistence of residual symptoms reminiscent of hypothyroidism on TSH-suppressive therapy were correlated with a low level of FT3 [20]. Altering the dose of TSH, or switching to a combination of LT4 and T3 administration did not induce a clear improvement of fatigue, however [21, 22]. Current guidelines for the management of hypothyroidism recommend that LT4 remains the frst-line treatment. Exercise appears to be an effective way of combating fatigue and improving the quality of life in this setting [21, 23]. A similar beneft was observed in LT4-treated breast cancer patients undergoing chemotherapy [24]. More clinical studies of this relatively common, and potentially disabling, complication of thyroid cancer management are needed [21].

#### **3 Thyroid Hormones and Cancer Risk**

Variations in thyroid hormones have been associated with changes in the risk of a wide range of cancer types [25]. Examples of effects of thyroid hormones on the risk of various tumour types in epidemiological studies are shown below. However, the results are often conficting and have to be judged cautiously since association does not prove causation.

**Thyroid:** Observational data have associated an increased circulating level of TSH with an increased risk of developing differentiated thyroid cancer [26, 27] and/ or a more advanced stage of this tumour at presentation [26]. Other studies found that low TSH increased the risk of thyroid cancer [14], that high TSH in men, but low TSH in women, was associated with thyroid cancer [28], or that the infuence of abnormal TSH on cancer risk was amplifed in non-diabetic subjects with higher levels of fasting serum glucose [29]. Fig. 1 shows the risk of cancer associated with thyroid nodules at different levels of TSH and other markers of thyroid homeostasis from two of these observational studies. Higher TSH levels were associated with a lower risk of incident differentiated thyroid cancer in one study (Fig. 1a) [14], while increases in TSH levels within the normal reference range increased thyroid cancer risk in the other study, in patients with thyroid nodules (Fig. 1b) [26].

**Breast:** Hyperthyroidism (high TT4 or FT4 and/or low TSH) has been associated with increased risk of breast cancer in some observational studies [30–32]. This association was shown to extend into the euthyroid range [33], and to be present pre- and post-menopause [34]. There was no effect of variation of TSH in other studies [31, 35], and the impact of anti-thyroid antibodies on breast cancer risk was variable [30– 32]. A meta-analysis of 8 cross-sectional studies found a positive association between elevated T4, T3, anti-thyroid peroxidise antibodies and anti-thyroglobulin antibodies and the prevalence of breast cancer [36]. Likewise, autoimmune thyroiditis has been found to be more common in women with vs. without breast cancer [37].

A population-based case-control study from Taiwan (65,491 breast cancers, 261,964 controls) found that LT4 administration vs. no LT4 use was associated with a modestly higher risk of breast cancer, with a greater effect in older (≥65 years) patients (odds ratio [OR] 1.45 [95%CI 1.23–1.71], *p* < 0.01) compared with younger patients (OR 1.19 [95%CI 1.09–1.29], *p* < 0.01) [38]. However, the ORs were similar for patients who received LT4 for ≤1 year (1.22) and >1 year (1.26), and further study is required to confrm this association.

**Prostate:** Low TSH/high T4 increased the risk of prostate cancer in a populationbased observational study [30]. Conversely, and consistent with this study, high TSH was protective against prostate cancer in the population of a clinical trial conducted to answer a clinical question that was unrelated to thyroid function [39].

**Gastrointestinal:** A population-based study found no effect of TSH or FT4 levels on colorectal cancer risk [30]. However, high FT4, but not a diagnosis of hypothyroidism or hyperthyroidism, predicted shorter survival in a cohort of 258 patients with advanced gastro-oesophageal cancer [40]. Low FT3 was associated with prolonged survival in this study, which is diffcult to reconcile with the adverse effect of high FT4 [40].

A large population-based case-control study from a UK general practice database (The Health Improvement Network, 20,990 colorectal cancer cases and 82,054 controls) found that both hyperthyroidism and untreated hypothyroidism predicted an increased risk of having colorectal cancer [41]. Long-term treatment with LT4 was associated with a reduced risk of colorectal cancer, with a lower risk for a longer treatment duration [41].

**Liver:** Higher TSH was associated with larger tumours in a cohort of 838 patients with advanced hepatocellular carcinoma, and higher FT4 (≥16.6 ng/L) predicted poorer survival vs. lower levels of FT4 [42].

**Pancreas:** A retrospective study found that survival with pancreatic cancer did not vary according to hypothyroid or euthyroid status overall, but that hypothyroid patients taking LT4 demonstrated higher tumour stage, and more localised and distant tumour spread than euthyroid patients [43]. However, this study is diffcult to interpret, as there were only 71 hypothyroid patients included, and there was no information presented on how many were taking LT4 [43].

Table 1 summarises briefy some potential mechanisms that have been demonstrated in clinical or experimental studies to explain an association between thyroid hormone status and tumorigenesis [44–67]. Thyroid hormones mediate their effects

**Table 1** Potential mechanisms linking thyroid hormone actions to tumourigenesis or tumour suppression

on the cancer cell through several non-genomic pathways including activation of integrin avβ3 promoting metastasis and angiogenesis within tumours. Furthermore, cancer development and progression are affected by dysregulation of local bioavailability of thyroid hormones and thyroid hormone receptor changes [25, 45, 49, 68–70].

Tetraiodothyroacetic acid may oppose these actions [69]. The thyroid receptor, TRβ is downregulated in many tumours, and activation of this receptor has been proposed as a strategy for increasing the sensitivity of triple-negative breast cancer cells to chemotherapy [71].

Ovarian cancer is a highly metastatic tumour, and several thyroid hormone analogues exerted cytotoxic effects in ovarian cancer cell lines, probably by antagonising the effects of thyroid hormones on the integrin αvβ3 axis [72] A similar phenomenon has been observed in thyroid and lung cancer cells, among others [49, 51, 52, 69]. Tetraiodothyroacetic acid, a metabolite of T4, may reduce the resistance of cancer cells to radiotherapy [73]. Deiodinases modulate the local bioavailability of thyroid hormones, by controlling T4 conversion to T3 and other thyroid hormone derivatives and this expression of these enzymes differs in a range of tumour types, compared with non-neoplastic tissues [74, 75]. These observations provide promising avenues for future research on the development of novel anticancer agents.

#### **4 Conclusions**

Observational data have implicated variations in the levels of thyroid hormones with variations in the risk of a range of cancer types, including of the thyroid itself. This association extends to within the currently accepted "normal" range for thyroid hormones. In addition, the discovery of novel interactions between thyroid hormones and receptors both inside cells and in the extracellular space have opened up new avenues for anticancer research. Treatment with suppressive doses of LT4 is one of the key components of the management of differentiated thyroid cancers after surgery, where careful evaluation of the risk of cancer recurrence in the individual patient aids a balancing of the need to suppress TSH suffciently with the need to avoid over treatment.

#### **References**

American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1–133.

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

## **Practical Application of Levothyroxine-Based Therapy**

**Takashi Akamizu**

**Levothyroxine (LT4) is a natural, endogenous hormone. Adverse events associated with this treatment are mostly symptoms of over-treatment (a state of functional thyrotoxicosis), which can be avoided by careful titration of the LT4 dosage to keep thyrotropin within an appropriate reference range that is relevant to the needs of the individual patient.**

#### **1 Introduction**

The intention of this chapter is to complete this book on the role of levothyroxine (LT4) in the management of thyroid dysfunction, with a summary of the practical application of this treatment. The focus of the chapter will be on the management of hypothyroidism; for information relating to the implications of TSH-suppressive doses of LT4, the reader should consult chapter "Levothyroxine and Bone" and chapter "Levothyroxine and Cancer". I will consider how to dose LT4, how patients should take it and the tolerability and safety implications long-term LT4-based therapy. This approach will involve reviewing important information from prescribing documentation for preparations of LT4 from Europe [1] and the USA [2], as these impact on clinical practice across a large area of the world beyond the borders of those regions. For example, physicians in Middle-Eastern countries are infuenced by, but not bound by, labelling from both of these regions. Physicians should always consult their local labelling, where available, before prescribing LT4, however. Finally, the chapter will provide a resource of guidelines for the management of hypothyroidism around the world.

T. Akamizu (\*)

Wakayama Medical University, Wakayama, Japan

Kuma Hospital, Kobe, Japan e-mail<EMAIL_ADDRESS><EMAIL_ADDRESS>
#### **2 Safety and Tolerability of Levothyroxine**

#### *2.1 Avoiding Symptoms of Thyroid Dysfunction*

The prescribing documentation for levothyroxine (LT4) products for use in patients with hypothyroidism notes that the adverse events associated with this treatment generally refer to over-treatment with LT4, which induces a state of thyrotoxicosis. Alternatively, inadequate correction of TSH leaves the hypothyroid patient at risk of a range of adverse outcomes, including major adverse cardiovascular events and premature death (see chapter "Levothyroxine and the Heart" for more details) [3, 4]. Accordingly, both over-treatment and under-treatment with LT4 leave the patient with hypothyroidism at increased risk of adverse long-term clinical outcomes, as well as troublesome symptoms of thyroid dysfunction (summarised in Fig. 1).

**Fig. 1** Overview of symptoms arising from suboptimal dosing of levothyroxine in patients with hypothyroidism. Symptoms of hyperthyroidism/thyrotoxicosis were from a the European Summary of Product Characteristics [1] and b US Prescribing Information [2] for levothyroxine (LT4) products. Symptoms of hypothyroidism were as listed by the United Kingdom National Health Service [3]

The goal of LT4 management is thus to optimise the LT4 dosage [1–5]. It is important to note that symptoms of thyroid dysfunction are often non-specifc in nature, and in some cases similar symptoms are identifed for both under- and over-treatment with LT4.

Increased actions of catecholamines are a feature of thyrotoxicosis, including following an overdose of LT4 [6]. Accordingly, a number of adverse consequences of thyrotoxicosis following over-treatment with LT4 are mediated via over-stimulation of β-adrenoceptors, such as tachycardia, anxiety, agitation and hyperkinesia. Treatment with a β-blocker may be helpful here. The European prescribing documentation also warns that over dosage of LT4 may increase the risk of acute psychosis (especially in patients at risk of this condition), and that long-term abuse of LT4 has been associated with cardiovascular death. Seizures are another rare complication of LT4 therapy [2].

The possibility of increased risk of cardiovascular events (see chapter "Levothyroxine and the Heart"), or of osteoporotic fractures (see chapter "Levothyroxine and Bone"), are among the more serious long-term consequences of thyrotoxicosis. This is a particular concern where TSH-suppressive doses of LT4 are administered. Long-term treatment with high doses of LT4 may be administered after total thyroidectomy for well-differentiated thyroid carcinoma in order to suppress secretion of TSH from the pituitary (e.g. see chapter "Levothyroxine and Cancer"), which induces a thyrotoxic status similar to a chronic form of subclinical hyperthyroidism [7–9]. These patients are likely to be at elevated risk of long-term adverse effects, such as those in the cardiovascular system (possible increased risk of adverse cardiovascular events, see chapter "Levothyroxine and the Heart") or the skeleton (possible increased risk of osteoporosis and fractures, especially in those at increased risk, such as postmenopausal women—see chapter "Levothyroxine and Bone").

#### *2.2 Adverse Reactions to the LT4 Tablet Itself*

Additionally, as with any medicinal product, hypersensitivity reactions in the skin or respiratory system may occur rarely in response to components of the LT4 tablet, possibly including LT4 itself [1, 2]. Such reactions tend to manifest with symptoms, such as urticaria, eczema-like rashes, fever and disturbances of liver function tests, and may persist when different LT4 products are prescribed [10–13]. Excipients vary somewhat between LT4 preparations, and so changes the brand of LT4 may help to resolve the issue; however, hypersensitivity to LT4 itself may effectively prevent the effective management of hypothyroidism [14]. Procedures for oral desensitisation have been described, where administration of successively increasing LT4 dosages (e.g. at 30-min intervals, from an initial dose as low as 0.01 μg) enable subsequent chronic therapy with doses of LT4 that are clinically effective [10–13].

#### **3 How to Prescribe and Take Levothyroxine**

Hypothyroidism usually requires patients to take LT4 for life. Accordingly, patients must be educated on how to take their LT4 tablets correctly, to have any chance of achieving stable, euthyroid-like thyroid hormone function over the long term (Table 1). Food has a markedly inhibitory effect on the absorption and bioavailability of LT4 (see chapter "Administration and Pharmacokinetics of Levothyroxine"). Accordingly, it is important that LT4 is taken on an empty stomach, and that no

**Table 1** How to take levothyroxine (LT4): examples from products available in Europe and in the USA

#### **Table 1** (continued)

Compiled from information presented in Refs. [1, 2]

a The exact starting dose depends on other factors, such as thyrotropin (TSH) level and body weight b For the frst 3 months of life

c Start low, go slow in adults with hypothyroidism and CHD, and consider the possibility of a lower maintenance dose than in an adult without CHD

d Angina, arteriosclerosis, hypertension

e Healthy, non-elderly patients with recent onset hypothyroidism

f Guidance on doses for children of different ages is provided

food, coffee, etc. is consumed for at least 30 min (according to European guidance, and up to 1 h, according to guidance from the USA) after taking the LT4 tablet (half a glass of water or so is permitted to allow the tablet to be taken). The usual recommendation is to take LT4 frst thing in the morning, so that the 30 min before needing to eat is occupied by the usual morning rituals of bathing, etc. In principle, LT4 can be taken at bedtime although the need to wait for 3 h after the evening meal before taking the tablet [15, 16] may be diffcult to maintain consistently, with a consequent reduction in the stability of LT4's biological actions.

The administration of LT4 in the management of hypothyroidism is tailored to the individual needs of the patient, according to an individually determined target for thyrotropin (thyroid-stimulating hormone, TSH) [17, 18]. Starting and maintenance doses (Table 1) vary according to a number of factors, including the therapeutic indication for LT4, age and comorbidity (especially where there is concomitant cardiovascular disease). Starting doses of LT4 for the management of hypothyroidism, and perhaps long-term targets for the TSH level, are likely to be lower in patients with certain comorbidities. US labelling for LT4 permits initiating treatment at the estimated full LT4 dose for T4 replacement in a patient with recent onset hypothyroidism uncomplicated by comorbidities, however. The speed at which the LT4 dose is titrated to achieve control of TSH also varies with the characteristics of the individual patient.

Contraindications and warnings associated with LT4 usually relate to use in patients with comorbidities where the potential harm of accidental over-treatment with LT4 is highest. These relate especially to comorbidities in the cardiovascular and adrenal systems and the risk of osteoporosis (Table 1).

#### **4 Overview of Guidelines on the Management of Hypothyroidism**

This book has drawn on major guidelines from Europe and the USA to summarise the current role of LT4 in the management of hypothyroidism, as described in its individual chapters. Many other sources of guidance are available; however, we have listed some of these in Table 2, alongside those from Europe and the USA, as a resource our readers in these areas [17–32]. For clarity and brevity, we have restricted this slit to guidelines that impact on the management of hypothyroidism: please consult chapter "Levothyroxine and Cancer" for detailed information on the use of LT4 in the management of differentiated thyroid cancer.

**Table 2** Selection of guidelines for the management of hypothyroidism

**Table 2** (continued)

Guidelines published in or after 2010 are considered here. *AACE* American Association of Clinical Endocrinologists, *ACB* Association for Clinical Biochemistry, *ATA* American Thyroid Association, *BTA* British Thyroid Association, *BTF* British Thyroid Foundation, *DoH* Department of Health, *ES* Endocrine Society, *ETA* European Thyroid Association, *JTA* Japan Thyroid Association, *LATS* Latin American Thyroid Association, *NA* not available from source, *RCPA* Royal College of Pathologists of Australia, *TOP* towards optimised practice, *LT4* levothyroxine

Guidelines from the American Thyroid Association tend to be comprehensive and cover multiple aspects of thyroid dysfunction, while those from the European Thyroid Association tend to focus on specifc aspects, such as subclinical hypothyroidism in special patient populations. Hypothyroidism is especially diffcult to manage in the setting of pregnancy and breastfeeding, and guidelines from these expert societies address this need. Regional guidelines are available from Latin America, also, as well as individual countries including the UK and Japan.

#### **5 Conclusions**

The LT4 molecule is identical chemically with the endogenous thyroid hormone, T4. Accordingly, other than rare hypersensitivity reactions to excipients or other pharmaceutical components of the LT4 tablet, symptoms reported by people with hypothyroidism receiving LT4 treatment will relate to the dosage of LT4 they receive, and the severity of their thyroid dysfunction. Novel, re-engineered formulations of LT4 have the potential to increase the reproducibility and constancy of exposure to LT4 during long-term management, which may help to achieve optimal dose titration of LT4 (see chapter "Administration and Pharmacokinetics of Levothyroxine" for an example). Some patients are given supra-physiologic doses of LT4 as a deliberate part of their management, such as those undergoing LT4-based suppression of TSH levels to reduce the risk of disease recurrence after thyroidectomy for thyroid cancer, or to reduce the growth and potential for malignancy of thyroid nodules. Research is continuing to determine the most appropriate LT4-based management algorithms for these patients, to optimise their long-term clinical outcomes.

We, the authors, hope that you have enjoyed reading this book, and that you have found it useful in your clinical practice.

#### **References**

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**Mahmoud Elkazaz 1,2, Mark Sumner 1,\*, Seksak Pholboon 1, Richard Davies 1 and David Thomas 1**

Received: 1 June 2020; Accepted: 1 July 2020; Published: 3 July 2020

**Abstract:** Home energy management systems (HEMS) are a key technology for managing future electricity distribution systems as they can shift household electricity usage away from peak consumption times and can reduce the amount of local generation penetrating into the wider distribution system. In doing this they can also provide significant cost savings to domestic electricity users. This paper studies a HEMS which minimizes the daily energy costs, reduces energy lost to the utility, and improves photovoltaic (PV) self-consumption by controlling a home battery storage system (HBSS). The study assesses factors such as the overnight charging level, forecasting uncertainty, control sample time and tariff policy. Two management strategies have been used to control the HBSS; (1) a HEMS based on a real-time controller (RTC) and (2) a HEMS based on a model predictive controller (MPC). Several methods have been developed for home demand energy forecasting and PV generation forecasting and their impact on the HEMS is assessed. The influence of changing the battery's capacity and the PV system size on the energy costs and the lost energy are also evaluated. A significant reduction in energy costs and energy lost to the utility can be achieved by combining a suitable overnight charging level, an appropriate sample time, and an accurate forecasting tool. The HEMS has been implemented on an experimental house emulation system to demonstrate it can operate in real-time.

**Keywords:** distribution systems; smart home; battery energy storage; energy forecasting; model predictive control; real-time control


**Author details**

Adina L. Milac1 and Gabriela Negroiu2 \*

\*Address all correspondence to<EMAIL_ADDRESS>
1 Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania

2 Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania