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Clinical and epidemiological studies on thyroid function
Roos, Annemieke
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8
General discussion and future perspectives
113
Chapter 8
Part A. Effects of levels of thyroid stimulating hormone (TSH),
free t­ hyroxine (FT4) and free triiodothyronine (FT3) within the
euthyroid range on cardiovascular risk factors and mortality
1. Metabolic syndrome
In this thesis we have shown that a low normal thyroid function is associated with higher serum
cholesterol levels, increased insulin resistance and four out of five metabolic syndrome traits
in the general population (chapter 2). These findings have recently been confirmed in Korean,
Hispanic, German and Belgian populations.1–4 It has also been shown that serum free thyroxine
(FT4) levels are inversely related to carotid artery intima media thickness in euthyroid subjects.5,6
Two questions arise considering the clinical relevance of these epidemiological associations.
First, what is the impact of a low normal thyroid function on health? Surveillance could be
indicated in case of a low health impact, whereas additional investigations like screening for
cardiovascular risk factors or even medical intervention by e.g. treatment with levothyroxine
could be indicated in case of a high health impact. Second, is an earlier identification required
of subjects with a low normal thyroid function (low normal FT4 and/or a high normal thyroid
stimulating hormone (TSH)? Obviously, this low normal thyroid function is determined by the
definition of what is considered to be a normal TSH concentration, which has been discussed
extensively over the last decade.7,8
Taylor et al. have discussed the question regarding the impact of a low normal thyroid
function on health. They emphasize the association of higher TSH levels with the metabolic
syndrome.9 By extrapolation, they suggest that carefully monitored treatment of even slight
elevations of TSH may have substantial health benefits. They, however, also suggest that these
potential benefits will only be modest. Unfortunately, no prospective randomized intervention
trials have been performed to evaluate the influence of metabolic syndrome traits in euthyroid
subjects. Finally, they mention the risk of overtreatment, resulting in TSH suppression. This
may increase the risk for development of osteoporosis, atrial fibrillation and even cardiovascular
death.9–11
There are several reasons to propose early detection of subjects with a low normal thyroid
function. Firstly to identify subjects at risk for developing overt hypothyroidism. This topic
will further be discussed in part B of this general discussion. Secondly to prevent the possible
negative metabolic effects of a low normal thyroid function. This raises the question whether the
treatment of a low normal thyroid function is justified. Overt hypothyroidism is normally treated
114
General discussion and future perspectives
with levothyroxine. This treatment reduces or abolishes the various complaints associated with
thyroid dysfunction and normalizes the accompanying lipid abnormalities (chapter 6). In case of
subclinical hypothyroidism with a serum TSH ≥ 10 mIU/L and normal free T4 level, treatment
with levothyroxine is generally recommended, even when no symptoms are present.12–15 This is
in contrast with the recommendation for subjects with subclinical hypothyroidism, with only
mildly elevated serum TSH levels between 4.0 and 10.0 mIU/L, where treatment is generally
not recommended.
In conclusion, to date, no evidence is available which justifies early medical intervention
in subjects with low normal thyroid function, even though low normal thyroid function is
associated with higher serum cholesterol levels, increased insulin resistance and four out of
five metabolic syndrome traits.
2. Mortality
In a case-cohort study performed within the PREVEND study, we have demonstrated a clear
association of serum levels of both FT4 and free triiodothyronine (FT3) and the ratio of FT3
and FT4 with mortality in euthyroid subjects. Higher FT4 levels were associated with higher
cardiovascular mortality, while lower FT3 levels were associated with higher non-cardiovascular
and all-cause mortality during a median follow-up of 5.4 years. A lower FT3/FT4 ratio was
associated with both cardiovascular and non-cardiovascular, thus higher all-cause mortality
(chapter 3). These associations were independent of age, sex and other confounders like BMI,
blood pressure and serum cholesterol levels. In contrast to other observations,16 we found no
association of TSH with mortality.
It can be hypothesized that the association of low normal FT3 with mortality might be an
extension of the low T3 syndrome where low FT3 levels are associated with a poor prognosis.
In several types of acute and chronic illness, activity of type I deiodinase (D1) is reduced in
response to increased exposure to pro-inflammatory cytokines, thereby reducing T3 levels,17,18
known as ‘non-thyroidal illness (NTI)’. Serum levels of FT3 below the normal reference range
have been shown to be a predictor of poor prognosis.19–21 However, it is also known that the
laboratory measurement of FT3 is cumbersome. Therefore, the importance of our finding
remains to be established.
Until now, controversy exists about the relation of cardiovascular disease and mortality with
thyroid function within the euthyroid range. Yeap et al. found an association of higher FT4
levels and all-cause mortality in elderly males,22 which is in part consistent with our finding of an
115
Chapter 8
association of higher FT4 levels with higher cardiovascular mortality. In contrast to our results,
other research groups did find an association of both a low normal TSH and a high normal TSH
with mortality. In a large study of more than 40,000 subjects in Israel, Pereg et al. concluded that
a low normal TSH is associated with increased risk for all-cause mortality.16 Contrary, in a large
Norwegian study (the HUNT study) in more than 25,000 subjects with a median follow-up of
8.3 years, Asvold et al. concluded that TSH levels within the reference range were positively and
linearly associated with coronary heart disease mortality in women.23 However, they could not
confirm their conclusion after extension of the follow-up to 12 years and they did not provide
a plausible explanation for this apparent discrepancy unfortunately.24 Finally, in a prospective
observational study of a population-based cohort of individuals aged 85 years, increasing levels
of TSH and decreasing levels of free T4 were associated with a survival benefit, but no upper
limit of the TSH level was mentioned.25
In conclusion, we found associations of higher FT4 levels, lower FT3 levels and lower
FT3/FT4 ratio with mortality in euthyroid subjects and postulated potential underlying
pathophysiological mechanisms.
Part B. Prediction of the development of hypothyroidism
In this part of our studies, we confirmed the existence of a positive relationship of presence of
TPOAbs with high normal serum TSH. We showed that both presence of TPOAbs and high
normal TSH level – and particularly the combination of both – predict future development of
hypothyroidism, in initially euthyroid subjects originating from the general population. This is
in agreement with studies carried out in selected populations, like female relatives of patients
with autoimmune thyroid disease and middle-aged females.26,27
A prospective evaluation within the HUNT study has addressed, whether slightly elevated
TSH levels do predict the development of primary hypothyroidism. In men with TSH levels
between 4.0 and 4.5 mIU/L, the 11-year incidence of manifest primary hypothyroidism was
14.7 %. In women, this incidence was even 30%. In this study, manifest primary hypothyroidism
was defined as either the prescription of levothyroxine during follow-up or biochemical evidence
of hypothyroidism (TSH > 4.5 mIU/L combined with free T4 <9.0 pmol/L) at the follow-up
examination. It was additionally found that subjects with TSH 4.0–4.5 mIU/L, who tested
116
General discussion and future perspectives
positive for TPOAbs, had an approximately two-fold higher risk of development of primary
hypothyroidism compared to subjects with these levels of TSH, who tested negative.28
It would be of particular interest to know which euthyroid subjects are at risk for development
of thyroid dysfunction in the near future. Then, an advice about the control of thyroid
function during follow-up could be given. In our study population, we showed a more than
8-fold increase in incidence of hypothyroidism in subjects with a TSH level in the highest
quartile compared to those with a TSH level in the lowest quartile. We also found a more than
8-fold increase in the incidence of hypothyroidism in TPOAbs positive subjects compared to
TPOAbs negative subjects. A clear cut-off level of the TSH that predicts the increased risk of
developing hypothyroidism could not be identified.29 Strieder et al. developed a simple score
to predict the risk of developing overt hypothyroidism or hyperthyroidism based on the results
of thyroid function test, family history, and exposure to some environmental factors at study
entrance.26 This numerical score, the Thyroid Events Amsterdam (THEA) score, estimates the
5-year risk of overt thyroid dysfunction in female relatives of patients with autoimmune thyroid
disease. However, in view of the small number of observed events, the investigators called for an
independent validation of the THEA score. Unfortunately, we could not assess this in our study
because data about the family history of thyroid disease in our subjects are lacking.
Warren et al. also discussed the issue of thyroid function screening.30 They studied euthyroid
patients with type 1 or type 2 diabetes mellitus. During a mean follow-up of 6.1 years, a baseline
TSH concentration higher than 1.53 mIU/L (approximately defining the lower level of the top
quartile) predicted thyroid dysfunction; 21 out of 406 euthyroid subjects developed a serum
TSH above the normal reference range. No development of overt thyroid dysfunction was
found in 293 patients with baseline TSH levels lower than 1.53 mIU/L. The authors proposed
to stop annual thyroid screening in this latter group, but stated that confirmation was necessary.
In the HUNT study, no distinct cutoff value for TSH associated with an increased risk of
hypothyroidism was identified. The investigators showed that most people with a TSH value
between 2.5 and 4.5 mIU/L did not develop hypothyroidism during 11 years of follow-up.28
Table 1 shows the results of the prediction studies that are mentioned in this paragraph.
In conclusion, a clear cut off of a TSH level that predicts future hypothyroidism cannot be
given. Up till now, there is no evidence for standard follow-up of thyroid function in euthyroid
subjects. However, clinicians must be aware that, even in euthyroidism, both a higher TSH and
the presence of anti-TPO antibodies are associated with future hypothyroidism.
117
118
Asvold et al.
28
Strieder et al.
n=15,106 (33%)
n= 790 (100%)
n= 2394 (51%)
Roos et al.29
26
Study population
(%F)
Author
52
36
48
Age
Table 1. Incidence of hypothyroidism
1.5
2.1 (mean)
1.33 vs. 1.73
Median TSH
(TPO neg vs. pos)
(mIU/L)
n.a.
26.1%
8.4%
TPO-Abs
positive
(%)
11
5
9.1
3.5 vs. 1.3%
7.5%
0.6%
n.a.
n.a.
0.4 vs. 3.5
Incidence of
Incidence of
Follow up
hypothyroidism in
hypothyroidism
time
TPO neg vs. pos subjects
(F vs. M)
(yrs)
Chapter 8
General discussion and future perspectives
Part C. The treatment of overt hypothyroidism
Treatment of patients with primary hypothyroidism has been generally started with a dose of
25–50 µg levothyroxine, that is gradually increased towards a full supplementation dose.31 This
classical approach has been proven to be safe, although in the majority of patients it takes a long
period to reduce hypothyroidism-related complaints like fatigue, depression, cold intolerance
and weight gain. Due to the often long existing period of hypothyroidism before diagnosis and
increased likelihood of presence of subclinical atherosclerosis, some patients may experience
cardiac symptoms after dose increments, due to increased cardiac oxygen consumption in
combination with coronary artery dysfunction. These cardiac symptoms were the reason for
the standard approach of slow levothyroxine titration for several decades. However, the cardiac
symptoms may have been elicited by varying amounts of fast acting T3 that was part of the
desiccated thyroid extract prescribed in the past, while treatment nowadays only consists of
synthetical T4. In contrast to the conservative approach, we have demonstrated that subjects
with primary hypothyroidism without cardiac symptoms, treated with a full starting dose of
1.6 µg/kg body weight of levothyroxine (T4), did not show cardiac complaints. We postulated
that this might be more convenient and cost-effective than a low starting dose regimen. However,
even though serum TSH and FT4 levels had normalized 12 weeks earlier in the full starting dose
group compared to the low starting dose group, signs and symptoms of hypothyroidism and
quality of life improved at a comparable rate.
In our study, all patients underwent a thorough cardiac evaluation before start of the treatment,
and showed a normal resting electrocardiography, exercise test and stress-echocardiography,
possibly explained by the age of the patients (mean 47 years). Cardiac evaluation in patients
with hypothyroidism patient before starting levothyroxine is not common practice, and not
likely to be cost-effective. It could therefore be suggested to evaluate the cardiac risk –based on
age, medical history and present cardiac complaints – in order to decide to start with a low or a
full starting dose of levothyroxine. Subjects without a history or presence of cardiac complaints
who are no older than the arbitrary and non-evidence based age of 60 years can then be treated
with a full starting dose of levothyroxine. Although both regimens resulted in a comparable
improvement of hypothyroid complaints, a full strating dose may be more easy and clear, and
therefore more convenient, for patients.
In conclusion, we showed that a full starting dose of levothyroxine in cardiac asymptomatic
patients with primary hypothyroidism is safe. Present evidence-based guidelines on the
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Chapter 8
treatment of hypothyroidism all refer to our study when they recommend that, when initiating
therapy in young (< 60 years) healthy adults, a full replacement dose can be given.11,32,33
Perspective
History
Although the use of seaweed for the treatment of goiter has already been mentioned by the
Chinese around 2700 BC, and the presence of goiter can already be found in a pre-Colombian
sculpture, it was not until 1500 AD that Leonardo da Vinci was the first person to recognize and
draw the thyroid gland. Thomas Wharton in 1656, however, named this gland “thyroid” after the
shape of an ancient Grecian shield.34,35 In 1888, the Clinical Society of London published that
cretinism, myxedema, and post-thyroidectomy changes all were due to a deficiency of thyroid
hormone.36 This observation was soon followed by G.R. Murray’s introduction of the use of
sheep thyroid extract to treat myxedema.37 At present, more than a century later, clinical and
epidemiological studies on thyroid function are still frequently performed.
Variety in clinical presentation of hypothyroidism
In the past, primary hypothyroidism was considered to be a simple disease of organ malfunction,
characterized by the specific complaints of thyroid hormone deficiency: tiredness, feeling cold,
obstipation, weight gain, etc. This deficiency necessitates the supplementation of the specific
thyroid hormone, resulting in normalization of the metabolism and the clinical situation of a
patient. Nowadays, these concepts have changed. First of all we know that severe hypothyroidism
can go unnoticed. This knowledge is both based on epidemiological studies and the frequent
measurement of TSH. In a cross-sectional evaluation of TSH levels in the general population it
was found that 0.8% of participants has TSH levels of 10 mIU/L or higher.38 Moreover, healthrelated quality of life assessed by an SF-36 questionnaire was identical between subjects with a
normal TSH and subjects with a TSH above 10 mIU/L. The box depicts the clinical spectrum
of three patients with autoimmune hypothyroidism or Hashimoto thyroiditis. Their differing
clinical presentations and clinical outcomes underline the heterogeneity of the disease.
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General discussion and future perspectives
Case A: found by accidental screening
This woman, aged 27 years, did not report any spontaneous complaints other than a
slightly cold feeling, which she blamed to the time of the year (snowy weather in winter),
but showed with a TSH level of 180 mIU/L, a free T4 level of 1.2 pmol/L and positive
anti-TPO levels. After starting levothyroxine, she reported an increase in energy levels,
3 kg weight loss, feeling less cold, and quite all of a sudden she became pregnant, while in
the preceding 3 years she did not become pregnant.
Case B: severe complaints, mildly elevated serum TSH level
This woman, aged 22 years, reported severe complaints of fatigue, muscle and
concentration problems and a slightly enlarged and painful goiter, but only showed lightly
elevated TSH with normal free T4 levels and high levels of anti-TPO antibody titers. She
was treated with the combination of levothyroxine and triiodothyronin, but many of her
complaints remained, and could not be explained by another coinciding disorder.
Case C: severe clinical hypothyroidism of short duration
This patient was a woman, aged 34 years, who rapidly experienced complaints of fatigue,
muscle aches, and dyspnea on exertion. She turned out to have TSH level of 101 mIU/L,
while 6 weeks earlier her thyroid function proved to be absolutely normal. After
treatment with thyroid hormone, she rapidly improved and her TSH and FT4 levels
normalized within two months.
Up till now, this variety in clinical presentation, independent of the degree of hypothyroidism,
cannot be explained easily. It can be hypothesized that the auto-immune origin may play a
more important role than the severity of the hypothyroidism itself, for the level of TPOAbs is
associated with symptom load and quality of life. This was prospectively studied by Ott et al.
in female euthyroid patients who underwent surgery for benign goiter. The mean number of
reported symptoms was significantly higher in the group of patients with elevated TPO Abs,
while there was no difference in preoperative TSH levels.39 So a TSH level of 8 mIU/L could be
accompanied with more complaints in a subject with higher TPOAbs in comparison to a subject
with a lower TPOAbs level. However, this could not be confirmed in a study of Wekking et al. in
141 patients with primary hypothyroidism on adequate T4 treatment. They found that patients
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Chapter 8
showed poor performance on various domains of neurocognitive functioning compared with
mean standard reference values. Moreover, the levels of well-being were significantly lower
for patients compared with those of the general population. Neither serum TSH nor thyroid
antibodies were determinants of neurocognitive functioning and well-being.40 Another
hypothesis to explain the variety in the clinical presentation of primary hypothyroidism is the
presence of polymorphisms in type 2 deiodinase (DIO2) as a determinant of well-being. This
was shown in 552 treated hypothyroid patients on one stable dose of T4 therapy: different
genotypes were associated with different levels of well-being.41 The authors concluded that
this is likely to reflect an effect on local deiodination of T4 by the DIO2 in the brain for the
specific polymorphisms had no impact on circulating thyroid hormone levels. More research
on the pathophysiological backgrounds of both physical and psychological complaints of
hypothyroidism is needed in order to clarify this subject and to be able to understand our
patients better.
Screening for hypothyroidism?
A number of subjects with primary hypothyroidism are diagnosed by chance, as nowadays TSH
measurement is part of a more comprehensive evaluation of health. The complaints present in
hypothyroidism can also be found in the general population without hypothyroidism or are
associated with other diseases. Unexplained fatigue, elevated cholesterol levels, vitamin B12
deficiency42 and vitiligo43 may be a reason to consider the presence of primary hypothyroidism.
Standard screening for hypothyroidism in the general population is, however, a matter of
discussion. Wilson and Jungner were the first to propose general criteria for the World Health
Organization that justify screening.44 These criteria have been further developed and adjusted.
In the Netherlands, the Dutch Health Council has published a report about this topic and has
stated five principles for responsible screening.45 First, the disease should be a significant health
problem and the early detection of the disease should be of important benefit. Furthermore,
the screening test should be reliable and validated. Screening should be based on free choice of
the individual and respect for autonomy is important. Finally, the use of healthcare resources
should be cost-effective and appropriate.45 With regard to screening for hypothyroidism,
these criteria are not fulfilled. There is no evidence that early detection and treatment with
levothyroxine improves clinically important outcomes in individuals with hypothyroidism
detected by screening. Therefore it is suggested to only conduct case-finding: to screen the
subjects with an increased risk of hypothyroidism, based on the presence of goiter, history of
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General discussion and future perspectives
auto-immune disease, diabetes, previous radioactive iodine therapy and the use of medications
that may impair thyroid function, such as amiodarone and lithium carbonate, independent of
age and sex.46,47
Treatment of subclinical hypothyroidism?
Treatment of subclinical hypothyroidism, defined as an elevated serum TSH level with a normal
free T4 level, is generally recommended in subjects with serum TSH > 10 mIU/L, irrespective
of the presence of symptoms.9–12 However, recommendations for subjects with only a mildly
elevated TSH (4–10 mIU/L) are lacking. Intervention studies with levothyroxine in these
subjects have shown conflicting results with regard to metabolic syndrome traits, cardiovascular
parameters and complaints.10 Beneficial effects on serum lipids48 and absence of effect on
cholesterol levels49 have been demonstrated. Studies on complaints and quality of life did not
show significant differences in subjects with a TSH<10 mIU/L treated with levothyroxine,49–51
while Razvi et al. reported a significant improvement in symptoms of tiredness.49 One small,
prospective study in 27 patients – with a mean TSH of 7.1 mIU/L – suggested that thyroid
replacement therapy in subclinical hypothyroidism may help to prevent atherosclerosis in this
group of patients, since a marked improvement of endothelial function after levothyroxine
therapy was observed.52 An improvement of left ventricular systolic and diastolic function
was also observed after levothyroxine treatment in these patients.53 However, studies on ‘hard
clinical endpoints’ are lacking.
Vanderpump defended treatment in patients with mildly elevated TSH concentrations54
when symptomatic, pregnant or intending to become pregnant, younger than 65 years, and older
subjects with evidence of heart failure. To answer this question, we look forward to the results of
the TRUST (Thyroid Hormone Replacement for Subclinical Hypo-Thyroidism Trial) study.55 In
this study, the effects of thyroid hormone supplementation are prospectively evaluated in 3,000
subjects with subclinical hypothyroidism, defined as a TSH level between 4.5 and 20 mIU/L
and free T4 levels within the normal range. Primary outcome is the development of fatal and
non-fatal cardiovascular events and one of the secondary outcomes is thyroid-specific quality of
life. In a sub-study in the Netherlands, elderly participants of 80 years and older will be studied
to answer the additional value of the treatment of subclinical hypothyroidism on the same
endpoints in these very old people.56
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Chapter 8
Treatment of overt hypothyroidism
We sometimes keep on adjusting daily levothyroxine dose without ever reaching normal
TSH levels. Possible reasons are incompliance and interference with gastro-intestinal uptake
of thyroxine by food or medication. In our prospective intervention study, all patients took
the levothyroxine tablets in the morning before breakfast. Bolk et al. studied in a randomized
double-blind cross-over trial the effects of morning versus evening intake of levothyroxine. They
showed that levothyroxine taken at bedtime significantly improved thyroid hormone levels.
Although patients’ quality of life did not change, possibly due to the short period of bedtime
levothyroxine treatment, bedtime administration was more convenient for many patients.57 So
clinicians should inform their patients about the possibility of taking levothyroxine at bedtime
to provide them the possibility of the most convenient application.
Not uncommonly, patients’ complaints do not completely disappear, even after reaching
TSH concentrations within the normal reference range.40,58 This issue has received considerable
attention in the literature.40,41,58–60 One hypothesis is the presence of polymorphisms in type 2
deiodinase (DIO2) as a determinant of well-being while being in an hypothyroid state. Panicker
et al. showed that common variation in the DIO2 gene predicted psychological well-being in
552 treated hypothyroid patients on one stable dose of T4 therapy: the rare genotype (CC with
rs225014) was associated with poorer well-being.41 This is likely to reflect an effect on local
deiodination of T4 by the DIO2 in the brain for the specific polymorphisms had no impact on
circulating thyroid hormone levels.41,61 In contrast to these findings, in the study of Appelhof et
al. no association was found between the presence of polymorphisms in DIO2 and well-being
in 141 treated hypothyroid patients.59 They did, however, find an association of polymorphisms
in the brain-specific thyroid hormone transporter OATP1C1 with complaints of fatigue and
depression, measured by means of self-report questionnaires.60 Despite this association,
OATP1C1 polymorphisms did not explain differences in neurocognitive functioning. The
authors hypothesize that the determinants of decreased levels of well-being may well be of a
different origin then the determinants of impaired neurocognitive functioning.60
In our primary hypothyroidism study group we observed that the symptoms score – reported
by the patients – improved, but not fully normalized, despite adequate TSH levels. Strikingly,
the clinical score – reported by the physician – declined to zero after treatment, illustrating
that the physician judged that the patient did not have any sign or symptom of hypothyroidism
anymore. One explanation for this discrepancy might be that the symptoms score is too general
to score the symptoms of hypothyroidism. Also the frequent hospital visits during the initial
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General discussion and future perspectives
phase of the substitution therapy may have sustained the awareness of the disease in the patients.
One could question whether these frequent visits, together with frequent TSH measurements,
are always necessary, since in 105 hypothyroid patients on adequate levothyroxine therapy, in
which each patient served as his or her own control, Bolk et al. did not find significant changes
in quality-of-life-questionnaires while thyroid hormone levels significantly either improved or
worsened in that same period.55 On the other hand, many of the symptoms like fatigue, coldness,
tiredness and weight gain are also reported by patients with completely normal thyroid function.
Therefore, other explanations may apply to the persistence of complaints.
A possible solution to relieve the persistent complaints is a combination treatment of both
levothyroxine and liothyronine (T3). There are several publications with conflicting results on
the topic of combination treatment of T4 with T3.62–65 A recent paper by Biondi and Wartofsky
defended a personalized regimen of thyroid hormone replacement therapy, consisting of T4 and
T3. They conclude that the majority of prior studies on this topic has methodological drawbacks,
like suboptimal dosing regimens resulting in subclinical hypo- or hyperthyroidism in the
majority of these studies. Moreover, they state that new insights into deiodinase polymorphisms
may explain differences in both tissue and relative individual clinical responses to treatment.
Finally, they conclude that experimental and clinical evidence suggests that a TSH level within
the reference range is not a sufficient marker of adequate thyroid hormone replacement therapy
in hypothyroid patients. They recommend further large prospective, double-blind randomized
studies in order to clarify the potential beneficial effects of combination treatment with T3
and T4 vs. L-T4 monotherapy to improve symptoms.66 It remains to be discussed how serum
levels of T3 can support the benefit of this combined approach. It also remains difficult to
assess whether serum levels of T3 are a good reflection of tissue levels of thyroid hormones
and whether in vivo generation of T3 from T4 is equivalent to thyroidal secretion of T3.67 Even
with low dosages of T3, patients may experience symptoms like palpitations. A slow-release
preparation of T3 has been advocated,66,68,69 but still not commercially available. Although
some patients take their refuge in using animal thyroid hormone preparation, this use cannot
be recommended based on the unpredictable amounts of T3. The recent Dutch guidelines for
specialists in internal medicine suggest and support to try the T3/T4-combination for a limited
time in those subjects with persistent complaints despite longstanding normalization of serum
TSH and FT4. In contrast, the current Dutch guidelines for general practitioners completely
rejects the use of T3/T4 combination because of the lack of evidence and limited knowledge
of the long term consequences.
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Chapter 8
Recommendations for further research
In this discussion and perspectives four topics are discussed that need further research. First,
because the benefit and position of screening for hypothyroidism is not clear yet, more studies
on the health benefit and cost-effectiveness should be performed in order to be able to have
a broader debate on this topic. Second, in order to determine the TSH level indicating that
levothyroxine treatment will be beneficial in subclinical hypothyroidism, we look forward to the
results of the TRUST study. Third, to find out the patients who benefit or risk most from T3/
T4 combination therapy in the treatment of hypothyroidism, a large prospective, randomized,
controlled trial should be designed. Fourth, the pathophysiology of persisting complaints after
normalization of TSH in patients treated for hypothyroidism should be elucidated, in order to
be able to treat patients with persistent complaints in a better way.
Research in the thyroid field is necessary and must be developed and executed in cooperation
with the patients to optimize their quality of life.
126
General discussion and future perspectives
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