1. health and fitness
2. disease
3. thyroid disease

Edited by: Peter PA Smyth, UCD, Dublin · Published by: Merck KGaA, Darmstadt, Germany
1 | 2012
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Practical Approach to Management
of subclinical hypothyroidism
Simon HS Pearce & Salman Razvi
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Production Date: August 2012
Thyroid International 1 2012
Practical Approach to Management
of subclinical hypothyroidism
Simon HS Pearce1,2, Salman Razvi1,3
1. Institute of Genetic Medicine, Newcastle University,
Newcastle upon Tyne, UK
2. Endocrine Unit, Royal Victoria Infirmary,
Newcastle upon Tyne, UK
3. Department of Endocrinology, Gateshead Health
NHS Foundation Trust, Gateshead, UK
Address for Correspondence:
Prof. Simon Pearce,
Institute of Genetic Medicine, Newcastle University,
International Centre for Life, Central Parkway,
Newcastle upon Tyne,
NE1 3BZ, UK.
Email: [email protected]
Tel. 44-191-241-8674 Fax. 44-191-241-8666
2
Thyroid International 1 2012
Simon Pearce, MB,BS; MD; FRCP
Professor of Endocrinology, Newcastle University, UK.
Honorary Consultant Physician, Royal Victoria Infirmary,
Newcastle upon Tyne, UK.
Salman Razvi, MB,BS; MD; FRCP
Consultant Endocrinologist, Gateshead Hospitals NHS
Foundation Trust, UK.
Honorary Senior Lecturer, Newcastle University, UK
Simon Pearce qualified in Medicine MB,BS 1st class
honours from Newcastle University. Following internal
medicine training, he undertook postgraduate training
in endocrinology at the Royal
Postgraduate
Medical
School,
Hammersmith, London (MD degree
awarded with distinction); Brigham
& Women’s Hospital, Boston, USA;
and latterly in Newcastle, UK. He
was appointed as Senior Lecturer in
Endocrinology in 2001 at Newcastle
University, and promoted to Professor in 2007, affiliated to the Institute of Genetic Medicine. The main
themes of his research programme are in regenerative
medicine approaches to adrenal failure, genetics of
autoimmune endocrine disease and long-term management of thyroid diseases.
Salman Razvi completed MB,BS in 1996 from AP
University of Health Sciences, India prior to commencing postgraduate training in the UK. In 2006, he was
awarded MD with commendation
(Newcastle University) for his thesis
on effects of levothyroxine on vascular, endothelial and quality of life
markers in subclinical hypothyroidism. He currently practices as a
Consultant Endocrinologist with a
special interest in thyroid diseases
and research interests include cardiovascular effects of
thyroid disease, long-term outcomes of thyroid diseases and effects of aging on thyroid function.
Thy­roid Inter­na­tional
­Editor-in-Chief: Peter PA Smyth, UCD, Dublin
This is the title of a publication series published by and with
financial support from Merck KGaA, Darmstadt, Germany.
The Editor-in-Chief is publishing papers from renowned
international thyroid experts in order to pass on the extensive experience which the authors possess in their field to
a wide range of physicians d
­ ealing with the diagnosis and
ther­apy of thy­roid dis­
­­ eases. Please refer to the full disclaimer
on the inside front cover.
Respon­sible at M
­ erck KGaA, Darmstadt, Germany: Gernot Beroset
Photo: Angle of the North, Newcastle
by Adrian S Lock/flickr
Thy­roid Inter­na­tional · 1–2012
­ erck KGaA, Darmstadt, Germany, D-64271 Darm­stadt
M
ISSN 0946-5464
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Practical Approach to Management of subclinical hypothyroidism
Practical Approach to Management
of subclinical hypothyroidism
Abstract
Subclinical hypothyroidism is a common finding when
laboratory thyroid function testing is requested, but its
management is not straightforward. Learned guidelines
based on a systematic literature review that were published in 2004, concluded that the benefits of treating
such patients with L-thyroxine remain unproven.
Symptomatic benefits of L-thyroxine treatment are
marginal and inconsistent between different studies.
However, several large epidemiological studies have
shown an association between subclinical hypothyroidism and risk of vascular events. No randomized controlled trials of L-thyroxine in subclinical hypothyroid
patients have examined long-term vascular disease outcome or mortality. Nevertheless, information from several studies of surrogate vascular markers and from an
observational study of real-life primary care practice
suggest no harmful effects of L-thyroxine therapy.
Indeed, the latter study was consistent with some benefit, particularly in young to middle-aged individuals
with SCH. The various recent strands of evidence are
discussed in this article to inform the current optimal
management of the patient with subclinical hypothyroidism.
Introduction
Subclinical hypothyroidism (SCH) is defined by an
elevation of the serum TSH above the reference range,
with circulating free thyroid hormone concentrations
that are within the reference range.1 It is a common
problem in clinical practice, with a population prevalence of between 2 and 10 %, which increases in an
age-related fashion.2,3 More than three quarters of individuals with SCH have serum TSH concentrations
between 5 and 10 mU/l. Although, treatment of the mild
thyroid failure of SCH with L-thyroxine would seem to
be a logical approach to management, only small number of individuals with SCH have symptoms that are
typical of hypothyroidism.4-6 Although some randomized trials of SCH have shown significant improvements
in tiredness and other symptoms during L-thyroxine
therapy,7,8 several other studies have failed to demonstrate improvement in such symptoms or health-related
quality of life.9-12
3
4
Thyroid International 1 2012
What is the evidence for adverse vascular outcomes of SCH?
More than 40 years ago, an association between borderline hypothyroidism and adverse vascular events
was first suggested by UK and Belgian investigators.13,14
Another early study showed a strong association
between mild hypothyroidism and angiographically
demonstrated coronary artery disease.15 However, after
several years of limited interest, it was the Rotterdam
Heart study,16 which showed a doubling of heart attacks
and atheromatous vascular calcification in SCH women
compared to euthyroid participants, that re-ignited this
area of investigation. In this study, SCH contributed as
much to the risk of ischaemic heart disease (IHD) in
these community-dwelling women as did diabetes mellitus (14 % of the aetiological fraction), which was close
to the impact of cigarette use (15 %).16 Since then, there
have been several other cross-sectional studies,2,17-21 as
well as longitudinal studies that have assessed this
relationship.16-25 A 20-year follow-up of 2779 participants in the Whickham study did not originally reveal
an association between autoimmune thyroid disease
and cardiovascular disease.22 However, a recent reanalysis of this dataset, using a definition of SCH based
on TSH measurement, rather than on the presence of
autoimmune thyroiditis (excluding antibody-positive
euthyroid patients) did confirm an adverse effect of SCH
on cardiovascular event rate and mortality.26 An
increase in cardiovascular disease, comprising either
prevalent heart disease or incident IHD events has also
been found in several other well-powered cohort and
longitudinal studies.17,18 Interestingly, Rodondi found
no difference in prevalent IHD in SCH patients over
70 years old compared to euthyroid subjects, but during
4 years of follow up congestive heart failure was commoner in the SCH group with serum TSH > 7.0 mU/l.19
In contrast, a longitudinal study of 1,191 people aged
more than 60 years from Birmingham, UK, showed no
increased risk of CV disease in the group with baseline
serum TSH > 5.0 mU/l during 10-years follow-up.23
Similarly, the prevalence of cardiovascular disease was
not increased in SCH patients in a cross-sectional survey of 3,233 North American people over 65 years old.21
Furthermore, a longitudinal study of Dutch 85 year olds
found that a raised serum TSH appeared to be modestly
protective from cardiovascular events at older ages.24
Thus, several large studies have made conflicting findings concerning the relationship between SCH and
vascular disease. These differences are quite likely to be
due to the different population samples studied (inclusion or exclusion of subjects with history of thyroid
disease, previous CV events) as well as variations in the
definition of IHD, length of follow-up and whether
patients subsequently treated with L-thyroxine were
excluded.
In order to further clarify whether SCH is detrimental
overall to cardiovascular health, several authors have
performed meta-analyses.27-32 Overall, these metaanalyses signal that SCH is associated with cardiovascular disease (Table 1). Two studies that investigated
this showed a significant excess of IHD or IHD events
Table 1 Summary of meta-analysis results relating subclinical hypothyroidism, cardiovascular events and mortality
Author
Number
Cardiovascular events*
Cardiovascular mortality
All cause mortality
Singh 2008 (27)
13,267
1.53 (1.31–1.79)
1.28 (1.02–1.60)
1.12 (0.99-1.26)
Ochs 2008 (28)
14,449
1.20 (0.97-1.49)
1.18 (0.98-1.42)
1.12 (0.99 to 1.26)
Haentjens 2008 (29)
14,619
NI
NI
1.22 (0.95-1.57)
Razvi 2008 (30)
29,022
1.23 (1.02– 1.48)
1.09 (0.84 –1.41)
NI
Rodondi 2010 (31)
55,287
1.18 (0.99- 1.42)
1.14 (0.99- 1.32)
1.09 (0.96-1.24)
Thvilum 2012 (32)
35,740
NI
NI
1.17 (1.00-1.37)
Studies with significant results are shown in blue. *Relative risks with 5-95% confidence intervals are shown for each meta-analysis.
NI = Not investigated.
Practical Approach to Management of subclinical hypothyroidism
in SCH cohorts, with a further two studies showing a
suggestive trend. However, the link between excess
cardiovascular and/or all cause mortality is less consistent, being found in the most recent meta-analysis
containing the largest dataset,32 but not in all previous
studies (summarised in table 1). These meta-analyses
also give some important clues to the demographics of
the patients who might be most at risk. Razvi and
coworkers investigated whether age is an important
determinant of vascular risk in SCH.30 In studies that
enlisted populations over the age of 65 years, there was
no excess in incident vascular events or vascular mortality in SCH compared to euthyroid subjects (p = 0.83
& 0.44, respectively); whereas these complications were
significantly associated with SCH in younger patient
cohorts (p = 0.0003 & 0.02, respectively).30 This phe-
nomenon was confirmed with an individual-level data
meta-analysis, showing that the adverse affects of SCH
on vascular events and mortality was attenuated at
older ages.31 Similarly, this study was able to confirm
that cardiovascular event rates are proportionate to the
elevation in serum TSH concentration: patients with
serum TSH between 4.5–6.9 mU/l had no increase in
cardiovascular mortality (relative risk [RR] 1.09 [0.911.30]), but this became significant in patients with TSH
levels over 7.0 mU/l (RR 1.42 [1.03–1.95]).31 Thus, both
age and degree of serum TSH elevation seem to be
important clinical variables that predict poor vascular
disease outcomes in SCH patients. What remains
unknown is whether intervention in younger people
with higher serum TSH levels will be beneficial.
What are the mechanisms linking vascular disease and SCH?
Thus far, there has been no randomised controlled trial
(RCT) that has investigated the effect of L-thyroxine on
CV disease incidence. However, a number of L-thyroxine
intervention studies have looked at various surrogate
cardiovascular risk factors in SCH patients. Most consistently, many studies have shown a beneficial effect
of L-thyroxine on cardiac function (including systolic
and diastolic function) in SCH patients.33-38, reviewed 39
Similarly, a few trials that studied endothelial dysfunction found that L-thyroxine had a beneficial effect.7,40
Circulating endothelial progenitor cells (EPC), an emerging marker of vascular risk, have been shown to be
reduced in number in SCH.41 Furthermore, treatment
with L-thyroxine improved EPC numbers to healthy
values.41 Meta-analysis of several cohort studies shows
an average increase in systolic blood pressure of about
2 mmHg in SCH, with diastolic blood pressure being
0.75 mmHg raised in SCH individuals.42 However, blood
pressure has not shown significant changes during
L-thyroxine intervention.7 Similarly, the effect of
L-thyroxine on serum lipids in SCH appears variable.43,44 A meta-analysis has shown that the reduction
in total cholesterol ranges from 0.2 to 0.4 mmol/L and
LDL cholesterol by 0.26 mmol/L.44 There was no alteration in serum HDL cholesterol or triglycerides.
Reductions in plasma factor VIII and von Willebrand
factor have also been noted in SCH and improved following L-thyroxine treatment.45 Thus several mechanisms, either acting singly or in combination could
account for the adverse vascular risk found in SCH.
Results of analysis of real-life practice
Although an RCT of L-thyroxine intervention in SCH
with cardiovascular outcomes as an endpoint is underway (the ‘TRUST study’),46 it is likely to be more than
5 years before the results are reported. Thus, we currently face a relative vacuum of evidence regarding the
long-term outcomes of people with SCH during
L-thyroxine treatment. One of the commonly raised
criticisms of a strategy of treating people with SCH, is
that up to 50 % of people taking L-thyroxine will have
poorly controlled thyroid function as judged by serum
TSH.4,47,48 It is possible that there may be significant
deleterious effects from overtreatment of such patients,
5
Thyroid International 1 2012
in terms of atrial fibrillation, vascular outcomes and
bone health.
We sought to address this problem using data from
about 320,000 participants in the UK General Practice
Research Database who had a serum TSH estimation
during 2001.49 Of these records, 4,735 individuals over
40 years of age had a serum TSH between 5 and 10 mU/l
and their outcome was studied up to 2008, a median
period of 7.6 years. Participants were divided by age
into those between 40 and 70 years of age, and those
over 70 years, and those taking thyroid altering medications and with heart or vascular disease at baseline were
excluded. Approximately 50 % of each age-group were
treated with L-thyroxine by their primary care physician over the follow up period. Women and people with
a higher TSH and lower FT4 measurements were more
likely to be treated in each age-group, but there were
no other differences at baseline.49 In the younger agegroup, fatal and nonfatal cardiovascular events were
about 40 % fewer over time in the L-thyroxine treated
group, than in the untreated SCH group, following
multivariate analysis (Figure 1). However, this was not
the case in the group over 70 years of age. Similarly, all
cause mortality was found to be less in the L-thyroxine
treated group than in the untreated group for patients
between 40 and 70 years, but not in the older patients.
Importantly, atrial fibrillation was not more common in
patients taking L-thyroxine, even in the older agegroup.49 Although we have scrutinized this dataset
carefully for evidence of confounding by indication,
including analysis of socioeconomic status, frequency
of clinic visits and concurrent medication use, we can
find no evidence of bias. Similarly, the findings were
robust to multiple sensitivity analyses, including removing patients who had vascular events early on during
follow-up. Thus, the data contained within this analysis
of real-life practice, coupled with our understanding of
the pathophysiological changes in SCH, are reassuring
that L-thyroxine treatment of patients less than 70
years old wasn’t harmful. Indeed, these findings are
consistent with a modest beneficial effect of L-thyroxine
treatment on medium-term vascular outcomes in
younger but not older individuals with SCH.49
Figure 1 Multivariate-adjusted cumulative event plots for levothyroxine sodium–treated and untreated individuals
with subclinical hypothyroidism for fatal and nonfatal ischemic heart disease. A, Younger patients (P = .02). B,
Older patients (P = .56). Multivariate analysis shown is adjusted for age, sex, body mass index, socioeconomic
deprivation score, total cholesterol level, index serum thyrotropin level, smoking status, systolic and diastolic
blood pressure, history of diabetes mellitus, and levothyroxine use as a time-dependent covariate. Reproduced
from citation 49.
A
B
0.06
0.16
No levothyroxine treatment
Levothyroxine treatment
0.14
Cumulative Events
0.05
Cumulative Events
6
0.04
0.03
0.02
0.12
0.10
0.08
0.06
0.04
0.01
0.00
0.02
0
20
40
60
80
100
0.00
0
20
Follow-up, mo
Events
Participants at risk
58
3035
87
3006
114
2979
40
60
80
100
155
1487
192
1450
Follow-up, mo
138
2955
165
2928
Events
Participants at risk
74
1568
117
1525
139
1503
Practical Approach to Management of subclinical hypothyroidism
What is the expert view?
In order to explore the factors that clinicians take into
account in making a decision about treatment of SCH,
a debate on this subject was held during the 14th
International Thyroid Congress (Paris, September 13th
2010). Three hundred and eighty clinicians (60 % of
whom were from Europe) responded electronically to
questions about their use of L-thyroxine for several
clinical case scenarios.50 For the case of a fifty three
year old woman with difficulty losing weight, feelings
of exhaustion and lack of mental focus with a serum
TSH of 6.8 mU/l and normal circulating free thyroxine
concentration, about half of respondents would treat
with L-thyroxine (Figure 2). However, if dyslipidaemia
(LDL-cholesterol 6.5 mmol/l) was also present, 75 %
would then treat with L-thyroxine. Notably, for a more
elderly patient (84 years) with identical serum thyroid
function only 8 % would treat with L-thyroxine.50 The
is significant disparity in clinical practice, even amongst
expert thyroidologists. Furthermore, the results are at
odds with a postal survey of members of the American
Thyroid Association carried out in 2001, in which 95
and 92 % of respondents would treat a patient with a
serum TSH of 8.2 mU/l, at the ages of 26 and 71 years,
respectively.51 This might reflect differences in the
clinical details of the cases, additional information
about the risks and benefits of treating SCH that have
come to light over the last 10 years, or differences in
clinical practice influenced by alternative healthcare
re-imbursement models.
results of the participants’ opinion are shown in figure 2. The result of this small survey shows that there
Figure 2 53 or 84 year old female, TSH 6.8 mU/L
Percent 90
80
92%
Treat with LT4
80
Do not treat
75%
70
70
60
50
40
60
49%
50
51%
40
30
30
25 %
20
20
10
0
90 Percent
10
8%
53 yo, no dyslipidaemia
(n =344)
53 yo, dyslipidaemia
(n = 363)
Voting of 380 thyroidologists attending the ITC (from Pearce et al.50)
84 yo, no goitre
(n=377)
0
7
8
Thyroid International 1 2012
Practical Approach to Management
of subclinical hypothyroidism
When faced with a patient with an elevated serum TSH
hypothyroidism it is reasonable to consider a therapeuconcentration, what should the clinician do? Firstly the
tic trial of L-thyroxine. This is particularly the case in
TSH should be repeated, along with serum free thyroxindividuals with higher serum TSH levels, with a
ine and thyroid peroxidase auto- Box 1 Treat subclinical hypothyroidism
threshold of around 7.0 mU/l
antibodies. In up to 50 % of cases
being reasonable. A trial of close
with levothyroxine
TSH will normalise on repeat
to a full replacement dose (75 or
Treat at all ages if:
testing.52 Many cases of SCH will
100 µg daily L-thyroxine) for 3
• TSH >10.0 mU/l
be asymptomatic, but the typical
or 4 months should be per• Pregnancy
or
pre-pregnancy
symptoms of hypothyroidism
formed, with a review of sympshould be sought. In particular,
toms at the end of the trial.55 If
Consider treatment, if:
patients with SCH may complain
symptoms are improved, then it
• Symptoms or signs of hypothyroidism
of generalized fatigue, and menis reasonable to continue
• Age
less
than
70
yrs
tal befuddlement and forgetfulL-thyroxine lifelong, adjusting
• TSH
>7.0
mU/l
ness. An examination of the carthe dose to aim for a serum TSH
• Goitre
diovascular system and thyroid is
concentration in the lower half
• High vascular risk including
worthwhile, as a significant goiof the reference interval.55 If
Ischaemic heart disease
ter would be a factor favoring
symptoms are not improved,
Diabetes
treatment. Pregnancy or a plan
then TSH monitoring should be
Dyslipidaemia
for pregnancy in the near future
undertaken. The interval of
are unequivocal indications for
monitoring should reflect the
53,54
L-thyroxine treatment,
so this should be identified
risk of deterioration to overt hypothyroidism or a
early (Box 1). Similarly, patients with a serum TSH
> 10.0 mU/l should generally receive treatment. In contrast, patients with a TSH between 5 and 10 mU/l over
the age of 70 may be unlikely to benefit from treatment,24,25,49 and a monitoring strategy should generally be implemented. In younger patients, in the absence
of goiter or pregnancy, if the patient has symptoms of
serum TSH > 10.0, and this is determined by the autoantibody status. For individuals with positive thyroid
peroxidase antibodies, the risk of progression to overt
disease is around 4.5 % annually, so annual TSH
monitoring is reasonable.56 For those with negative
antibodies, the risk is around 2 % so 2 or 3 yearly
monitoring is sufficient.56
Summary
Despite the persisting lack of the level 1 evidence from
an RCT of L-thyroxine in SCH, the last 4 years have
brought several advances in knowledge about the vascular risks of mild hypothyroidism, and what might be
expected during its treatment. In particular, the differential effects of age and serum TSH on vascular risk,
and the safety of L-thyroxine treatment in a large
cohort observing the outcome of real-life practice are
now understood. These advances should allow the clinician to target L-thyroxine therapy for appropriate
patients with SCH with a greater degree of confidence
than ever before.
Practical Approach to Management of subclinical hypothyroidism
References
  1.Evered DC, Ormston BJ, Smith PA, Hall R, Bird T. Grades of
Hypothyroidism. Br Med J 1973; 5854: 657–662.
  2. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark
F, Evans JG, Young E, Bird T, Smith PA. The spectrum of thyroid
disease in a community: the Whickham survey. Clin Endocrinol
1977; 7: 481-93.
  3. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter
EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid
antibodies in the United States population (1988 to 1994):
National Health and Nutrition Examination Survey (NHANES III).
J Clin Endocrinol Metab 2002; 87: 489-99.
  4. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado
thyroid disease prevalence study. Arch Intern Med 2000; 160:
526-34.
 5.Razvi S, Ingoe LE, McMillan CV, Weaver JU. Health status in
patients with sub-clinical hypothyroidism. Eur J Endocrinol
2005; 152:713-7.
  6. Reuters VS, Teixeira Pde F, Vigário PS, Almeida CP, Buescu A,
Ferreira MM, de Castro CL, Gold J, Vaisman M. Functional capacity and muscular abnormalities in subclinical hypothyroidism.
Am J Med Sci 2009; 338:259-63.
  7. Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU 2007
The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab
2007; 92:1715–1723
  8. Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR,
Drewe J, Huber P, Herzog R, Müller B. TSH-controlled L-thyroxine
therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial
(Basel Thyroid Study). J Clin Endocrinol Metab 2001; 86: 4860-6.
 9.Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC.
L-Thyroxine therapy in subclinical hypothyroidism. A doubleblind, placebo-controlled trial. Ann Intern Med 1984; 101: 18-24.
10. Jorde, R., Waterloo, K., Storhaug, H., Nyrnes, A., Sundsfjord, J. &
Jenssen, T.G. Neuropsychological function and symptoms in
subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab 2006; 91: 145-153.
11.Nyström E, Caidahl K, Fager G, Wikkelsö C, Lundberg PA,
Lindstedt G. A double-blind cross-over 12-month study of
L-thyroxine treatment of women with 'subclinical' hypothyroidism. Clin Endocrinol (Oxf) 1988; 29: 63-75.
12. Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone
replacement for subclinical hypothyroidism. Cochrane Database
Syst Rev 2007; 3:CD003419.
13. Fowler PBS, Swale J, Andrews H. Hypercholesterolaemia in borderline hypothyroidism: Stage of premyxoedema. Lancet 1970;
2(7671): 488-491.
14.Bastenie PA, Vanhaelst L, Bonnyns M, Neve P, Staquet M.
Preclinical hypothyroidism: a risk factor for coronary heart-disease. Lancet 1971;1(7692):203-4.
15. Dean JW, Fowler PBS. Exaggerated responsiveness to thyrotrophin releasing hormone: a risk factor in women with coronary
artery disease. Br Med J (Clin Res Ed). 1985; 290: 1555-61.
16. Hak, A.E., Pols, H.A., Visser, T.J., Drexhage, H.A., Hofman, A. &
Witteman, J.C. Subclinical hypothyroidism is an independent risk
factor for atherosclerosis and myocardial infarction in elderly
women: the Rotterdam Study. Ann Intern Med 2000; 132: 270278.
17. Imaizumi, M., Akahoshi, M., Ichimaru, S., Nakashima, E., Hida,
A., Soda, M., Usa, T., Ashizawa, K., Yokoyama, N., Maeda, R.,
Nagataki, S. & Eguchi, K. Risk for ischemic heart disease and allcause mortality in subclinical hypothyroidism. J Clin Endocrinol
Metab 2004; 89: 3365-3370.
18. Walsh, J.P., Bremner, A.P., Bulsara, M.K., O'Leary, P., Leedman,
P.J., Feddema, P. & Michelangeli, V. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med
2005; 165: 2467-2472.
19.Rodondi, N., Newman, A.B., Vittinghoff, E., de Rekeneire, N.,
Satterfield, S., Harris, T.B. & Bauer, D.C. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and
death. Arch Intern Med 2005; 165: 2460-2466.
20. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke
GL, Tracy RP, Ladenson PW. Thyroid status, cardiovascular risk,
and mortality in older adults. JAMA 2006; 295:1033-41.
21. Lindeman RD, Romero LJ, Schade DS, Wayne S, Baumgartner RN,
Garry PJ. Impact of subclinical hypothyroidism on serum total
homocysteine concentrations, the prevalence of coronary heart
disease (CHD), and CHD risk factors in the New Mexico Elder
Health Survey. Thyroid 2003; 13:595-600.
22. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates
D, Clark F, Grimley Evans J, Rodgers H, Tunbridge F, Young ET.
The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English
community. Thyroid 1996; 6:155-60.
23. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA.
Prediction of all-cause and cardiovascular mortality in elderly
people from one low serum thyrotropin result: a 10-year cohort
study. Lancet 2001; 358: 861-865.
24.Gussekloo J, van Exel E, Craen AJM, Meinders AE, Frölich M,
Westendorp RGJ. Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004; 292: 2591-2599.
25.Boekholdt SM, Titan SM, Wiersinga WM, et al. Initial thyroid
status and cardiovascular risk factors: the EPIC-Norfolk prospective population study. Clin Endocrinol (Oxf) 2010; 72: 404-410.
26. Razvi S, Weaver JU, Vanderpump MP, Pearce SHS. The incidence
of ischemic heart disease and mortality in people with subclinical
hypothyroidism: re-analysis of the Whickham Survey cohort. J
Clin Endocrinol Metab 2010; 95: 1734-40.
27. Singh S, Duggal J, Molnar J, Maldonado F, Barsano CP, Arora R.
Impact of subclinical thyroid disorders on coronary heart disease,
cardiovascular and all-cause mortality: a meta-analysis. Int J
Cardiol 2008; 125: 41-8.
38. Ochs N, Auer R, Bauer DC, Nanchen D, Gussekloo J, Cornuz J,
Rodondi N. Meta-analysis: subclinical thyroid dysfunction and
the risk for coronary heart disease and mortality. Ann Intern Med
2008; 148: 832-45. 29.Haentjens P, Van Meerhaeghe A, Poppe K, Velkeniers B.
Subclinical thyroid dysfunction and mortality: an estimate of
relative and absolute excess all-cause mortality based on timeto-event data from cohort studies. Eur J Endocrinol 2008;
159:329-41.
30. Razvi S, Shakoor A, Weaver JU, Vanderpump M, Pearce SH. The
influence of age on ischeamic heart disease and mortality in
subclinical hypothyroidism – a meta-analysis. J Clin Endocrinol
Metab 2008; 93: 2998-3007
31. Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh
JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A,
Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman
AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E,
Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality.
JAMA 2010; 304:1365-74.
9
10
Thyroid International 1 2012
32. Thvilum M, Brandt F, Brix TH, Hegedüs L. A review of the evidence for and against increased mortality in hypothyroidism. Nat
Rev Endocrinol 2012 doi: 10.1038/nrendo.2012.29 [Epub ahead
of print]
49.Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine
Treatment of Subclinical Hypothyroidism, Fatal and Nonfatal
Cardiovascular Events, and Mortality. Arch Intern Med 2012
[Epub ahead of print] PMID: 22529180
33. Forfar JC, Wathen CG, Todd WT, Bell GM, Hannan WJ, Muir AL,
Toft AD.Left ventricular performance in subclinical hypothyroidism. Q J Med 1985; 57:857-65.
50. Pearce SH, Vaisman M, Wemeau JL. Management of subclinical
hypothyroidism: The thyroidologists’ view. Eur Thyroid J 2012;
1: 45-50.
34. Földes J, Istvánfy M, Halmágyi M, Váradi A, Gara A, Pártos O.
Hypothyroidism and the heart. Examination of left ventricular
function in subclinical hypothyroidism. Acta Med Hung 1987;
44: 337-47.
51. McDermott MT, Haugen BR, Lezotte DC, Seggelke S, Ridgway EC.
Management practices among primary care physicians and thyroid specialists in the care of hypothyroid patients. Thyroid 2001;
11:757-64.
35. Arem R, Rokey R, Kiefe C, Escalante DA, Rodriguez A. Cardiac
systolic and diastolic function at rest and exercise in subclinical
hypothyroidism: effect of thyroid hormone therapy. Thyroid
1996; 6: 397-402.
52.Meyerovitch J, Rotman-Pikielny P, Sherf M, Battat E, Levy Y,
Surks MI. Serum thyrotropin measurements in the community:
five-year follow-up in a large network of primary care physicians. Arch Intern Med 2007; 167: 1533-8.
36. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A,
Bonè F, Lombardi G, Saccà L. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol
Metab 1999; 84: 2064-7.
53. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, StagnaroGreen A. Increased pregnancy loss rate in thyroid antibody
negative women with TSH levels between 2.5 and 5.0 in the first
trimester of pregnancy. J Clin Endocrinol Metab 2010; 95:E44-8.
37. Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C,
Ferranini E. Effect of L-thyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebocontrolled study. J Clin Endocrinol Metab 2001; 86:1110–1115
54. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman
J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga
W; American Thyroid Association Taskforce on Thyroid Disease
During Pregnancy and Postpartum. Guidelines of the American
Thyroid Association for the diagnosis and management of thyroid
disease during pregnancy and postpartum. Thyroid 2011;21:1081125.
38. Yazici M, Gorgulu S, Sertbas Y, Erbilen E, Albayrak S, Yildiz O,
Uyan C. Effects of thyroxin therapy on cardiac function in
patients with subclinical hypothyroidism: index of myocardial
performance in the evaluation of left ventricular function. Int J
Cardiol 2004; 95:135-43.
39. Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical
hypothyroidism. Thyroid 2000;10:665-79.
40. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni
L, Salvetti D, Ferranini E, Monzani F. Impaired endotheliumdependent vasodilatation in subclinical hypothyroidism: beneficial effect of L-thyroxine therapy. J Clin Endocrinol Metab 2003;
88:3731–3737.
41. Shakoor SK, Aldibbiat A, Ingoe LE, Campbell SC, Sibal L, Shaw
J, Home PD, Razvi S, Weaver JU. Endothelial progenitor cells in
subclinical hypothyroidism: the effect of thyroid hormone
replacement therapy. J Clin Endocrinol Metab 2010 ; 95: 319-22.
42. Cai Y, Ren Y, Shi J. Blood pressure levels in patients with subclinical thyroid dysfunction: a meta-analysis of cross-sectional
data. Hypertens Res 2011; 34: 1098-105.
43. Teixeira PF, Reuters VS, Ferreira MM, Almeida CP, Reis FA, Melo
BA, Buescu A, Costa AJ, Vaisman M. Treatment of subclinical
hypothyroidism reduces atherogenic lipid levels in a placebo-controlled double-blind clinical trial. Horm Metab Res 2008; 40: 50-5.
44. Danese MD, Ladenson PW, Meinert CL, Powe NR. Clinical review
115: effect of thyroxine therapy on serum lipoproteins in patients
with mild thyroid failure: a quantitative review of the literature.
J Clin Endocrinol Metab 2000; 85:2993–3001.
45.Gullu S, Sav H, Kamel N. Effects of L-thyroxine treatment on
biochemical and hemostasis parameters in patients with hypothyroidism. Eur J Endocrinol 2005; 152:355-61.
46. TRUST study website. www.trustthyroidtrial.com
47.Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC.
Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or
overtreatment. Br J Gen Pract 1993; 43:107-9.
48.Okosieme OE, Belludi G, Spittle K, Kadiyala R, Richards J.
Adequacy of thyroid hormone replacement in a general population. QJM 2011; 104: 395-401.
55. Vaidya B, Pearce SHS. Management of hypothyroidism in adults.
BMJ 2008;337: 284-89.
56. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates
D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F,
et al. The incidence of thyroid disorders in the community: a
twenty-year follow-up of the Whickham Survey. Clin Endocrinol
(Oxf) 1995; 43:55-68.
Practical Approach to Management of subclinical hypothyroidism
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Former Editions of Thyroid International
No 4-2011 D
iagnosis and Treatment of Graves’ Disease
in Children and Adolescents:
Challenges & controversies
(Rosalind S. Brown, MD, CM, FRCP (C))
No 3-2011 A View of Diabetes from the Thyroid Corner
(Gabriela Brenta, M.D.)
No 2-2011 Antithyroid Drugs (Luigi Bartalena)
No 1-2011 Guidelines for the Diagnosis and Management
of Thyroid Nodules (Mahmood Gharib, Hossein
Gharib)
No 5-2010 Highlights of the 14th International Thyroid
Congress 11th–16th September 2010, Palais
des Congrès, Paris (Clara V Alvarez, Stephen W
Spaulding, Peter PA Smyth)
No 4-2010 The interaction between growth hormone and the
thyroid axis (Lucy Ann Behan, Amar Agha)
No 3-2010 Transient Hypothyroxinemia of Prematurity: Current
State of Knowledge (Nevena Simic, Joanne Rovet)
No 2-2010 3-Iodothyronamine (T1AM): A new thyroid
­hormone? (Barbara D Hettinger, Kathryn G Schuff,
Thomas S Scanlan)
No 1-2010 R
eport on the 34th Annual Meeting of the
European Thyroid Association
(Clara V Alvarez and Peter PA Smyth)
No 5-2009 F actors Affecting Thyroid Hormone Gastrointestinal
Absorption (Kenneth D. Burman, M.D.)
No 4-2009 Iodine Deficiency Disorders: Silent Pandemic
(Fereidoun Azizi)
No 3-2009 A
merican Thyroid Association:
Highlights of the 79th Annual Meeting
(Stephen W Spaulding, P.P.A. Smyth)
No 2-2009 E pidemiology of Thyroid Dysfunction –
Hypothyroidism and Hyperthyroidism
(M.P.J. Vanderpump)
No 1-2009 R
eport on the 33rd Annual Meeting
of the European Thyroid Association
(L.H. Duntas, P.P.A. Smyth)
No 4-2008 T hyroid autoimmunity and female infertility
(Kris Poppe, Daniel Glinoer, Brigitte Velkeniers)
No 3-2008 N
ew reference range for TSH?
(Georg Brabant)
No 2-2008 A
merican Thyroid Association: Highlights of the
78th Annual Meeting (Stephen W Spaulding, Peter
PA Smyth)
No 1-2008 R
eport of the 32th Annual Meeting of the European
Thyroid Association (GJ Kahaly, P.P.A. Smyth)
(John H Lazarus, Peter PA Smyth)
No 1-2007 The story of the ThyroMobil (F. Delange,
C.J. Eastman, U. Hostalek, S. Butz, P.P.A. Smyth)
No 3-2006 Thyroid Peroxidase – Enzyme and Antigen
(Barbara Czarnocka)
No 2-2006 Genetics of benign and malignant thyroid tumours
(Dagmar Führer)
No 1-2006 Highlights of the 13th ITC
(Sheue-yann Cheng, Peter PA Smyth)
No 4-2005 Thyroid Eye Disease: Current Concepts and the EUGOGO Perspective
(Gerasimos E Krassas, Wilmar M Wiersinga)
No 3-2005 Clinical Expression of Mutations in the TSH
Receptor: TSH-R Disorders
(Davide Calebiro, Luca Persani, Paolo Beck-Peccoz)
No 2-2005 Transient Hypothyroxinaemia and
Preterm Infant Brain Development
(Robert Hume, Fiona LR Williams, Theo J Visser)
No 1-2005 The Spectrum of Autoimmunity in Thyroid Disease
(Anthony P. Weetman)
No 5-2004 Postpartum Thyroiditis: An Update
(Kuvera E. Premawardhana, John H. Lazarus)
No 4-2004 Report of the 29th Annual Meeting of the European
Thyroid Association (G. Hennemann)
No 3-2004 Autoimmune Thyroiditis And Pregnancy
(Alex F. Muller, Arie Berghout)
No 2-2004 Report of the 75th Annual Meeting of the American
Thyroid Association (G. Hennemann)
No 1-2004 Thyroid and Lipids: a Reappraisal
(Leonidas H. Duntas)
No 5-2003 Use of Recombinant TSH in Thyroid Disease:
An Evidence-Based Review (Sara Tolaney M.D.,
Paul W. Ladenson M.D.)
No 4-2003 New Insights for Using Serum Thyroglobulin
(Tg) Measurement for Managing Patients with
Differentiated Thyroid Carcinomas (C.A. Spencer)
No 3-2003 The Significance of Thyroid Antibody Measurement
in Clinical Practice (A. Pinchera, M. Marinò, E. Fiore)
No 2-2003 Etiology, diagnosis and treatment of Graves’ disease
(A.P. Weetman)
No 1-2003 Report of the 74th Annual Meeting of the American
Thyroid Association (G. Hennemann)
No 6-2002 R
eport of the 28th Annual Meeting of the European
Thyroid Association (G. Hennemann)
No 4-2007 T he Thyroid and Twins (Pia Skov Hansen, Thomas
Heiberg Brix, Laszlo Hegedüs)
No 5-200 2 Iodine Deficiency in Europe anno 2002
(François M. Delange, MD, PhD)
No 2-2007 R
eport of the 31th Annual Meeting
of the European Thyroid Association
No 3-200 2 Congenital Hypothyroidism (Delbert A. Fisher)
No 3-2007 C
linical Aspects of Thyroid Disorders in the
Elderly (Valentin Fadeyev)
No 4-200 2 Thyroid Imaging in Nuclear Medicine
(Dik J. Kwekkeboom, Eric P. Krenning)
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