Psychoneuroendocrinology 25 (2000) 201211

Long-term residual complaints and

psychosocial sequelae after remission of
hyperthyroidism
J.J. Fahrenfort
a,1
, A.M.L. Wilterdink
a
, E.A. van der Veen
b
a
Bureau Fahrenfort, Epidemiologic Research, Herensteeg 3, 2311 SG Leiden, The Netherlands
b
Department of Endocrinology, Academic Hospital, Vrije Uni6ersiteit, P.O. Box 7057, 1007 MB,
Amsterdam, The Netherlands
Received 3 July 1998; accepted 23 July 1999
Abstract
The issue of residual complaints after treatment for hyperthyroidism in current euthyroid
patients was investigated by means of a survey. Patients treated for hyperthyroidism were
selected from medical records of the previous 6 years in two Dutch University Clinics. After
the exclusion of patients with comorbidity, 303 one-time hyperthyroid respondents were
included in the analysis. A total of 77% of these patients had been diagnosed with Graves
Disease. The newly developed Hyperthyroidism Complaint Questionnaire (HCQ), was used
to quantify problems of somatic and mental functioning. The SymptomsCheckList-90
(SCL-90) was used to assess self-reported psychopathological symptoms, the Notttingham
Health Prole was used to measure perceived health/quality of life. Dysthyroid patients
(n=20) had a mean HCQ-score of 14.5 ( 98.1) complaints; patients who reported euthy-
roidism for less than 12 months (n=171) had a mean of 9.3 ( 97.6) residual complaints;
patients who reported euthyroidism for more than 12 months (n=54) a mean of 6.6 (96.8)
residual complaints. On each dimension of psychopathology covered by the SCL-90,
including depression and anxiety, approximately one third of the total sample had a score
exceeding 80% of adult females. According to the NHP lack of energy was evident in 53% of
all respondents. Over one third of patients with a full-time job were unable to resume the
same work after treatment. It appears that many of these patients are in need of psycholog-
ical support. 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Hyperthyroidism; Euthyroidism; Psychopathology; Neuropsychological functioning; Graves
disease; Quality of life
www.elsevier.com/locate/psyneuen
1
Deceased.
0306-4530/00/$ - see front matter 2000 Elsevier Science Ltd. All rights reserved.
PII: S0306- 4530( 99) 00050- 5
202 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
1. Introduction
Physical complaints commonly associated with hyperthyroidism, for example
exhaustion, excessive perspiration, and loss of weight are produced by changes in
vegetative functioning. Hyperthyroidism also causes a number of neurologic (Swan-
son et al., 1981; Perrild et al., 1986) cognitive (Robbins and Vinson, 1960; Whybrow
et al., 1969; Wallace et al., 1980; Perrild et al., 1986; Trzepacz et al., 1988), and
emotional impairments (Robbins and Vinson, 1960; Greer et al., 1973; MacCrimmon
et al., 1979; Wallace et al., 1980; Bommer et al., 1990; Paschke et al., 1990; Stern
et al., 1996), symptoms that imply a general dysfunction of the nervous system. The
disease may also compromise the social and professional performance of patients and
thus endanger their social or professional status. An additional distinct category of
complaints, specically associated with Graves disease is due to ophtalmopathy, a
subject not addressed at present.
The treatment of hyperthyroidism is directed towards the patient regaining a stable
euthyroid metabolism. The extent of recovery is judged by peripheral thyroid
hormone levels. In the past it has sometimes been taken for granted that remission
of hyperthyroidism implies resolution of symptoms, and ipso facto of most emotional
complaints (Lishman, 1987). Some research appears to support this assumption
(Robbins and Vinson, 1960; Rockey and Griep, 1980; Kathol et al., 1986). One
comprehensive controlled study reported alleviation of depression in the majority of
depressed patients after 612 months follow-up, but marked residual disturbance in
some patients (MacCrimmon et al., 1979; Wallace et al., 1980; Wallace and
MacCrimmon, 1990). In a more recent and larger controlled study of 45 formerly
hyperthyroid patients pronounced psychopathology was found in 43% of current
euthyroid subjects versus 10%of controls (Bommer et al., 1990). Vegetative symptoms
such as sleep disturbance, tremor and diarrhea, and neuropsychological decits were
also documented.
The objective of this study is to assess the variety and prevalence of vegetative and
emotional complaints of patients who have received treatment for hyperthyroidism
according to the state-of-the-art, and to take into account the extent of remission.
In addition sequelae for patients professional and social functioning are explored.
The principal issue addressed is the extent of recovery and of residual malfunction.
2. Methods
2.1. Patients
To select the target population, medical records of the Departments of En-
docrinology of two University Hospitals
2
were screened for any patients diagnosed
2
Participating clinics were the Department of Endocrinology, Academic Medical Centre, University
of Amsterdam and the Department of Endocrinology, Academic Hospital Vrije Universiteit, Amster-
dam.
203 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
with and treated for hyperthyroidism, ICD-code E05. From records of 6 previous
years, 566 one-time hyperthyroid patients were identied, all of whom were
included in the preliminary screening. This screening involved a request to the
general practitioner to notify the researchers in case the person would be deceased
or otherwise unable to participate, a procedure required for ethical reasons. In 81
cases there was a negative response from the general practitioner, for the following
reasons: death of the patient (n=9), present address unknown (n=40) or unspe-
cied reasons (n=32). A letter of invitation to participate in the study, involving
the completion and return of three questionnaires, was mailed to all remaining 485
patients. Among these 73 were unwilling or failed to reply and 12 letters were
undelivered because of a change of residence. Questionnaires were mailed to 400
recipients. The questionnaires were completed and returned by 350, a response rate
of 88% from 400, or 72% from 485. Because of comorbidity, a topic addressed in
the questionnaire, 47 respondents were excluded from the analysis, which nally
included 303 (former) patients.
A total of 77% of the respondents reported that they had been diagnosed with
Graves disease, 23% were uncertain of this or replied that a different diagnosis had
been made. Because a further specication of the diagnosis by the patient might be
unreliable, this was not requested. All respondents conrmed that they had received
treatment for hyperthyroidism.
2.2. Measurement instruments
The Hyperthyroidism Complaint Questionnaire (HCQ) is designed by the au-
thors to quantify the somatic and mental discomfort that is typical for patients
suffering from hyperthyroidism. In the rst stage of development descriptions of
complaints were gathered by informal interviews with a few patients. Characteristic
problems were selected, to produce a list of 31 items, phrased and edited as close
as possible to the original wording of patients. This list was included as a whole in
order to be checked by an empirical item-analysis after data collection. A decision
to exclude any of the items was made dependent on the criterion of internal
consistency. The items are reproduced in Table 1. Eye-complaints were not included
in the list (they were assessed in a separate section of the survey, but the results are
not reported here). Respondents were requested for each complaint to state whether
it was currently present, formerly present, or absent. No attempt was made to
exclude complaints that could be caused by conditions other than hyperthyroidism.
The occurrence of any specic complaint could be unrelated to hyperthyroidism,
but statistical analysis showed for each item that the score indicating the presence
of the complaint is markedly correlated to a composite score from the other items:
Pearson correlations (r
it
) range from .21 to .70 with a median of .50. The statistics
are reported in more detail in Table 1. Because the results indicated a contribution
from each single item to the internal consistency of the scale, all 31 items were
maintained. The basic scale is dened by the number of complaints that are
currently present (after treatment this is the number of residual complaints). An
additional scale is dened as the number of complaints that were formerly present.
The scales as a pair yield some information on improvement.
204 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
The reliability coefcient alpha of both scales is .93, which implies that both
scales are highly reliable in terms of internal consistency, therefore the inclusion or
exclusion of any particular complaint in the scale can not be a serious cause of bias.
Table 1
Hyperthyroidism complaint questionnaire (HCQ)
Entire sample (N=303) % yes, Corrected item test Item
at present correlation (r
it
a
)
.60 40 1. Lack of energy
O yes, at present
b
O in the past, not at present
b
O not
b
.70 45 2. Quickly exhausted
.64 43 3. Fickle energy
29 .58 4. Feeling muddled
.47 39 5. Oversensitive to heat
6 6. Loss of weight .21
.34 15 7. Trembling hands
.49 33 8. Excessive perspiration
30 .50 9. Aching muscles
22 .48 10. Muscle weakness
21 .41 11. Stiffness of the neck
.50 32 12. Palpitations
13. Aching joints 31 .43
.23 14. Irregular menstrual cycle 9
.42 32 15. Reduced libido
16. Sleeplessness 27 .44
29 .60 17. Despondency
18. Anxiety or panic .57 26
39 .49 19. Abnormal tiredness
39 .49 20. Forgetfulness
23 .51 21. Oversensitive to sound
22. Lacking the familiar sense of 40 .69
self
.63 23. Changing moods, apparently 44
without cause
.62 24. Feeling oppressed by minor 44
things
41 .59 25. Lack of concentration
26. Exaggerated emotional .61 46
responses
41 27. Unable to relax .64
58 .59 28. Much need of rest
29. Avoiding large gatherings .46 34
30. Constantly feeling hurried 35 .49
31. Unable to think clearly .61 35
a
r
it
is the Pearson correlation of the item score with the aggregate score from other items, which is
signicantly (PB.01) higher than zero for each item. The items are translated from the Dutch language.
b
These three options are identical for each item.
205 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
The SCL-90 (Derogatis & Cleary, 1977; Arrindell & Hettema, 1986) is a
selfreport instrument, consisting of 90 items, designed to assess various dimensions
of psychopathology. Respondents are requested to report experiences (symptoms of
disturbance) over the last week, including the day the questionnaire is completed.
Only current, not former complaints are investigated by this questionnaire. Rele-
vant dimensions of the SCL-90, obtained by multivariate analyses of population
data are: I, interpersonal sensitivity: dissatisfaction with or distrust towards other
people in general; II, hostility: aggression or resentment towards others; III,
depression; IV, anxiety; V, agoraphobia; VI, insufciency of functioning: dissatis-
faction with the performance of practical tasks; and VII, sleeping problems. The
alpha coefcients reported for these scales range from .73 to .92. Population norms
were available from studies carried out in The Netherlands (Arrindell & Hettema,
1986), which is important for the present purpose.
Of the 303 respondents who completed and returned the other questionnaires, 25
failed to return the SCL-90. SCL-data are therefore available for 278 respondents,
i.e. 92% of the sample. The explanation for failure to return the questionnaire may
be the number of items.
The Nottingham Health Prole (NHP) is a self-report instrument designed to
quantify percei6ed health or quality of life as experienced by a specic study
population (Hunt et al., 1981). Part I, which was used in this study, comprises 38
items, formulated as simple yes/no questions, divided in 6 sections: physical
mobility, pain, sleep, energy, social isolation and emotional reaction to disease.
Alpha coefcients for the separate scales range from .52 to .85 for a Dutch
population. The validity of the instrument has been supported in a number of
studies (Ko nig-Zahn et al., 1993).
Information concerning general characteristics of respondents, comorbidity, on-
set, treatment and remission of hyperthyroidism, and concerning the social prob-
lems encountered by the patients was collected in addition to the quantitative data.
3. Results
3.1. General description
The mean age of the respondents was 44.0 years (SD=11.2, range 17-74), and
that of the non-respondents 41.8 (SD=11.6). This difference is minor, and not
signicant: t =1.60; P=.11. Of the respondents, 87% were female, whereas only of
74% of the non-respondents were female, which implies that males more frequently
failed to respond and are therefore somewhat under-represented:
2
=6.35; df =1;
P=.01.
Of the entire sample (n=303), 31 patients (10%) reported that they had under-
gone surgery of the thyroid, 151 (50%) had received treatment with
131
I, excluding
the use of
131
I for diagnostic purposes, which is carefully distinguished in the
questionnaire, 78 (26%) were currently undergoing treatment with a specic thyreo-
static drug, either carbimazol, methimazol or propyl-thiouracil, and 166 (55%) were
206 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
Fig. 1. Means on hyperthyroidism complaint questionnaire (HCQ) (numbers within the bars represent
the rounded mean number of complaints. The error bars represent the 95% condence intervals of the
mean number of residual complaints.
currently undergoing treatment with levo-thyroxine. A total of 119 patients (40%)
reported that they needed no more drug treatment for the thyroid at the time of the
survey. Obviously the treatments distinguished here are not mutually exclusive, so
percentages do not add up to 100.
3.2. Complaints, past and present
The mean residual HCQ-score of the Graves group of subjects is 10.1 (SD=7.8;
n=230); for unspecied cases of hyperthyroidism it is 9.1 (SD=8.1; n=73), a
small, nonsignicant difference. Of the entire sample, 20 patients (7%) reported that
they were denitely not in euthyroid state, 58 (19%) patients were not certain about
this, 171 (56%) were comparatively certain that they were euthyroid, but had not
yet been so for 12 months, and 54 (18%) reported that they had been euthyroid for
at least 1 year. Complaints measured by the HCQ are unevenly distributed between
these categories as is shown in Fig. 1. A one-way analysis of variance of the
HSQ-scores indicates signicant differences between these categories: F=10,1; df 3,
299; PB.001. Post hoc analysis according to the Tukey HSD indicates a marginally
signicant difference between the 54 long-term euthyroid patients and the 171
short-term euthyroid patients (P=.052) as well as signicant differences between
the latter group and the (as yet) non-euthyroid categories (PB.05). These ndings
207 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
suggests a relationship between the remission of hyperthyroidism and the remission
of complaints. Euthyroid patients have less complaints. Patients who have been
euthyroid for 12 months or longer are even better off, but their mean number of
residual complaints is still 6.6 (96.8).
The most frequently reported residual complaints in the fourth group of patients,
i.e. those who had been euthyroid for twelve months or longer, were a6oiding large
gatherings (31%), changing moods, apparently without cause (35%), and much need of
rest (41%). Corresponding percentages for the dysthyroid group were: 25, 65 and
75% (n=20). Complaints that had almost disappeared in the long-term euthyroid
group of subjects are loss of weight (4%), aching muscles (6%), and irregular
menstrual cycle (7%).
If patients who conrm euthyroidism are considered to be recovered, 74% of the
sample would qualify. But if only patients with less than three complaints are
considered to be recovered, only 23% of the sample, or 31% of the euthyroid
subjects would qualify. The number of complaints reported was not found related
to age or gender.
3.3. Psychopathology
The SCL-90 was completed by 92% of the total sample. The results are presented
in Fig. 2 as percentages of respondents exceeding a norm for a particular dimension
Fig. 2. Dimensions of psychopathology from SCL-90.
208 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
of disturbance. The norms represent a boundary between above normal and
high; they are established as the score corresponding to the 80th percentile of a
representative sample of 432 adult Dutch females (Arrindell and Hettema, 1986).
For the minority of males this norm is conservative, in the sense that it slightly
under-estimates the extent of disturbance. As should be evident from the gure, the
population studied here is signicantly elevated on each dimension.
3.4. Quality of life
The NHP was completed by all respondents. Scores exceeding 15, a standard
based on a population of healthy subjects (Bonsel et al., 1992) are indicative of
problems. Quality of life, as measured by the NHP-scores, is divided into six
domains, two of which (pain and insufcient mobility), are not expected to be
elevated because of hyperthyroidism. As a check on validity it is useful to know
whether respondents tend to conrm complaints unrelated to hyperthyroidism.
Therefore, the outcomes in all six domains are reported here. The percentages of
respondents with scores higher than 15 were: pain 14.9%, insufcient mobility
19.5%, social isolation 30.7%, emotional reaction to disease 36.3%, sleeping prob-
lems 36.3%, and lack of energy 53.5%.
Problems concerning personal relationships and work were explored in the main
questionnaire. It appears that the impairment of functioning tends to be disruptive.
Of the respondents 49.8% reported problems with social relationships. For 33.7%,
however, such problems were only encountered in an earlier stage of the illness.
More frequent conicts than before the onset of disease were reported by 41.3%,
and lack of understanding or sympathy was experienced by 36.6%. Professional
psychosocial help was enlisted by 16.6%, but an additional 20.3% reported that they
had felt the need for such assistance.
A total of 107 respondents had a full-time job at the time of the onset of the
disease. Within this category, 35.3% were unable to resume the same work even
after remission of hyperthyroidism and 29.5% have been ofcially registered as
completely or partially disabled. Of respondents for whom the household was the
principal activity 62.3% reported a decline in competence.
4. Discussion
This study is the rst to investigate the epidemiology of somatic and somatopsy-
chic complaints in patients with remitted hyperthyroidism. The population studied
is larger than the number of subjects in prior studies. One earlier study (Stern et al.,
1996) was the rst large-scale survey of complaints caused by Graves disease, but
its ndings do not distinguish between remitted and unremitted subjects. The high
prevalence of various complaints reported from by Stern et al. is conrmed by the
ndings of the present study.
It should be noted that the patients surveyed at present were drawn from
University Clinics; less severe cases may be treated in other settings. With regard to
209 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
the validity of self-report in this context, it should be mentioned that several
investigators have found close agreement between patient self-report when struc-
tured by questionnaires, and clinical assessment (Robbins and Vinson, 1960; Greer
et al., 1973; Trzepacz et al., 1988; Bommer et al., 1990).
The difference between means on the HCQ that were found between patients
diagnosed with Graves disease and unspecied (formerly) hyperthyroid patients
was small and insignicant. However, whereas just 77% of the respondents an-
swered yes when asked whether Graves disease was diagnosed, only 8% (24
respondents) replied, by means of multiple choice, that they had a different
diagnosis and 16% replied they did not know their diagnosis. We estimate that
more than 77% of the respondents have been diagnosed with Graves disease.
Therefore, the data are not sufcient for analysing differences between diagnostic
categories of hyperthyroidism.
Figure 1 conrms that regular treatment can result in improvement for many
patients. However, the mean number of 6.6 (96.8) HCQ-complaints reported by
patients who have been euthyroid for at least 12 months demonstrates persistent
illness, despite the remission of hyperthyroidism. The HCQ-scores reect vegetative
as well as mental disturbances. The outcomes are broadly in agreement with the
ndings of Bommer et al. (1990), including their observation that the duration of
remission seems benecial. This is suggested also by the results depicted in Fig. 1
and by the analysis of variance reported in the text. Although complaints appear to
be more persistent than commonly expected, these complaints are not found to be
irreversible. The large standard deviation of residual complaints reects that some
patients have no residual complaints, other (euthyroid) patients rather many.
Signs of psychopathology, specied by the SCL-90 data, are present in all
dimensions of potential disturbance. The supercially obvious interpretation of
such disturbances as psychoneurotic should be substituted here by interpretation in
terms of organic dysfunction. Endocrinological disturbances of the brain should
explain both emotional and cognitive symptoms. The most conspicuous deviant
scores were related to insufciency of functioning (40.5%). This dimension is
embodied in aspects such as impaired memory, feeling worried about inaccuracy or
forgetfulness, feeling hampered in carrying out various tasks, etc. Such impairment
is easily confused with neurosis, and may sometimes reect emotional disturbance.
However, the major or most likely cause of this specic impairment in (formerly)
hyperthyroid patients is cognitive neuropsychological dysfunctioning. Cognitive
decits have not objectively measured in the present study, but have been clearly
revealed by other studies (Wallace et al., 1980; Wallace and MacCrimmon, 1990).
Signicant differences in ability between remitted hyperthyroid patients and con-
trols were found on ve of ten neuropsychological tests (Bommer et al., 1990). In
an earlier study Perrild et al. found EEG-abnormalities 10 years after treatment in
68% of 26 former hyperthyroid patients versus 41% among controls. Impairment
was observed in seven out of 11 tests concerning attention, memory and abstraction
( Perrild et al., 1986). The as yet unknown relationship between actual duration of
hyperthyroidism itself and the duration of such impairments represents an impor-
tant topic for future research.
210 J.J. Fahrenfort et al. / Psychoneuroendocrinology 25 (2000) 201211
Whereas cognitive neuropsychological dysfunctioning is perhaps more common,
emotional disturbances, in particular depression or anxiety, may cause severe
distress, during thyrotoxicosis, and also for a minority of patients long after
remission. The variety of emotional symptoms detected by the SCL-90 is a
conrmation of previous research with older questionnaires for assessment of
psychopathology such as the MMPI and the POMS.
At a more abstract level the impairment of quality of life is made explicit by the
NHP-data. Comparison across NHP-domains conrms validity, in the sense that
elevated scores are clearly related to the nature of the disease. Sleeping problems
are experienced by approximately one third of patients as shown by NHP and
SCL-90 alike, a conrmation of previous studies. A principal nding is the fact that
53% of patients suffer from insufency of available energy. To the extent that
dysfunctioning in cured patients is persistent, the psychological problems associated
with the disease present a serious handicap for patients and a challenge for clinical
practice. A severe shortcoming of regular medical attention provided for hyperthy-
roid patients is that psychological problems are frequently ignored because of the
traditional division of tasks in care.
The problems encountered by patients in their personal relationships and work
demonstrate the practical importance of emotional and cognitive dysfunctioning.
Considerable discomfort in daily life is caused by social consequences of the
symptoms discussed here. It appears, as implied by Stern et al. (1996), that
psychological support is desirable or necessary for many patients during and after
recovery from hyperthyroidism.
Acknowledgements
Professor Dr W.M. Wiersinga (AMC) has supported this study by his coopera-
tion and contributed some helpful comment. Extensive assistance in the collection
of data was provided by M. Boerrigter (AMC) by N. Pliester (VU) and A. Nicolaas
(VU). We are very grateful for their important contribution. We also wish to thank
all the people who were willing to answer the lengthy questionnaires.
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