Treating Hypothyroidism with Thyroxine/Triiodothyronine Combination Therapy in Denmark: Following Guidelines or Following Trends?

Article (PDF Available)inEuropean Thyroid Journal 4(3):174-180 · August 2015with197 Reads
DOI: 10.1159/000437262
Abstract
Background: Five to ten percent of patients with hypothyroidism describe persistent symptoms despite being biochemically well regulated on levothyroxine (L-T4). Thyroxine (T4)/triiodothyronine (T3) combination therapy [L-T4/liothyronine (L-T3) or desiccated thyroid] are still regarded as experimental with no evidence of superior effect on persistent symptoms according to meta-analyses. However, some randomized controlled trials have demonstrated patients' preference for T4/T3 combination therapy as compared to L-T4 monotherapy. In 2013, attention to combination therapy increased in Denmark after a patient published a book describing her experiences with hypothyroidism and treatment. Objective: To investigate current Danish trends in the use of T4/T3 combination therapy. Methods: We used an Internet-based questionnaire, distributed as a link via two Danish patient fora. Further, information was obtained from the Division of Pharmacies and Reimbursement at the Danish Health and Medicines Authority and from the only pharmacy in Denmark producing desiccated thyroid and L-T3 tablets. Results: A total of 384 patients answered the questionnaire, and 293 responders were included. Sixty-nine percent of the responders had six or more symptoms, and 84% reported a treatment effect. Forty-four percent of the responders received their prescriptions from general practitioners; 50% received desiccated thyroid and 28% reported that they adjust their dose themselves. Responders followed by general practitioners more frequently received desiccated thyroid and adjusted their dose themselves. Conclusions: Increased media focus has changed the prescription pattern of thyroid hormones; European guidelines on T4/T3 combination therapy are not always followed in Denmark and many patients adjust their medication themselves and may therefore be at risk of overtreatment.
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E-Mail karger@karger.com
Clinical Thyroidology / Original Paper
Eur Thyroid J 2015;4:174–180
DOI: 10.1159/000437262
Treating Hypothyroidism with Thyroxine/
Triiodothyronine Combination Therapy in Denmark:
Following Guidelines or Following Trends?
LubaFrejaMichaelsson a BjarkeBorregaardMedici a JeppeLerchelaCour a,b
ChristianSelmer a MichaelRøder c,d HansPerrild e NilsKnudsen e JensFaber a,f
BirteNygaard a
a Department of Endocrinology, Herlev Hospital, University of Copenhagen, b Department of Clinical Physiology,
Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen,
c Department of Medicine, Gentofte Hospital,
University of Copenhagen,
d Division of Pharmacies and Reimbursement, Danish Health and Medicines Authority,
e Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, and f Faculty of Health and Medical
Sciences, University of Copenhagen, Copenhagen , Denmark
based questionnaire, distributed as a link via two Danish pa-
tient fora. Further, information was obtained from the Divi-
sion of Pharmacies and Reimbursement at the Danish Health
and Medicines Authority and from the only pharmacy in
Denmark producing desiccated thyroid and L-T
3 tablets. Re-
sults: A total of 384 patients answered the questionnaire,
and 293 responders were included. Sixty-nine percent of the
responders had six or more symptoms, and 84% reported a
treatment effect. Forty-four percent of the responders re-
ceived their prescriptions from general practitioners; 50%
received desiccated thyroid and 28% reported that they ad-
just their dose themselves. Responders followed by general
practitioners more frequently received desiccated thyroid
and adjusted their dose themselves. Conclusions: Increased
media focus has changed the prescription pattern of thyroid
hormones; European guidelines on T
4 / T 3 combination ther-
apy are not always followed in Denmark and many patients
adjust their medication themselves and may therefore be at
risk of overtreatment. © 2015 European Thyroid Association
Published by S. Karger AG, Basel
Key Words
Hypothyroidism · Triiodothyronine · Thyroid ·
Levothyroxine · Liothyronine
Abstract
Background: Five to ten percent of patients with hypothy-
roidism describe persistent symptoms despite being bio-
chemically well regulated on levothyroxine (L-T
4 ). Thyroxine
(T
4 )/triiodothyronine (T 3 ) combination therapy [L-T 4 /liothy-
ronine (L-T
3 ) or desiccated thyroid] are still regarded as ex-
perimental with no evidence of superior effect on persistent
symptoms according to meta-analyses. However, some ran-
domized controlled trials have demonstrated patients’ pref-
erence for T
4 / T 3 combination therapy as compared to L-T 4
monotherapy. In 2013, attention to combination therapy in-
creased in Denmark after a patient published a book describ-
ing her experiences with hypothyroidism and treatment.
Objective: To investigate current Danish trends in the use of
T
4 / T 3 combination therapy. Methods: We used an Internet-
Received: May 8, 2015
Accepted after revision: June 26, 2015
Published online: August 14, 2015
Luba Freja Michaelsson
Department of Endocrinology O
Herlev Hospital, University of Copenhagen
Herlev Ringvej 75, DK–2730 Copenhagen (Denmark)
E-Mail luba.freja.liubov.michaelsson
@ regionh.dk
© 2015 European Thyroid Association
Published by S. Karger AG, Basel
2235–0640/15/0043–0174$39.50/0
www.karger.com/etj
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Treating Hypothyroidism with T
4 /T
3
Combination Therapy in Denmark
Eur Thyroid J 2015;4:174–180
DOI: 10.1159/000437262
175
Introduction
To prescribe triiodothyronine (T
3 ) as an add-on to le-
vothyroxine (L-T
4 ) treatment or not to prescribe T
3 is a
question which is nowadays considered by many physi-
cians. Patients are also seeking alternative treatments of
hypothyroidism, and the Internet is a popular source for
answers
[1] .
Hypothyroidism is common in Denmark with an in-
cidence rate of 32.8 per 100,000 person-years
[2] . In
2011, 118,000 patients (2% of the total Danish popula-
tion) received medical treatment for hypothyroidism
(data from The Danish Register of Medicinal Product
Statistics).
The standard treatment of hypothyroidism is L-T
4 .
However, 5–10% of patients continue to have symptoms
despite being biochemically well regulated on L-T
4
monotherapy. Some researchers suggest that T
3 – the bi-
ological active form of thyroid hormone – should be used
in these cases
[3] . It has also been suggested that some
patients are not able to benefit from monotherapy due to
defects in their deiodinase enzymes converting thyroxine
(T
4 ) to T
3 , qualifying these patients for combination
therapy
[3] .
T
4 /T
3 combination therapy can be given as combina-
tion of L-T
4 /liothyronine (L-T
3 ) or as desiccated thyroid.
The therapy is controversial: T
3 is easy to overdose, which
can lead to suppressed thyroid-stimulating hormone
(TSH), with an increased risk of complications such as
heart disease
[4] , osteoporosis [5, 6] and potentially de-
mentia
[7] . A meta-analysis showed no evidence of effect
of T
4 /T
3 combination therapy compared to L-T
4 mono-
therapy on bodily pain, depression, anxiety, fatigue, qual-
ity of life or body weight
[8] . However, four randomized
controlled trials and one parallel study have demonstrat-
ed patients’ preference for L-T
4 /L-T
3 combination thera-
py compared to L-T
4 [3] . Indeed, one of these studies
demonstrated significantly better scores in 7 of 11 tested
quality of life and depression scores on L-T
4 /L-T
3 combi-
nation therapy in a selected patient group with autoim-
mune thyroiditis and high baseline psychological dis-
comfort
[9] .
This treatment has become a ‘hot’ topic on patient as-
sociations’ websites
[3] and the demand for it has been
increasing. A Dutch population study from 2012 showed
a rise in the use of T
4 /T
3 combination therapy of more
than 60% between 2005 and 2011
[10] . In May 2013, a
Danish patient suffering from hypothyroidism published
a book
[11] telling her story of a miraculous recovery on
L-T
4 /L-T
3 combination therapy, encouraging other pa-
tients to follow her example. Shortly thereafter, many
Danish clinicians reported an increased demand for T
4 /
T
3 combination therapy among patients, inspiring us to
perform this study.
Our aim was to look at Danish trends in prescribing
T
4 /T
3 combination therapy and to investigate whether
the European guidelines
[3] were being followed and how
the therapy is monitored, prescribed and adjusted. Fur-
thermore, we aimed at characterizing the patient group
who receives T
4 /T
3 combination therapy.
Materials and Methods
We had three different sources of information: (1) an Internet-
based questionnaire conducted by the authors, (2) data from the
Danish Register of Medicinal Product Statistics and Division of
Pharmacies and Reimbursement at the Danish Health and Medi-
cines Authority and (3) data from Glostrup Pharmacy, the only
pharmacy in Denmark that produces desiccated thyroid and L-T
3
5-μg tablets (the most used L-T
3 preparation in Denmark).
Questionnaire
We used an Internet-based questionnaire via Survey Xact
(Rambøll Management Consulting, © 2013–2014 Rambøll). The
link to the questionnaire was open for patient replies from Febru-
ary 11, 2014 until April 2, 2014, and was distributed via two patient
fora (‘Thyreoidea landsforeningen’, a 10-year-old society for pa-
tients suffering from all thyroid diseases, and ‘Stofskiftesupport’, a
new forum initiated by hypothyroid patients that is particularly
based on people’s interest in the book mentioned above
[11] and
pages like http://www.stopthethyroidmadness.com, and alterna-
tives to the established societies). We asked the respondents about
age, sex, education level, medication, symptoms, recent blood test
results, which T
3 medication they received, the effect of T
4 /T
3 com-
bination therapy, and which physician prescribed and adjusted
their medication. The inclusion criterion was: all patients on any
kind of T
4 /T
3 combination therapy who responded on the ques-
tionnaire. The exclusion criterion was: not answering the question
about which T
4 /T
3 combination therapy the responder was taking.
Investigating Trends in T
4 /T
3 Combination Therapy
Through the Division of Pharmacies and Reimbursement at
the Danish Health and Medicines Authority, we were able to quan-
titate the number of applications for reimbursement of T
4 /T
3 com-
bination therapy from March 2012 to November 2014. Further-
more, Glostrup Pharmacy provided us with data on sales of these
products during 2013.
Statistical Methods
Results from the questionnaire were analyzed with descriptive
statistics and with subgroup analysis using a Mann-Whitney test
for numerical data and a χ
2 test for categorical data (IBM SPSS Sta-
tistics ver. 22). Selected answers in the questionnaire were dichot-
omized in order to perform statistical analysis ( table1 ).
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Michaelsson etal.
Eur Thyroid J 2015;4:174–180
DOI: 10.1159/000437262
176
Results
Patient Characteristics
There were 384 responders to the survey, and 293 were
included after excluding responders according to the ex-
clusion criterion. Patient characteristics are summarized
in table1 . Of those who received medical treatment for
other conditions (n = 157), 111 respondents answered
which other condition they were treated for: vitamin D
insufficiency (50%), depression or anxiety (9%), high
blood pressure (8%), diabetes (3%), heart disease (3%),
and others (28%).
As for the most recent TSH levels, 14% of respondents
reported that their TSH level was less than 0.01 mU/l (to-
tally suppressed). The TSH level at the time of diagnosis
of hypothyroidism was reported being below 4 mU/l in
26%, i.e. below the recommended upper normal refer-
ence range in Denmark.
Table 1. Characteristics of respondents (n = 293) in a Danish Internet-based questionnaire study of T4/T3 combination therapy
All responders
(n = 293)
Responders treated
by endocrinologists
(n = 114)
Responders treated by
general practitioners
(n = 122)
Responders on L-T4/
L-T3 combination
therapy (n = 110)
Responders on
desiccated
thyroid (n = 126)
Sex
Female 275 (94) 107 (94) 117 (96) 105 (95) 119 (94)
Age
40 years 58 (20) 29 (25) 19 (16) 23 (21) 25 (20)
41 60 years 186 (63) 71 (62) 82 (67) 73 (66) 80 (63)
61 years 49 (17) 14 (12) 21 (17) 14 (13) 21 (17)
Education
Primary or secondary education 31(11) 12 (11) 8 (7) 9 (8) 11 (9)
Vocational or short tertiary education
<3 years
83 (28) 33 (29) 37 (30) 29 (26) 41 (33)
Tertiary education >3 years 175 (60) 67 (59) 75 (61) 70 (64) 72 (57)
No answer 4 (1) 2 (2) 2 (2) 2 (2) 2 (2)
Duration of hypothyroidism
0 12 months 13 (4) 5 (4) 3 (2) 3 (3) 5 (4)
1 3 years 43 (15) 14 (12) 20 (16) 21 (19) 13 (10)
3 10 years 105 (36) 46 (40) 44 (36) 44 (40) 46 (37)
>10 years 132 (45) 49 (43) 55 (45) 42 (38) 62 (49)
TSH level at diagnosis
Did not remember TSH at diagnosis 77 (26) 28 (25) 27 (22) 35 (32) 20 (16)
<4 mU/l 75 (26) 29 (25) 32 (26) 23 (21) 38 (30)
4 10 mU/l 53 (18) 26 (23) 20 (16) 28 (25) 18 (14)
10 20 mU/l 33 (11) 15 (13) 11 (9) 8 (7) 18 (14)
20 50 mU/l 19 (6) 8 (7) 9 (7) 6 (5) 11 (9)
>50 mU/l 36 (12) 8 (7) 23 (19) 10 (9) 21 (17)
TSH level at the most recent control
<0.01 mU/l 41 (14) 9 (8) 23 (19) 9 (8) 23 (18)
0.01 1.0 mU/l 157 (54) 65 (57) 77 (63) 68 (62) 74 (59)
1.0 2.5 mU/l 42 (14) 18 (16) 14 (11) 17 (15) 15 (12)
2.5 4.0 mU/l 24 (8) 13 (11) 7 (6) 12 (11) 8 (6)
>4.0 mU/l 16 (5) 9 (8) 1 (1) 4 (4) 6 (5)
No answer 13 (4) 0 (0) 0 (0) 0 (0) 0 (0)
Duration of T4/T3 combination therapy
<3 months 85 (29) 43 (38) 28 (23) 41 (37) 30 (24)
3 6 months 79 (27) 38 (33) 33 (27) 40 (36) 31 (25)
6 12 months 48 (16) 11 (10) 30 (25) 12 (11) 29 (23)
1 3 years 42 (14) 13 (11) 22 (18) 8 (7) 27 (21)
>3 years 28 (10) 9 (8) 9 (7) 9 (8) 9 (7)
No answer 11 (4) 0 (0) 0 (0) 0 (0) 0 (0)
Values represent n (%). Excluded from subgroups: responders who answered ‘other’ to the question of which T4/T3 combination therapy used and/or
those who answered ‘purchase on the Internet’ to the question ‘who prescribed their medicine’. For subgroup analyses and p values see text in the Results
section.
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Treating Hypothyroidism with T
4 /T
3
Combination Therapy in Denmark
Eur Thyroid J 2015;4:174–180
DOI: 10.1159/000437262
177
Symptoms before Initiating T
4 /T
3 Combination
Therapy
When respondents were on T
4 monotherapy, before
starting T
4 /T
3 combination therapy, they had many dif-
ferent symptoms ( fig.1 ). As many as 69% of the patients
had six or more different symptoms (median 7, IQR:
5–8). The frequency of the different symptoms can be
seen in table2 .
T
4 /T
3 Combination Therapy
In total, 43% of the respondents used L-T
3 : 28% used
5-μg tablets, 13% used 20-μg tablets and 1% did not an-
swer which dose of L-T
3 tablets they took. Desiccated thy-
roid was used by 50% of the respondents: 39% used desic-
cated thyroid from Glostrup Pharmacy, whereas 11% an-
swered that they used other kinds of desiccated thyroid
purchased on the Internet. A minor percentage (7%) of
respondents answered ‘other drug’ regarding their T
4 /T
3
combination therapy, and 1% answered that they took
both L-T
3 and desiccated thyroid. In 44% of the cases,
general practitioners prescribed the medication, and 28%
of respondents answered that they adjust their medicine
themselves ( table3 ).
A positive effect was described by 84% of respondents,
and the effect was described as ‘miraculous’ (19%), ‘much
better’ (43%), ‘better’ (22%), ‘no difference’ (6%) and
‘worsening’ (2%); 8% did not answer this question. Re-
spondents were also asked if they wanted to continue
the therapy: 81% answered ‘yes’, 2% answered ‘no’, 5%
answered that they ‘have not decided yet’, and 12% did
not answer this question.
Subgroup Analyses
We compared the following subgroups: (1) patients
treated by general practitioners (n = 122) with patients
treated by endocrinologists (n = 114), and (2) patients re-
ceiving desiccated thyroid (n = 126) with patients receiv-
ing L-T
4 /L-T
3 combination therapy (n = 110). Patients
who answered ‘purchase their medicine on Internet’ and
those who answered ‘other’ T
3 treatment were excluded
Table 2. Frequency of different symptoms before initiation of T4/
T3 combination therapy (i.e. on L-T4 monotherapy) among re-
sponders in a Danish Internet-based questionnaire study on T4/T3
combination therapy
Main symptom All symptoms
n% n%
Being tired 78 27 267 91
Lack of energy 49 17 256 87
Cognitive problems 32 11 244 83
Musculoskeletal symptoms 30 10 222 76
Weight problems 23 8 220 75
Pain 12 4 145 49
Diffuse symptoms 13 4 142 48
Depression 7 2 114 39
Constipation 5 2 124 42
Sweating 1 0.3 92 31
Other 43 15 105 36
Total 293 100
Responders were asked to select their symptoms from a list of
11 different symptoms, and to choose only one main symptom.
20
%
18
16
14
12
10
8
6
4
2
0
12
0%
5%
3
5%
4
7%
5
14%
6
Symptoms
16%
7
18%
8
12%
9
11%
10
6%
11
5%
Fig. 1. Number of symptoms per participant.
Table 3. Who prescribes the medicine and who adjusts the dose?
n%
Who prescribes?
General practitioner 130 44
Specialist 119 41
Bought on the Internet 13 4
No answer 31 11
Total 293 100
Who adjusts?
Physician, on the basis of blood samples 129 44
Physician, on the basis of symptoms 51 17
I adjust myself on the basis of symptoms 82 28
No answer 31 11
Total 293 100
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178
from all of these analyses. Furthermore, in analyses of
TSH levels at the time of diagnosis, those who answered
‘do not remember TSH at diagnosis’ were excluded ( ta-
ble1 ).
Comparing patients treated by endocrinologists ver-
sus general practitioners, we found no significant differ-
ences for the following variables: age, level of education,
disease duration, TSH levels at diagnosis and number of
symptoms. Patients treated by general practitioners had
significantly lower ‘most recent’ TSH levels (p < 0.0001),
had been relatively longer on T
4 /T
3 combination therapy
(p = 0.004), had better self-reported effect of the treat-
ment (p < 0.0001), used more desiccated thyroid than
L-T
3 (χ
2 test, p < 0.0001) and more of them adjusted their
dose themselves (χ
2 test, p < 0.0001).
Compared to patients receiving L-T
4 /L-T
3 combina-
tion therapy, patients receiving desiccated thyroid had
been significantly longer on combination therapy (p =
0.001), had better self-reported effect of the treatment
(p < 0.0001) and had lower ‘most recent’ TSH levels (p =
0.047). More of them adjusted their dose themselves (χ
2
test, p < 0.0001). When comparing age, level of education,
disease duration, TSH levels at diagnosis and number of
symptoms, no significant differences were found.
Amount of Prescribed T
3 Therapy
Glostrup Pharmacy started local Danish production of
desiccated thyroid in 2011, and the production of L-T
3
5-μg tablets was started in July 2012 – all sales were exclu-
sively for Danish patients. Before July 2012 a small num-
ber of patients in Denmark were treated with L-T
3 2 0 - μ g
tablets, produced by Nycomed, Sweden. Some of these
patients were changed from 20- to 5-μg tablets in 2012
(the exact number cannot be quantified). Table4 de-
scribes the sale of L-T
3 and desiccated thyroid during
2012 and 2013. Sales of L-T
3 increased sixfold in less than
a year: 150 packs of L-T
3 (100 tablets, each 5 µg) were sold
in the first quarter of 2013 compared to 900 packs of L-T
3
during the last quarter of 2013. A smaller increase in sales
from 225 to 400 packs of desiccated thyroid (100 tablets,
each 60 mg) was observed in the first quarter of 2013 and
the last quarter of 2013, respectively.
It was not possible to extract exact data from the the
Danish Register of Medicinal Product Statistics in order
to determine how many patients were given a prescrip-
tion for T
4 /T
3 combination therapy. However, the Divi-
sion of Pharmacies and Reimbursement at the Danish
Health and Medicines Authority was able to provide us
with data on the number of applications for reimburse-
ment of T
4 /T
3 combination therapy. This figure was used
as a surrogate for the number of new patients starting T
4 /
T
3 combination therapy, assuming that nearly all of the
physicians prescribing L-T
3 or desiccated thyroid also
applied for individual reimbursement for their patients.
We compared the number of applications from July 2012
to June 2013 with the number of applications from July
2013 to June 2014 and found a 3.8-fold increase. The in-
creased number of applications seems to have stabilized
for the rest of 2014 ( fig.2 ).
Discussion
To our knowledge, this is the first questionnaire-based
study on patients receiving T
4 /T
3 combination therapy.
The main findings were: (1) patient demand for T
4 /T
3
combination therapy in Denmark increased abruptly in
2013, probably due to increased focus in the media, (2)
the European Guidelines were not followed consistently
in Denmark and (3) many patients adjusted their medica-
tion themselves and may therefore be at risk of overtreat-
ment.
A recent population-based case-control study on new-
ly diagnosed and untreated hypothyroid patients report-
ed a median of 5 symptoms (IQR: 3–7)
[12] . We found an
even higher number of symptoms in our patients when
only receiving L-T
4 monotherapy (median 7; IQR: 5–8).
Frequent symptoms in our patients on L-T
4 monothera-
Table 4. Number of sold packages of 100 tablets of L-T3 and desiccated thyroid during 2012 2013 from Glostrup
Pharmacy, Denmark
2012 2013
Quarters 1 2 3 4 1 2 3 4
L-T3 tablets (5 μg) – 10 79 150 171 513 900
Desiccated thyroid tablets (60 mg) 53 96 151 176 225 228 414 400
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Treating Hypothyroidism with T
4 /T
3
Combination Therapy in Denmark
Eur Thyroid J 2015;4:174–180
DOI: 10.1159/000437262
179
py, before initiating T
4 /T
3 combination therapy, were ‘be-
ing tired’ (in 91% of respondents), ‘constipation’ (42%)
and ‘pain’ (49%). Carle et al.
[12] reported appearance of
these symptoms in untreated hypothyroid patients/
healthy controls: ‘tiredness’ in 81/41%, ‘constipation’ in
39/17% and ‘generalized pain’ in 47/39%. This seems to
indicate that when our patient group were on L-T
4 mono-
therapy, they had symptoms alike or even more severe
than untreated hypothyroid patients. Otherwise, the
characteristics of sex, age and education were similar to
the typical Danish hypothyroid patient
[2] , i.e. a middle-
aged woman with a middle or high level of education.
The rather diffuse symptoms reported as most fre-
quent in our study have previously been explained by the
inability of coping with the chronic nature of the disease
[3] , or by the hypothesis that some patients blame hypo-
thyroidism for any symptoms. Another possible hypoth-
esis is that some hypothyroid patients are more vulnera-
ble compared to the basic population
[9] . The latter hy-
pothesis is in accordance with recent studies describing
increased psychiatric morbidity as well as risk of disabil-
ity pension in hypothyroid patients before as well as after
L-T
4 therapy [13, 14] .
With regard to the form of hypothyroidism designated
subclinical hypothyroidism, there is an ongoing discus-
sion of when to treat and at what level the cutoff for the
upper reference limit of TSH should be. In a very recent
cohort study of 52,298 individuals in the UK, a falling
threshold of TSH for initiating treatment of subclinical
hypothyroidism was demonstrated, with the median TSH
at the initiation of L-T
4 therapy decreasing from 8.7 in
2001 to 7.9 mU/l in 2009
[15] . Further, this study demon-
strated a high risk of overtreatment since 10% had re-
duced TSH
[15] . A register study in Denmark describes
an increase of prescriptions of L-T
4 , with an incidence
rate increase of 81% over 9 years from 1997 to 2008
[16] .
These changes could partly be due to the iodine fortifica-
tion or a higher diagnostic activity with regard to thyroid
dysfunction, but could also be due to an intensified treat-
ment of subclinical hypothyroidism
[16] . In the context
of overtreatment, it was striking that we found 28% of the
respondents adjust their medicine themselves (probably
due to changes in the pattern of symptoms) and 14% of
all respondents reported a suppressed TSH <0.01 mU/l.
This indicates a high level of autonomy in this respondent
group and that a portion of the respondents were poten-
tially overtreated. Thus, the guidelines, including those
from the European Thyroid Association, that propose a
rather stringent dosage ratio between T
4 and T
3 , might
in general be read by doctors, but not by patients. The
European Thyroid Association recommends that T
4 /T
3
combination therapy should be given by experts in the
field, and in this context it is interesting that patients
treated by general practitioners as compared to those
treated by endocrinologists had significantly lower ‘most
recent’ TSH levels, used more desiccated thyroid and
more often adjusted their dose themselves. It might be as-
sumed that there are differences between general practi-
tioners and expert endocrinologists with regards to how
to handle nonscientific information on a special topic like
T
4 /T
3 combination therapy when brought by their patient
from the Internet or as in the ‘Danish case’ supplemented
by a nonscientific book. Similarly, there might be differ-
ences between these two groups of therapists with regards
to following specific guidelines in endocrinology, in-
cluding those provided by the European Thyroid Asso-
ciation
[3] .
Internet-based questionnaires have obvious flaws, the
major one being selection bias. We expect that the pa-
tients who experienced a positive effect of the combina-
tion treatment were overrepresented. Further, 56% of the
patients answering the questionnaire had been treated for
a period of less than 6 months, which might increase the
probability of a positive response, which is often seen dur-
ing the initial treatment of a disease. Nevertheless, this
120
n
100
Total
80
60
40
20
0
March 2012
May 2012
July 2012
September 2012
November 2012
January 2013
March 2013
May 2013
July 2013
September 2013
November 2013
January 2014
March 2014
May 2014
July 2014
September 2014
November 2014
Endocrinologists
General practitioners
Fig. 2. Number of applications for reimbursement of T
4 /T
3 treat-
ment.
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Michaelsson etal.
Eur Thyroid J 2015;4:174–180
DOI: 10.1159/000437262
180
questionnaire gives us systematic insight into the patient
experience, the same experience that is shared on patient
sites on the Internet and read by numerous other patients.
Conclusions
The demand for T
4 /T
3 combination therapy in Den-
mark increased dramatically in 2013. The European
guidelines of hypothyroidism are not followed consis-
tently in Denmark. Furthermore, many respondents re-
port that they adjust their medication themselves. More
evidence-based information on the effect and potential
side effects of this treatment modality is clearly needed
for both endocrinologists, general practitioners and, most
importantly, for the patients.
Acknowledgments
We would like to thank the Agnes and Knut Mørks Foundation
for financial support.
Disclosure Statement
None of the authors have any conflict of interest.
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  • [Show abstract] [Hide abstract] ABSTRACT: Thyroid function has a profound effect on the heart, and both all-cause and cardiovascular mortality rates are increased in hyperthyroidism. New-onset atrial fibrillation carries a prolonged risk for the development of hyperthyroidism, suggesting altered availability of thyroid hormones at the cellular level. Subclinical hyperthyroidism is associated with increased left ventricular mass of the heart, which reverts after obtaining euthyroidism. Mortality and risk of major cardiovascular events are increased. Subclinical hypothyroidism is also associated with subtle changes in the heart, e.g. its increased stiffness, which reverts after treatment with levothyroxine. Mortality seems mildly reduced, although the risk of myocardial infarction is increased. The risk of atrial fibrillation is related to thyroid function over the whole spectrum: from a reduced risk in overt and subclinical hypothyroidism, a progressively increased risk in people with different levels of reduced TSH to a physiologically 'dose-dependent' effect of thyroid hormones on the heart in overt hyperthyroidism. Heart failure represents an intriguing clinical situation in which triiodothyronine treatment might be beneficial. In conclusion, subclinical dysthyroid states affect the heart with subsequent changes in morbidity and mortality. Subclinical hyperthyroidism seems a more serious condition than subclinical hypothyroidism, which should affect treatment decision in a more aggressive manner. © 2014 S. Karger AG, Basel.
    Full-text · Article · Jun 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Hypothyroidism is associated with an increased somatic and psychiatric disease burden. Whether there are any socio-economic consequences of hypothyroidism, such as early retirement or loss of income, remains unclarified. Aim: To examine, compared with a matched control group, the risk of receiving disability pension (before the age of 60) and effect on labor market income in patients diagnosed with hypothyroidism. Methods: Observational register-based cohort study. By record-linkage between different Danish health registers, 1745 hypothyroid singletons diagnosed before the age of 60 were each matched with 4 non-hypothyroid controls and followed for a mean of 5 years (range 1-31). Additionally, we included 277 same sex twin pairs discordant for hypothyroidism. The risk of disability pension was evaluated by the Cox regression analysis. Changes in labor market income progress over 5 years were evaluated using a difference in difference model. Results: With a hazard ratio (HR) of 2.24 (95% confidence interval (CI): 1.73-2.89), individuals diagnosed with hypothyroidism had a significantly increased risk of disability pension. This remained significant when adjusting for educational level and comorbidity (HR 1.89; CI: 1.42-2.51). In an analysis of labor market income, two years before compared with two years after the diagnosis of hypothyroidism, the hypothyroid individuals had on average a 1605 € poorer increase than their euthyroid controls (P<0.001). Essentially similar results were found in the twin population. Conclusion: A diagnosis of hypothyroidism, before the age of 60, is associated with loss of labor market income and an 89% increased risk of receiving disability pension.
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  • Article · Jul 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Data suggest symptoms of hypothyroidism persist in 5-10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area. Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large. SUGGESTED EXPLANATIONS FOR PERSISTING SYMPTOMS INCLUDE: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research. L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use.
    Full-text · Article · Jul 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Thyroid hormones are necessary for fetal brain development, and hypothyroidism in adults has been associated with mood symptoms and reduced quality of life. Nevertheless, our knowledge regarding the association and temporal relation between hypothyroidism and mental disorders is ambiguous. Our objective was to investigate, at a nationwide level, whether a diagnosis of hypothyroidism is associated with psychiatric morbidity. Methods: This is an observational cohort study. On the basis of record linkage between different Danish health registers, 2822 hypothyroid singletons each matched with 4 nonhypothyroid controls were identified and followed over a mean period of 6 years (range 1-13). Additionally, we included 385 same-sex twin pairs discordant for hypothyroidism. Diagnoses of psychiatric disorders as well as treatment with antidepressants, antipsychotics, and anxiolytics were recorded. Logistic and cox regression models were used to assess the risk of psychiatric morbidity before and after the diagnosis of hypothyroidism, respectively. Results: Before the diagnosis of hypothyroidism, such individuals had an increased prevalence of diagnoses with psychiatric disorders (odds ratio, OR, 1.51; 95% confidence interval [CI 1.12-2.04]) and increased prevalence of treatment with antipsychotics (OR 1.49 [CI 1.29-1.73]), antidepressants (OR 1.50 [CI 1.35-1.67]), and anxiolytics (OR 1.28 [CI 1.16-1.41]). After the diagnosis of hypothyroidism, patients had a higher risk of being diagnosed with a psychiatric disorder (hazard ratio, HR, 2.40 [CI 1.81-3.18]), and an increased risk of being treated with antidepressants (HR 1.30 [CI 1.15-1.47]) and anxiolytics (HR 1.27 [CI 1.10-1.47]), but not antipsychotics (HR 1.13 [CI 0.91-1.41]). On the basis of the twin data, we could not demonstrate genetic confounding. Conclusions: Subjects with hypothyroidism have an increased risk of being diagnosed with a psychiatric disorder as well as being treated with antidepressants, antipsychotics, and anxiolytics both before and after the diagnosis of hypothyroidism.
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