Health status in patients with sub-clinical hypothyroidism
Salman Razvi1, Lorna E Ingoe1, Carolyn V McMillan2and Jolanta U Weaver1,3
1Department of Diabetes and Endocrinology, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK,2Health Psychology Research, Department
of Psychology, Royal Holloway, University of London, Egham, Surrey TW20 0EX, UK and3School of Clinical Medical Sciences, University
of Newcastle-upon-Tyne, NE2 4HH, UK
(Correspondence should be addressed to S Razvi; Email: email@example.com)
Objective: Sub-clinical hypothyroidism (SCH) is a common disorder. People with this condition may
have symptoms which could affect their perception of health. Therefore, the perceived health
status of people with SCH was assessed and compared with population-matched norms.
Design: A prospective cross-sectional survey.
Methods: Seventy-one adults with SCH, age range 18–64 years were studied. Perceived health status
was measured by the Short Form-36 (SF-36) version 2 questionaire, which has been validated in a UK
population setting. The SF-36 has eight scales measuring physical functioning, role physical, bodily
pain, general health, vitality, social functioning, role emotional and mental health. Their SF-36 scores
were compared with UK normative data after matching for age and sex and are reported as z-scores.
Results: Scores of all eight SF-36 scales were significantly lower in people with SCH compared with the
normative population. A negative score (compared with zero of the normative population) indicates
worse health status. The most significantly impaired aspects of health status were vitality and role
limitations due to physical problems (role physical scale) with z-scores (95% confidence intervals)
of 21.01 (20.74 to 21.29) and 20.73 (20.43 to 21.04) respectively. Thyroid autoimmunity
did not influence the results.
Conclusion: Perceived health status is significantly impaired in people with SCH when compared with
UK normative population scores. This needs to be taken into consideration by clinicians when mana-
ging patients with this disease.
European Journal of Endocrinology 152 713–717
Sub-clinical hypothyroidism (SCH) is a biochemical
diagnosis and refers to patients with elevated thyroid
stimulating hormone (TSH) levels and a normal free
thyroxine (fT4) level (1). It is a common disorder with
prevalence rates quoted between 5.8 and 17.4%
depending on the age of the population studied
(1–3). The presence of symptoms of hypothyroidism
in patients with SCH when compared with the general
population is controversial due to the non-specific
nature of many hypothyroid symptoms, which are
also common to many other conditions, and due to
the different types of patient samples studied (3–7).
The lifetime prevalence of depression in patients with
SCH is double that of the general population and has
been reported to reduce the efficacy of antidepressant
treatment (8); it is associated with anxiety (9) and
changes in mood and cognitive functioning (10).
There is also evidence that exercise capacity may be
impaired due to significant reduction of exercise-related
stroke volume, cardiac index, vital capacity and
reduced anaerobic thresholds (11). All these factors
may affect subjective perception of health status.
Subjective health status is a key component in the
evaluation of any medical condition and therapeutic
intervention (12). In patients with SCH, symptoms
may contribute to perceived impairment of health-
related quality of life (13). Health status can be
measured by the widely used generic Short Form-36
(SF-36) questionaire. As there have been some con-
cerns about the wording and layout of the original
SF-36 (14), the developers have designed a second ver-
sion – the SF-36v2. The normative data for the SF-
36v2 in the UK was obtained from a postal survey of
patients randomly selected from general practitioner
records, which achieved a response rate of 64.4%
(n ¼ 8889). The SF-36v2 was shown to have improved
reliability and reduced floor and ceiling effects com-
pared with the previous version of the SF-36 (15).
Respondents were also asked to report demographic
details and any long-term illnesses, and 36.6% reported
a chronic long-standing illness. In the present study, we
therefore assessed the health status of people with SCH
European Journal of Endocrinology (2005) 152 713–717ISSN 0804-4643
q 2005 Society of the European Journal of EndocrinologyDOI: 10.1530/eje.1.01907
Online version via www.eje-online.org
using the SF-36v2 and compared it with UK normative
Patients and methods
One hundred consecutive community living adults with
SCH were recruited over a 5-month period from pri-
mary care practices after identification from the labora-
tory database. Inclusion criteria were people with SCH
over 18 years of age. Exclusion criteria were people
with ischaemic heart disease, cerebrovascular disease,
neurological disease, diabetes mellitus, chronic renal
impairment, known psychological illnesses such as
depression, previous history of thyroid disease or pre-
vious thyroxine therapy, asthma, and pregnancy, so
as to reduce the effect of other co-morbid conditions
on perceived health status. All participants except one
had had at least three abnormal thyroid function tests
(TSH .4mU/l with normal fT4 levels) consistent
with SCH, their thyroid status having been checked
previously due to hypothyroid symptoms, or SCH was
an incidental finding. All participants gave written
informed consent and the Gateshead ethics committee
approved the study. Only 71 patients (mean age
(^S.D.) 48.7 years (^9.67), range 23–64; 15 males)
in the 18 to 64 year age group were considered for
comparison with the UK SF-36v2 normative data, as
normative data are not available for older adults. The
mean^S.D. TSH concentration was 6.6^2.5mU/l,
4.0mU/l) and the mean^S.D. fT4 concentration was
13.9^1.9pmol/l, range 10.3–19 (normal reference
range: 9–25pmol/l). The frequency of other chronic
diseases was: hypertension 9.5%, hypercholesterolae-
mia 1.3% and arthritis (osteoarthritis, gout or rheuma-
toid arthritis) 21.9%. Results of two participants found
to be on treatment for asthma were not included in the
analyses. The results of 27 participants aged 65 to 80
years were used for within-SCH group comparisons.
Perceived health status was evaluated by the SF-36v2
questionnaire. The questionnaire is composed of 36
items, 35 of which are classed into eight scales of vary-
ing length. For each SF-36v2 dimension, raw item
scores are coded, summed and transformed on to a
scale ranging from 0 (worst possible perceived health
status) to 100 (best possible health status). The single
item on perceived changes in health status over the pre-
vious 12 months was not considered in the present
study. The degree of divergence from the scores for
the normative population of an individual patient or
specific patient population can be measured using a z
transformation, taking into account the effects of age
and gender. For each SF-36v2 scale, a z-score was cal-
culated by subtracting the mean scale score of the nor-
mative population sample (matched for age and sex)
from the scale score of the study group and dividing
this difference by the standard deviation of the norma-
tive population sample. This was carried out individu-
ally for each participant for each scale and the overall
group mean was calculated. A z-score value of 0 corre-
sponds to the mean value of the normal population, a
z-score value of 21 or 22 corresponds to one or two
standard deviations below the normal population
respectively. Z-scoring was preferred to the 0–100
based scoring algorithm to compare with the UK nor-
mative scores because it provides a basis for meaningful
comparison across scales and for easier interpretation
(16, 17). Control values were obtained in relatively
large numbers from random samples of the UK popu-
lation aged between 18 and 64 years (n ¼ 8889), as
described above. This procedure has previously been
used in the UK in the study of health status in patients
with different diseases such as Parkinson’s disease and
multiple sclerosis (18), heart failure and left ventricular
systolic dysfunction (19) and low back pain, menorrha-
gia, suspected peptic ulcer and varicose veins (17), and
elsewhere in thyroid disease (20).
The tests were performed at the Queen Elizabeth Hospi-
tal Biochemistry Laboratory. Serum was collected using
standard sampling tubes containing separating gel.
TSH and fT4 were measured by an electro-chemilumi-
nescence immunoassay ‘ECLIA’ using Roche Elecsys
E170 immunoassay analysers (Roche Diagnostics,
UK). The Elecsys TSH test had been calibrated against
the 2nd IRP WHO Reference Standard 80/558. The
Elecsys fT4 test had been calibrated against Enzymunt-
est fT4. This, in turn, was calibrated using equilibrium
dialysis. Thyroid autoimmunity was determined by the
quantitative measurement of anti-thyroid peroxidase
autoantibodies (anti-TPO) by ELISA (ORGENTEC Diag-
nostika GmbH, Mainz, Germany) with a cut-off value
Data were analysed byone researcher (SR). Means^ S.D.
were used to report descriptive data and 95% confi-
dence intervals (95% CI) were used to report the differ-
ence in the means between the study participants and
the normative population. A 95% CI is significant if
the interval range does not cross zero, signifying that
the two populations are different (21). Student’s
unpaired t-test was used to compare the subgroup
means and Bonferroni’s post hoc multiple comparison
test for observed means was carried out to ensure that
multiple t-tests did not show a significant difference
where none exists, i.e. to reduce type I error (22).
S Razvi and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152
Z-scores were also used to report transformed scores as
discussed previously. A mean z-score ,0.2 was con-
sidered clinically non-significant, between 0.2 and 0.5
as a small difference, between 0.5 and 0.8 as a moder-
ate difference and .0.8 as a large difference (23, 24).
Correlation analysis (Spearman’s rho for non-para-
metric data or Pearson’s r for parametric data) was
used to assess the relationship between each SF-36
scale measured and biochemical and demographic par-
ameters. Internal consistency reliability - that is, the
extent to which there is a correlation between items
on a scale – was assessed by Cronbach’s alpha, an
inter-item correlation statistic, with a value range of
0–1 (25). Levels of .0.9 are usually agreed to signify
excellent internal consistency reliability (26). A P value
of ,0.05 was taken as statistically significant. SPSS
version 11.0 was utilised for computing the statistics
(SPSS Inc., Chicago, IL, USA).
In comparison with a large UK population reference
group, scores on all eight scales of the SF36v2 were
found to be significantly reduced (Table 1). The differ-
ence was attenuated but still significant when people
with SCH and other chronic diseases (e.g. arthritis,
excluded from the analyses (n ¼ 24). Z-scores for all
71 participants studied were significantly lower than
the normative data for all scales of the SF-36 but only
the vitality (VT) scale showed a large difference, that
is .0.8 (Fig. 1).
The rest of the z-scores showed either moderate (role
physical (RP), general health (GH), social functioning
ences. When analysed separately for men (n ¼ 15) and
women (n ¼ 56), the results of the z-score analysis
showed that women tended to have lower scores for all
scales compared with men, although not significantly
so (Fig. 2). Men had significantly lower z-scores in all
scales except PF when compared with men from the UK
norms (Fig. 2) whereas women had significantly lower
scores on all scales.
Health status scores did not differ in people with thyr-
TPO antibodies (n ¼ 39), although the two groups were
well matched for age, sex and biochemical thyroid func-
tion tests. None of the scales of the SF-36v2 correlated
with either TSH or fT4 levels. As expected, TSH values
P ¼ 0.04). The z-scores for the VT scale correlated sig-
nificantly with age (r ¼ 0.35, P ¼ 0.002), which was
statistically significant after Bonferroni correction
requiring a P value of 0.006 (0.05/8). Comparison of
absolute scores of older people with SCH (aged 65–80
years) (n ¼ 27) with the younger group studied
(n ¼ 71) showed that the older group had significantly
impaired health status only for the PF, RP and BP
withfT4(r ¼ 20.238,
Table 1 Differences in absolute SF-36 scores in patients with
SCH compared with age- and sex-matched normative data.
n ¼ 71)
(mean^S.D.; n ¼ 8660)
SF-36 score range: 0 to 100 (poor to excellent health status). PF, physical
functioning; RP, role physical; BP, bodily pain; GH, general health; VT,
vitality; SF, social functioning; RE, role emotional; MH, mental health.
Figure 1 SF-36v2 scale scores of patients with SCH (mean with
95% confidence interval) compared with age- and sex-matched
controls in a UK cohort (zero line). Note: a negative z-score indi-
cates lower health status in the SCH group compared with norma-
tive data. PF, physical functioning; RP, role physical; BP, bodily
pain; GH, general health; VT, vitality; SF, social functioning; RE,
role emotional; MH, mental health.
Figure 2 Sex differences in z-scores for each SF-36 scale for
patients with SCH (n ¼ 71). Solid bars, males; shaded bars,
Health status in subclinical hypothyroidism
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152
(6.4 2 29.04),
(2.97 2 26.89) respectively).
Cronbach’s alpha coefficient ranged from 0.91 to
0.93 signifying excellent internal consistency reliability
for all eight SF-36 scales in this sample of patients with
(1.32 2 26.54)
Perceived health status is more than just the presence
or absence of disease or symptoms and encompasses
social, physical and emotional dimensions. Clinicians
do not routinely assess patients’ perceptions of their
health status, but it is increasingly being argued that
the patient’s perspective is as valid as that of the clini-
cian in evaluation of a medical condition and its out-
comes (27). We have shown for the first time that
patients with SCH perceive significant impairment of
their health status, as measured by all eight scales of
the SF-36v2. The normative data in this study for com-
parison of scores for all scales comprised a random
sample from the general population and not a dis-
ease-free population. Hence it is probable that some of
these individuals had thyroid disease and therefore
the results obtained in this study may well be an under-
estimation of the true value. This is all the more likely
since 36.6% of the normative population reported
chronic long-standing illness (patients with chronic dis-
eases are more likely to respond to a postal health
survey than disease-free individuals), whereas patients
with such conditions, apart from hypertension, arthri-
tis and hypercholesterolaemia, were excluded in the
Bianchi and colleagues recently reported that there
were no differences in perceived health status (as
measured by the SF-36 and the Nottingham Health
Profile instruments) between their Italian patients
with SCH, and age- and sex-matched Italian population
norms (20). The results reported in this paper are differ-
ent from their observations. This may be due to the
different population and normative data used in the
analysis as well as the fact that the comparison
sample in the present study was younger owing to
the lack of normative data for people older than 64
years in the UK.
Limitations of this study are that patients were not
identified from a screening programme and were
recruited from primary care practices. Thus patients
with presence of symptoms at the higher end of the
scale and/or with other co-morbidities were more
likely to have been studied. However, the results
obtained still remain significantly different from the
normative scores even when data were analysed after
excluding people with other chronic conditions. It is
quite possible that some conditions such as hyperten-
sion and hypercholesterolaemia are ‘silent’ and hence
affect health status the least (28). Also, it would seem
that men tend not to have any impairment of physical
functioning as compared with normative scores for
men of the same age. We have no direct explanation
for this and further research is required. Also, older
people (.64 years) with SCH have significantly lower
scores on the physical scales (PF, RP and BP) when
compared with younger people. This was not an unex-
pected finding as others have obtained significant age
gradients in some SF-36 subscales (29), but the lack
of normative data for comparison with this older
group is disappointing, especially since SCH is more
prevalent in older people (30). There is some recent evi-
dence that SCH may not adversely affect the very old in
terms of disability, cognitive function and survival (31).
Although it is clear from this study that people with
SCH have impaired perceived health status, it is yet to
be clarified whether normalizing serum TSH level
would improve it. Previous studies have had conflicting
results in improving symptoms and health-related qual-
ity of life (4, 7, 32–34). It has also been shown that
people on adequate doses of
impaired psychological well-being (35).
In conclusion, we have shown that perceived health
status is significantly impaired in people presenting
with SCH and this should be considered when mana-
ging this condition.
Salman Razvi is funded by a Department of Health
Research and Development grant.
1 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). Journal of Clinical Endocrinology and Metabolism
2002 87 489–499.
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. Clinical Endocrin-
ology 1977 7 481–493.
3 Canaris GJ, Manowitz NR, Mayor G & Ridgway EC. The Colorado
thyroid disease prevalence study. Archives of Internal Medicine
2000 160 526–534.
4 Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg PA &
Lindstedt G. A double-blind cross-over 12-month study of L-thyr-
oxine treatment of women with ‘subclinical’ hypothyroidism.
Clinical Endocrinology 1988 29 63–75.
5 Eden S, Sundbeck G, Lindstedt G, Lundberg PA, Jagenburg R,
Landahl S & Svanborg A. Screening for thyroid disease in the
elderly. Serum concentrations of thyrotropin and 3,5,30-triio-
dothyronine in a representative population of 79-year-old
women and men. Comprehensive Gerontology. Section A, Clinical
and Laboratory Sciences 1988 2 40–45.
6 Zulewski H, Muller B, Exer P, Miserez AR & Staub JJ. Estimation of
tissue hypothyroidism by a new clinical score: evaluation of
patients with various 11 grades of hypothyroidism and controls.
S Razvi and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152
Journal of Clinical Endocrinology and Metabolism 1997 82 Download full-text
7 Cooper DS, Halpern R, Wood LC, Levin AA & Ridgway EC. L-Thyr-
oxine therapy in subclinical hypothyroidism. A double-blind, pla-
cebo-controlled trial. Annals of Internal Medicine 1984 101
8 Saddock BJ & Saddock V. Psychological factors affecting medical
conditions. In Kaplan and Saddock’s Comprehensive Textbook
of Psychiatry, pp 1765–1888. Eds A Stoudemie & JS McDaniel.
Philadelphia: Lippincott Williams and Willens, 2000.
9 Sait Gonen M, Kisakol G, Savas Cilli A, Dikbas O, Gungor K, Inal A
& Kaya A. Assessment of anxiety in subclinical thyroid disorders.
Endocrine Journal 2004 51 311–315.
10 Hendrick V, Altshuler L & Whybrow P. Psychoneuroendocrinology
of mood disorders. The hypothalamic–pituitary–thyroid axis.
Psychiatric Clinics of North America 1998 21 277–292.
11 Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical
hypothyroidism. Thyroid 2000 10 665–679.
12 Working for Patients. Secretaries of State for Health, England and
Wales, Northern Ireland, and Scotland. London: HMSO, 1989.
13 Jaeschke R, Guyatt G, Cook D, Harper S & Gerstein HC. Spectrum
of quality of life impairment in hypothyroidism. Quality of Life
Research 1994 3 323–327.
14 Jenkinson C & McGee H. Patient assessed outcomes: measuring
health status and quality of life. In Assessment and Evaluation of
Health and Medical Care. Ed. C Jenkinson. Buckingham: Open
University Press, 1997.
15 Jenkinson C, Stewart-Brown S, Petersen S & Paice C. Assessment
of the SF-36 version 2 in the United Kingdom. Journal of Epide-
miology and Community Health 1999 53 46–50.
16 Ware JE Jr, Kosinski M, Gandek B. SF-36 Health Survey: Manual
and Interpretation Guide. Lincoln, RI: QualityMetric Incorporated,
17 Garratt AM, Ruta DA, Abdalla MI, Buckingham JK & Russell IT.
The SF-36 health survey questionnaire: an outcome measure
suitable for routine use within the NHS? British Medical Journal
1993 306 1440–1444.
18 Riazi A, Hobart JC, Lamping DL, Fitzpatrick R, Freeman JA,
Jenkinson C, Peto V & Thompson AJ. Using the SF-36 measure
to compare the health impact of multiple sclerosis and
Parkinson’s disease with normal population health profiles.
Journal of Neurology, Neurosurgury and Psychiatry 2003 74
19 Hobbs FD, Kenkre JE, Roalfe AK, Davis RC, Hare R & Davies MK.
Impact of heart failure and left ventricular systolic dysfunction on
quality of life: a cross-sectional study comparing common chronic
cardiac and medical disorders and a representative adult popu-
lation. European Heart Journal 2002 23 1867–1876.
20 Bianchi GP, Zaccheroni V, Solaroli E, Vescini F, Cerutti R, Zoli M &
Marchesini G. Health-related quality of life in patients with thyr-
oid disorders. Quality of Life Research 2004 13 45–54.
21 Gardner MJ & Altman DG. Confidence intervals rather than P
values: estimation rather than hypothesis testing. British Medical
Journal (Clinical Research Edition) 1986 292 746–750.
22 Norman GR & Streiner DL. Biostatistics: The Bare Essentials.
Hamilton: B.C. Decker Inc., 2000.
23 Cohen J. Statistical Analysis for the Behavioural Sciences. New York:
Academic Press, 1977.
24 Kazis LE, Anderson JJ & Meenan RF. Effect sizes for interpreting
changes in health status. Medical Care 1989 27 S178–S189.
25 Cronbach LJ. Coefficient alpha and the internal structure of tests.
Psychometrica 1951 41 1395–1401.
26 Nunally JC & Bernstein IH. Psychometric Theory. New York:
27 Leplege A & Hunt S. The problem of quality of life in medicine.
Journal of the American Medical Association 1997 278 47–50.
28 Stewart AL, Greenfield S, Hays RD, Wells K, Rogers WH, Berry SD,
McGlynn EA & Ware JE Jr. Functional status and well-being of
patients with chronic conditions. Results from the Medical Out-
comes Study. Journal of the American Medical Association 1989
29 Brazier JE, Harper R, Jones NM, O’Cathain A, Thomas KJ,
Usherwood T & Westlake L. Validating the SF-36 health survey
questionnaire: new outcome measure for primary care. British
Medical Journal 1992 305 160–164.
30 Braverman LE & Utiger RD. The epidemiology of thyroid diseases.
In Werner’s and Ingbar’s The Thyroid: A Fundamental and Clinical
Text, pp 467–473. Philadelphia: JB Lippincott-Raven, 2000.
31 Gussekloo J, Van Exel E, De Craen AJ, Meinders AE, Frolich M &
Westendorp RG. Thyroid status, disability and cognitive function,
and survival in old age. Journal of the American Medical Association
2004 292 2591–2599.
32 Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D,
Harper S, Griffith L & Carbotte R. Does treatment with L-thyroxine
influence health status in middle-aged and older adults with sub-
clinical hypothyroidism? Journal of General Internal Medicine 1996
33 Kong WM, Sheikh MH, Lumb PJ, Naoumova RP, Freedman DB,
Crook M, Dore CJ, Finer N & Naoumova P. A 6-month randomized
trial of thyroxine treatment in women with mild subclinical
34 Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR,
Drewe J, Huber P, Herzog R & Muller B. TSH-controlled L-thyrox-
ine therapy reduces cholesterol levels and clinical symptoms in
subclinical hypothyroidism: a double blind, placebo-controlled
trial (Basel Thyroid Study). Journal of Clinical Endocrinology and
Metabolism 2001 86 4860–4866.
35 Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R &
Dayan CM. Psychological well-being in patients on ‘adequate’
doses of L-thyroxine: results of a large, controlled community-
based questionnaire study. Clinical Endocrinology 2002 57
of Medicine2002 112
Received 2 December 2004
Accepted 10 February 2005
Health status in subclinical hypothyroidism
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152