Key words
differentiated thyroid carcinoma - hypothyroidism induction - LT3- protocol - depression - anxiety - quality of life
Introduction
The intense scrutiny of the thyroid gland and widespread use of ultrasonography and
other modern diagnostic techniques have allowed the discovery of a large reservoir
of previously undetectable, small, and predominantly papillary thyroid tumors [1]
[2].
Hence, the improved population screening within the last decades yielded an
over-diagnosis of thyroid cancer, differentiated thyroid cancer (DTC) in particular,
incidentally on radiological imaging, as considered to reflect an enhanced detection
of subclinical disease rather than an actual increase [2]
[3]
[4]. Accordingly, the
health-related quality of life (HRQoL) of thyroid cancer patients has become of
great concern to clinicians globally, given the increasing survivor population, a
relatively low morbidity of the clinical diagnosis and the likelihood of unnecessary
treatment exposures [4]
[5]
[6].
The traditional follow-up of DTC comprises periodic surveillance to detect persistent
or recurrent disease with measurement of tumor marker serum thyroglobulin, neck
ultrasonography and total body scan with RIA for diagnostic and therapeutic
purposes, which necessitates adequately elevated blood levels of thyroid-stimulating
hormone (TSH≥30 mU/l) to stimulate sufficient radioactive
131iodine (RAI) uptake [4]
[6]
[7].
This can be achieved by stopping levothyroxine (LT4) replacement for at least 3
weeks (thyroxine withdrawal) or by intramuscular administration of recombinant human
TSH (rhTSH), while alternatively triiodothyronine (LT3) can be administered for 2
weeks followed by LT3-withdrawal for 2 weeks before RAI in an attempt to decrease
the duration of hypothyroidism [4]
[6]
[7].
Thyroxine withdrawal in preparation for RAI induces a profound state of
hypothyroidism with associated physical and mental (i. e., depression and
anxiety) complaints that may interfere severely with the patient’s
activities of daily living and may have a profound impact on HRQoL [7]
[8].
LT3-treatment strategy prior to RAI ablation therapy with shorter half-life of LT3 is
considered a conceptually attractive alternative to shorten the duration of overt
hypothyroidism [7]
[8]. However, there is limited and controversial
data regarding the impact of interim LT3 medication prior to RAI ablation therapy on
physical and physiological morbidity among DTC patients as well as the relation of
short-term hypothyroid induction with mood disorders (depression and anxiety) and
HRQoL [7]
[8]
[9]
[10].
This study aimed to compare “non-treated” versus
“LT3-treated” protocols of short-term hypothyroidism induction prior
to RAI ablation therapy in DTC patients in terms of hypothyroid complications, mood
disorders (depression and anxiety), and HRQoL before and after thyroxine
withdrawal.
Patients and Methods
Study population
A total of 120 patients with DTC (mean±SD age: 49.0±10.8 years,
80% were females) who had thyroxine withdrawal to induce hypothyroid
state prior to RAI ablation after initial surgery were included in this
prospective study conducted at a tertiary care hospital. ATA risk stratification
system was used to estimate the risk of persistent/recurrent disease.
Patients were divided into two groups based on characteristics of thyroxine
withdrawal period including those followed without treatment during the entire
4-week hypothyroidism induction period (non-treated group, n=62)
(mean±SD age: 49.7±11.7 years, 81.7% were females) and
those followed with 2-week administration and then 2-week withdrawal of LT3
(LT3-treated group, 25 mcg oral twice daily, n=58),
mean±SD age: 48.7±9.9 years, 78.3% were females). Adult
patients (over 18 years of age) with operated DTC (papillary thyroid carcinoma)
and available data on clinical and laboratory findings related to induction
period during their follow up at internal medicine and endocrine clinics were
included in the study. Illiteracy,<18 years or>65 years of age
and presence of comorbid diseases (i. e., malignancy, diabetes mellitus,
hepatic failure, kidney failure, hypertension), mental retardation, severe
psychotic disorder, organic mental disorder, previous psychiatric illnesses such
as depression, anxiety and treatments such as anxiolytics and antidepressants or
alcohol and substance abuse were the exclusion criteria.
Written informed consent was obtained from each following a detailed explanation
of the objectives and protocol of the study which was conducted in accordance
with the ethical principles stated in the “Declaration of
Helsinki” and approved by the institutional ethics committee.
Study parameters
Data on patient demographics (age, gender), body mass index (BMI,
kg/m2), complications of hypothyroidism, psychometric
instruments including Beck Depression Inventory (BDI), Hospital
Anxiety-Depression Scale (HADS) and SF-36 health related quality of life (SF-36
HRQoL) scores, tumor diameter and serum levels for triiodothyronine (T3),
thyroxine (T4), thyroid stimulating hormone (TSH), thyroglobulin (TG) and
anti-thyroglobulin (anti-TG) were recorded in each patient. Patients were
evaluated twice during euthyroid state under regular use of thyroxine therapy
and during hypothyroid state achieved (with or without LT3 treatment) at the
time of RAI ablation planning. Accordingly, patient demographics and hypothyroid
complications were evaluated with respect to thyroxine withdrawal method applied
for induction of hypothyroid state (non-treated vs. LT3-treated), while
psychometrics were evaluated with respect to thyroid status (euthyroid vs.
hypothyroid state) and thyroxine withdrawal method applied for induction of
hypothyroid state (non-treated vs. LT3-treated). In addition, serum levels for
thyroid hormones measured in the euthyroid and hypothyroid state and the tumor
diameter were also evaluated with respect to presence vs. absence of depression
and/or anxiety based on BDI and HADS categories.
Beck depression inventory (BDI)
BDI is a 21-item self-reporting questionnaire for evaluating the level and change
in severity of depression for the past two weeks based on physical, emotional,
cognitive and motivational symptoms [11].
Each item is scored on a 4-point scale from 0 (no symptom) to 3 (severe
symptoms), while the total score achieved by adding the highest ratings for all
21 items ranges from 0 to 63 with higher scores indicating greater symptom
severity [11]. Based on the total score
individuals are categorized to have severe depression (scores 30–63),
moderate depression (scores 19–29), mild depression (scores
10–18) and minimal level of depression (scores 0–9) [11]. The reliability and validity analysis
of Turkish version of BDI was performed by Hisli in 1989 [12].
Hospital anxiety-depression scale (HADS)
The HADS, developed by Zigmond and Snaith [13] is a fourteen item [seven relate to anxiety (HADS-A) and seven
relate to depression (HADS-D)] scale used to screen anxiety and depression in
medical outpatient settings [13]. Each
item on the questionnaire is scored from 0–3 leading overall score to
range between 0 and 21 for either anxiety or depression as categorized into
normal (scores 0–7), borderline abnormal (scores 8–10) and
abnormal (scores 11–21) status [13]. HADS was adapted to Turkish by Aydemir [14].
SF-36 HRQoL
The 36-item Short-form Health Survey (SF-36) is a self-administered questionnaire
that measures Health-Related Quality of Life across eight domains including
physical functioning, physical and emotional role limitations, bodily pain,
general health perception, vitality, social functioning and mental health [15]. Total scores range from 0 to 100 with
higher transformed scores indicating better health status [15].
Statistical analysis
Statistical analysis was made using IBM SPSS Statistics for Windows, version 17.0
(IBM Corp., Armonk, NY, USA). Chi-square (χ2) test was used
for the comparison of categorical data, while numerical data were analyzed using
independent sample t-test. Change over time was evaluated by the Wilcoxon
test. Correlation analysis was performed via Spearman and Pearson tests. Data
were expressed as mean±standard deviation (SD), median (minimum-maximum)
and percent (%) where appropriate. p-Value<0.05 was considered
statistically significant.
Results
Patient demographics and complications related to
hypothyroidism-induction
Non-treated (mean±SD age: 49.3±11.7 years, 81.7% were
females) and LT3-treated (mean±SD age: 48.7±9.9 years,
78.3% were females) groups were homogenous in terms of patient’s
demographics. Apart from the hearing loss and slowed movements, all hypothyroid
complications were significantly more common in non-treated vs. LT3-treated
groups during the hypothyroid state (p ranged 0.032 to<0.001) ([Table 1]).
Table 1 Patient demographics and complications related to
hypothyroidism-induction.
|
Short-term hypothyroidism induction
|
|
|
Non-treated (n=62)
|
LT3-treated (n=58)
|
p-Value
|
|
Patient characteristics
|
|
Age (year), mean±SD
|
49.3±11.7
|
48.7±9.9
|
0.7691
|
|
Gender, n (%)
|
|
|
|
|
Female
|
49 (81.7)
|
47 (78.3)
|
0.8202
|
|
Male
|
11 (18.3)
|
13 (21.7)
|
|
|
BMI (kg/m2), mean±SD
|
28.0±4.5
|
28.9±4.4
|
0.2271
|
|
Hypothyroid complications, n (%)
|
|
Hypohydrosis
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
8 (13.3)
|
1 (1.7)
|
0.032
|
|
Hoarse voice
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
31 (51.7)
|
12 (20.0)
|
0.001
|
|
Numbness
|
Euthyroid state
|
1 (0.8)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
35 (58.3)
|
4 (6.7)
|
<0.001
|
|
Dry skin
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
54 (90.0)
|
19 (31.7)
|
<0.001
|
|
Constipation
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
50 (83.3)
|
19 (32.2)
|
<0.001
|
|
Weight gain
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
41 (68.3)
|
11 (18.3)
|
<0.001
|
|
Hearing loss
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
6 (10)
|
1 (1.7)
|
0.114
|
|
Slowed movements
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
51 (85.0)
|
41 (68.3)
|
0.051
|
|
Edema
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
50 (83.3)
|
14 (23.3)
|
<0.001
|
|
Skin thickening
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
24 (40.0)
|
0 (0.0)
|
<0.001
|
|
Cold skin
|
Euthyroid state
|
0 (0.0)
|
0 (0.0)
|
–
|
|
Hypothyroid state
|
21 (35.0)
|
1 (1.7)
|
<0.001
|
BMI: Body mass index; LT3: Triiodothyronine.; 1 Independent
samples t test, 2 Chi-square test.
Serum levels for thyroid hormones in euthyroid and hypothyroid state in study
groups
In the euthyroid state, non-treated versus LT3-treated patients had significantly
lower serum levels for T4 [1.4 (0.1–2.8) vs. 1.5 (0–2.4),
p=0.026] and higher levels of anti-TG [1.7 (0.6–74.6) vs. 1.0
(0–108.9), p=0.001] ([Table
2]).
Table 2 Serum levels for thyroid hormones in euthyroid and
hypothyroid state in study groups.
|
Non-treated (n=62)
|
LT-3 treated (n=58)
|
p-Value
|
|
Thyroid hormone levels
|
Median (min-max)
|
Median (min-max)
|
|
|
T3
|
euthyroid
|
3.1 (1.8–4.1)
|
3.1 (2–4.5)
|
0.609
|
|
hypothyroid
|
1 (1–11)
|
1 (1–2.5)
|
0.290
|
|
T4
|
euthyroid
|
1.4 (0.1–2.8)
|
1.5 (0–2.4)
|
0.026
|
|
hypothyroid
|
0.4 (0.4–1.0)
|
0.4 (0.4–0.5)
|
0.021
|
|
TSH
|
euthyroid
|
0 (0–2.9)
|
0 (0–1.3)
|
0.074
|
|
hypothyroid
|
79 (34.4–100)
|
56.8 (30.8–100)
|
0.012
|
|
Anti-TG
|
euthyroid
|
1.7 (0.6–74.6)
|
1 (0–108.9)
|
0.001
|
|
hypothyroid
|
1.4 (0.3–51.1)
|
0.8 (0.3–97.1)
|
0.005
|
|
TG
|
euthyroid
|
0.2 (0–0.7)
|
0.2 (0.2–1.4)
|
0.599
|
|
hypothyroid
|
0.2 (0.2–2.4)
|
0.2 (0.2–0.7)
|
0.089
|
T3: Triiodothyronine; T4: Thyroxine; TSH: Thyroid stimulating hormone;
TG: Thyroglobulin; anti-TG: Anti-thyroglobulin.
In the hypothyroid state, non-treated versus LT3-treated patients had
significantly higher serum levels for T4 [0.4 (0.4–1) vs. 0.4
(0.4–0.5), p=0.021], TSH [79 (34.4–100) vs. 56.8
(30.8–100), p=0.012] and anti-TG [1.4 (0.3–51.1) vs. 0.8
(0.3–97.1), p=0.005]. No significant difference was noted
between non-treated and LT-3 treated patients in terms of serum T3 levels in the
euthyroid and hypothyroid state ([Table
2]).
Psychometrics with respect to thyroid status and thyroxine withdrawal
method
During the euthyroid state, no significant difference was noted between
non-treated and LT3-treated groups in terms of BDI (likelihood of
moderate-to-severe depression in 10% and 5.0% of patients,
respectively), HADS-D (presence of depression in 18.3% and
15.0%, respectively) and HADS-A (presence of anxiety in 6.7% and
13.3%, respectively) ([Table
3]).
Table 3 Psychometrics with respect to thyroid status and
thyroxine withdrawal method applied for induction of hypothyroid
state.
|
Non-treated (n=62) (A)
|
LT3-treated (n=58) (B)
|
p-Value (A vs. B)
|
|
Euthyroid state
|
Hypothyroid state
|
p-Value1
|
Euthyroid state
|
Hypothyroid state
|
p-Value1
|
Euthyroid
|
Hypothyroid
|
|
BDI category, n(%)
|
|
Minimal level of depression (scores 0–9)
|
44 (73.3)
|
30 (50.0)
|
<0.001
|
46 (76.7)
|
45 (75.0)
|
0.428
|
0.5252
|
0.034
2
|
|
Mild depression (scores 10–18)
|
10 (16.7)
|
16 (26.7)
|
11 (18.3)
|
10 (16.7)
|
|
Moderate depression (scores 19–29)
|
4 (6.7)
|
11 (18.3)
|
3 (5.0)
|
4 (6.7)
|
|
Severe depression (scores 30–63)
|
2 (3.3)
|
3 (5.0)
|
0 (0.0)
|
1 (1.7)
|
|
HADS-D, n (%)
|
|
Depression absent (<8)
|
49 (81.7)
|
33 (55.0)
|
<0.001
|
51 (85.0)
|
45 (75.0)
|
0.056
|
0.3332
|
0.035
2
|
|
Depression present (>8)
|
11 (18.3)
|
27 (45.0)
|
9 (15.0)
|
15 (25.0)
|
|
HADS-A, n (%)
|
|
Anxiety absent (<11)
|
56 (93.3)
|
40 (66.7)
|
<0.001
|
52 (96.7)
|
48 (80.0)
|
0.096
|
0.2772
|
0.1402
|
|
Anxiety present (>11)
|
4 (6.7)
|
20 (33.3)
|
8 (13.3)
|
12 (20.0)
|
|
SF-36 HRQoL Scores, mean±SD
|
|
Physical functioning score
|
86.6±16.1
|
68.4±23.9
|
<0.001
|
80.9±18.8
|
77.4±20.8
|
0.156
|
0.0763
|
0.0303
|
|
Role-physical score
|
90.2±19.3
|
66.2±31.2
|
<0.001
|
73.2±35.8
|
69.4±39.3
|
0.457
|
0.002
3
|
0.6233
|
|
Bodily pain score
|
83.7±18.6
|
68.0±26.0
|
<0.001
|
74.1±21.5
|
68.5±23.7
|
0.067
|
0.010
3
|
0.9153
|
|
General health score
|
69.1±17.0
|
54.9±18.1
|
<0.001
|
62.9±15.8
|
59.5±18.1
|
0.093
|
0.0413
|
0.173
|
|
Vitality score
|
67.5±17.4
|
54.9±20.5
|
<0.001
|
60.8±15.7
|
59.7±19.0
|
0.499
|
0.028
3
|
0.1883
|
|
Social functioning score
|
87.5±18.3
|
72.9±23.7
|
<0.001
|
80.2±19.9
|
74.9±21.2
|
0.109
|
0.040
3
|
0.6423
|
|
Role-emotional score
|
79.7±28.1
|
63.0±32.3
|
<0.001
|
65.0±31.9
|
58.1±38.9
|
0.178
|
0.0093
|
0.4533
|
|
Mental health score
|
71.5±16.5
|
58.1±17.0
|
<0.001
|
62.9±15.3
|
61.6±17.4
|
0.429
|
0.004
3
|
0.2553
|
BDI: Beck Depression Inventory; HADS: Hospital Anxiety-Depression Scale;
A: anxiety; D: depression; HRQoL: Health related quality of life; LT3:
Triiodothyronine.; 1 Wilcoxon text; 2 Chi-square
test; 3 Independent samples t-test.
During the hypothyroid state, non-treated vs. LT3-treated group of patients had
significantly higher likelihood of moderate-to-severe depression based on BDI
(23.3 vs. 8.4%, p=0.034) and depression based on HADS-D (45.0
vs. 25.0%, p=0.035) ([Table
3]).
SF-36 HRQoL revealed significantly higher role-physical score (p=0.002),
bodily pain score (p=0.010), vitality score (p=0.028), social
functioning score (p=0.040) and mental health score (p=0.044) in
the non-treated vs. LT3-treated groups during the euthyroid state, whereas in
the hypothyroid state the two groups had similar SF-36 HRQoL scores for each
domain ([Table 2]).
In the non-treated group, transition from euthyroid to hypothyroid state was
associated with significant increase in the likelihood of moderate-to-severe
depression on BDI (from 10.0% to 23.3%, p<0.001),
presence of depression on HADS-D (from 18.3% to 45.0%,
p<0.001) and presence of anxiety on HADS-A (from 6.7% to
33.3%, p<0.001) as well as significant decrease in all SF-36
HRQoL domain scores (p<0.001 for each) ([Table 3]).
In the LT3-treated group, no significant change occurred during transition from
euthyroid to hypothyroid state in the likelihood of moderate-to-severe
depression on BDI (from 5.0% to 8.4%, p=0.428), presence
of depression on HADS-D (from 15.0 to 25.0%, p=0.056) and
presence of anxiety on HADS-A (from 13.3% to 20.0%,
p=0.096) as well as in SF-36 HRQoL domain scores (p>0.05 for
each) ([Table 3]).
Serum thyroid hormone levels and the tumor diameter with respect to BDI and
HADS scores
In the non-treated group, T3 [3.7 (3–4.1) vs. 3.0 (1.8–4),
p<0.001] and T4 [1.6 (1.3–2.8) vs. 1.4 (1.1–2.4),
p=0.007] levels were significantly higher in those with versus without
HADS based depression during euthyroid state, while no significant difference
was noted in serum thyroid hormone levels with respect to BDI and HADS-A
findings. In the hypothyroid state, serum thyroid hormone levels did not differ
significantly with respect to BDI, HADS-D and HADS-A findings ([Table 4]).
Table 4 Serum levels for thyroid hormones and the tumor
diameter with respect to BDI and HADS scores in euthyroid and
hypothyroid state.
|
BDI (depression)
|
HADS-D (depression)
|
HAD-A (anxiety)
|
|
Median (min–max)
|
Minimal (n=90)
|
Mild (n=21)
|
Moderate (n=9)
|
p
|
Absent (n=100)
|
Present (n=20)
|
p
|
Absent (n=108)
|
Present (n=12)
|
p
|
|
Non-treated (n=62)
|
|
T3
|
euthyroid
|
3.1 (1.8–4.1)
|
3.1 (2.5–4.1)
|
3.3 (2.9–4.0)
|
0.580
|
3.0 (1.8–4)
|
3.7 (3–4.1)
|
<0.001
|
3.1 (1.8–4.1)
|
3.3 (2.5–4.1)
|
0.129
|
|
hypothyroid
|
1 (1–1.7)
|
1 (1–11)
|
1.1 (1–4)
|
0.297
|
1 (1–1.6)
|
1 (1–11)
|
0.320
|
1 (1–11)
|
1 (1–4)
|
0.781
|
|
T4
|
euthyroid
|
1.4 (1.1–2.8)
|
1.4 (0.1–2.1)
|
1.4 (1.2–2)
|
0.669
|
1.4 (1.1–2.4)
|
1.6 (1.3–2.8)
|
0.007
|
1.4 (1.1–2.8)
|
1.6 (1.3–2.1)
|
0.124
|
|
hypothyroid
|
0.4 (0.4–0.5)
|
0.4 (0.4–1)
|
0.4 (0.4–0.44)
|
0.795
|
0.4 (0.4–0.5)
|
0.4 (0.4–1)
|
0.667
|
0.4 (0.4–1)
|
0.4 (0.4–0.44)
|
0.851
|
|
TSH
|
euthyroid
|
0 (0–2.9)
|
0 (0–0.3)
|
0 (0–1)
|
0.835
|
0 (0–2.9)
|
0 (0–0.3)
|
0.078
|
0 (0–2.9)
|
0 (0–0.1)
|
0.882
|
|
hypothyroid
|
78.4 (37.7–100)
|
84.3 (34.9–100)
|
76.7 (34.4–100)
|
0.815
|
79.1 (37.7–100)
|
79 (34.4–100)
|
0.932
|
75.2 (34.9–100)
|
85.6 (34.4–100)
|
0.612
|
|
Anti-TG
|
euthyroid
|
1.8 (0.6–74.6)
|
1 (0.7–5.7)
|
2.3 (1–35.3)
|
0.129
|
1.8 (0.6–74.6)
|
1.5 (0.6–35.3)
|
0.226
|
1.7 (0.6–74.6)
|
1 (0.8–35.3)
|
0.590
|
|
hypothyroid
|
1.2 (0.3–51.1)
|
1.7 (0.3–11.2)
|
1.9 (0.4–36.5)
|
0.374
|
1.3 (0.3–51.1)
|
1.7 (0.3–36.5)
|
0.865
|
1.2 (0.3–51.1)
|
1.9 (0.4–36.5)
|
0.202
|
|
TG
|
euthyroid
|
0.2 (0–0.7)
|
0.2 (0–0.3)
|
0.2 (0.2–0.3)
|
0.390
|
0.2 (0–0.7)
|
0.2 (0–0.6)
|
0.075
|
0.2 (0–0.7)
|
0.2 (0–0.3)
|
0.294
|
|
hypothyroid
|
0.2 (0.2–1.7)
|
0.2 (0.2–0.3)
|
0.2 (0.2–2.4)
|
0.812
|
0.2 (0.2–1.7)
|
0.2 (0.2–2.4)
|
0.936
|
0.2 (0.2–1.7)
|
0.2 (0.2–2.4)
|
0.475
|
|
Tumor diameter
|
euthyroid
|
1.7 (0.5–7)
|
1.7 (1.1–4.8)
|
2.3 (1–4.3)
|
0.943
|
1.7 (0.5–7)
|
2.3 (0.8–4.8)
|
0.592
|
1.7 (0.7–7)
|
2 (0.5–4.8)
|
0.927
|
|
hypothyroid
|
1.6 (0.7–7)
|
1.7 (0.5–4.5)
|
2 (1–4.8)
|
0.973
|
1.7 (0.7–7)
|
1.8 (0.5–4.8)
|
0.821
|
1.7 (0.7–7)
|
1.4 (0.5–4.8)
|
0.323
|
|
LT3-treated (n=58)
|
|
|
|
|
|
|
|
|
|
|
|
|
T3
|
euthyroid
|
3.1 (2–4.5)
|
3 (2.2–4.4)
|
3.4 (2.9–3.8)
|
0.814
|
3 (2–4.2)
|
3.7 (2.3–4.4)
|
0.210
|
3 (2–4.2)
|
3.6 (2.2–4.5)
|
0.297
|
|
hypothyroid
|
1 (1–2.5)
|
1 (1–1.1)
|
1 (1–1.3)
|
0.729
|
1 (1–2.5)
|
1 (1–1.3)
|
0.868
|
1 (1–2.5)
|
1 (1–1.5)
|
0.245
|
|
T4
|
euthyroid
|
1.5 (1–2.4)
|
1.6 (0–2.4)
|
1.5 (1.3–1.6)
|
0.667
|
1.5 (0–2.4)
|
1.6 (1.5–2.1)
|
0.178
|
1.5 (1–2.4)
|
1.8 (0–2.1)
|
0.166
|
|
hypothyroid
|
0.4 (0.4–0.4)
|
0.4 (0.4–0.5)
|
0.4 (0.4–0.4)
|
0.299
|
0.4 (0.4–0.5)
|
0.4 (0.4–0.4)
|
0.421
|
0.4 (0.4–0.5)
|
0.4 (0.4–0.4)
|
0.490
|
|
TSH
|
euthyroid
|
0 (0–1.3)
|
0 (0–0.7)
|
0 (0–0.1)
|
0.125
|
0 (0–1.3)
|
0 (0–0.4)
|
0.926
|
0 (0–1.3)
|
0 (0–0.7)
|
0.426
|
|
hypothyroid
|
55.9 (30.8–100)
|
84.9 (38.2–100)
|
44.5 (37.8–84.8)
|
0.357
|
58.6 (30.8–100)
|
52.7 (37.8–100)
|
0.813
|
55.3 (30.8–100)
|
84.8 (37.8–100)
|
0.252
|
|
Anti-TG
|
euthyroid
|
0.9 (0.3–23.1)
|
1.1 (0–108.9)
|
0.7 (0.4–1)
|
0.434
|
1.2(0–108.9)
|
0.7 (0.3–1.4)
|
0.034
|
1 (0–108.9)
|
0.8 (0.3–2.9)
|
0.591
|
|
hypothyroid
|
0.8 (0.3–97.1)
|
0.8 (0.4–1.8)
|
0.8 (0.3–4.7)
|
0.945
|
0.8(0.3–97.1)
|
0.7 (0.3–4.7)
|
0.501
|
0.8 (0.3–97.1)
|
0.8 (0.3–4.7)
|
0.463
|
|
TG
|
euthyroid
|
0.2 (0.2–0.9)
|
0.2 (0.2–1.4)
|
0.2 (0.2–0.2)
|
0.181
|
0.2(0.2–1.4)
|
0.2 (0.2–0.2)
|
0.374
|
0.2 (0.2–1.4)
|
0.2 (0.2–0.7)
|
0.431
|
|
hypothyroid
|
0.2 (0.2–0.7)
|
0.2 (0.2–0.2)
|
0.2 (0.2–0.2)
|
0.638
|
0.2(0.2–0.7)
|
0.2 (0.2–0.2)
|
0.320
|
0.2 (0.2–0.7)
|
0.2 (0.2–0.2)
|
0.394
|
|
Tumor diameter
|
euthyroid
|
1.6 (0.8–8)
|
2 (0.3–3)
|
1.3 (1.2–1.8)
|
0.522
|
1.7(0.3–8)
|
1.8 (1–3)
|
0.539
|
1.7 (0.8–8)
|
1.3 (0.3–2.8)
|
0.287
|
|
hypothyroid
|
1.7 (0.3–8)
|
1.8 (1–3.5)
|
1.8 (1.3–3.6)
|
0.745
|
1.7(0.3–8)
|
1.4 (1–3.6)
|
0.367
|
1.7 (0.8–8)
|
1.4 (0.3–3.6)
|
0.605
|
BDI: Beck Depression Inventory; HADS: Hospital Anxiety-Depression Scale;
A: anxiety; D: depression; HRQoL: Health related quality of life; T3:
Triiodothyronine, T4: Thyroxine; TSH: Thyroid stimulating hormone; TG:
Thyroglobulin; anti-TG: Anti-thyroglobulin.
In the L3-treated group, other than significantly higher serum Anti TG levels in
patients with vs. without HADS based depression in the euthyroid state, no
significant difference was noted in serum thyroid hormone levels with respect to
BDI, HADS-D and HADS-A findings in either euthyroid or hypothyroid state ([Table 4]).
SF-36 HRQoL scores with respect to gender, age, tumor diameter in euthyroid
and hypothyroid states
Physical functioning, general health and vitality scores were significantly
higher in males than in females both in the euthyroid state (p=0.034,
p=0.003, and p=0.002, respectively) and hypothyroid state
(p<0.001, p=0.005, and p=0.009, respectively). Social
functioning (p=0.008), role-emotional (p<0.001), and mental
health (p=0.019) scores were also higher in males versus females in the
hypothyroid state ([Table 5]).
Table 5 SF-36 HRQoL scores with respect to gender and in
euthyroid and hypothyroid states.
|
Euthyroid
|
Hypothyroid
|
|
Female
|
Male
|
p-Value
|
Female
|
Male
|
p-Value
|
|
SF–36 HRQoL scores
|
|
Physical functioning
|
85 (15–100)
|
95 (50–100)
|
0.034
|
70 (5–100)
|
92.5 (25–100)
|
<0.001
|
|
Role-physical
|
100 (0–100)
|
100 (25–100)
|
0.210
|
75 (0–100)
|
100 (50–100)
|
<0.001
|
|
Bodily pain
|
74 (22–100)
|
100 (52–100)
|
0.003
|
62 (10–100)
|
92 (0–100)
|
<0.001
|
|
General health
|
66 (15–100)
|
72 (45–97)
|
0.031
|
52 (0–100)
|
72 (30–92)
|
0.005
|
|
Vitality
|
60 (20–100)
|
75 (55–100)
|
0.002
|
55 (0–100)
|
65 (20–100)
|
0.009
|
|
Social functioning
|
100 (37.5–100)
|
87.5 (37.5–100)
|
0.899
|
75 (10–100)
|
87.5 (38–100)
|
0.008
|
|
Role-emotional
|
66.7 (0–100)
|
83.4 (1–100))
|
0.450
|
66.7 (0–100)
|
100 (6.7–100)
|
<0.001
|
|
Mental health
|
64 (28–100)
|
69 (44–92)
|
0.411
|
58 (10–100)
|
66 (52–90)
|
0.019
|
Data are expressed as median(min–max); HRQoL: Health related
quality of life.; Mann–Whitney U-test.
SF-36 HRQoL scores were not correlated with tumor diameter in euthyroid state,
while there was a slightly positive correlation between vitality and tumor
diameter (r=0.184, p=0.045) in the hypothyroid state ([Table 6]). SF-36 HRQoL scores were not
correlated with age in the hypothyroid state, while bodily pain was negatively
correlated with age (r=–0.217, p=0.017) in the euthyroid
state ([Table 6]).
Table 6 Correlation of SF-36 HRQoL scores with age and
tumor diameter in euthyroid and hypothyroid states.
|
Euthyroid state
|
Hypothyroid state
|
|
Age
|
Tumor diameter
|
Age
|
Tumor diameter
|
|
SF-36 HRQoL scores
|
r, p
|
r, p
|
r, p
|
r, p
|
|
Physical functioning
|
–0.117, 0.120
|
0.159, 0.084
|
–0.128, 0.165
|
0.063, 0.491
|
|
Role-physical
|
–0.075, 0.414
|
0.002, 0.982
|
–0.135, 0.141
|
–0.022, 0.812
|
|
Bodily pain
|
–0.217, 0.017
|
0.085, 0.353
|
–0.130, 0.157
|
0.099, 0.282
|
|
General health
|
–0.054, 0.555
|
0.138, 0.132
|
–0.103, 0.262
|
0.167, 0.069
|
|
Vitality
|
–0.156, 0.089
|
–0.020, 0.831
|
–0.088, 0.338
|
0.184, 0.045
|
|
Social functioning
|
–0.088, 0.338
|
–0.009, 0.918
|
–0.008, 0.933
|
0.024, 0.792
|
|
Role-emotional
|
–0.058, 0.528
|
0.044, 0.630
|
0.036, 0.695
|
–0.123, 0.180
|
|
Mental health
|
0.059, 0.523
|
0.007,0.940
|
–0.038, 0.681
|
–0.038, 0.681
|
HRQoL: Health related quality of life; r: Correlation coefficient.
Discussion
Our findings revealed considerable disadvantages of using “no treatment
strategy” compared to “LT3 treatment strategy” during
short-term hypothyroidism induction prior to RAI ablation therapy in patients with
DTC. Non-treated patients had higher likelihood of experiencing hypothyroid
complications and depression than LT3-treated patients, as well as the marked
deterioration in HRQoL and increased risk of experiencing depression, anxiety and
major syndrome during transition from euthyroid to hypothyroid state. Also, the
interactions between thyroid hormones and depression/anxiety seem to be
stronger during the euthyroid rather than hypothyroid state along with stronger
adverse impact of hypothyroid state on HRQoL among females.
Similarly, previous studies indicated the association of traditional thyroid hormone
withdrawal with hypothyroid symptoms such as fatigue, lethargy, cold intolerance,
weight gain and non-pitting edema, as well as with the concomitant psychological
morbidity (i. e., depression) which in turn frequently impair the patient
QoL [4]
[16]
[17].
In the current study, all domains of SF-36 HRQoL deteriorated during hypothyroid
state in the non-treated group, while no change in SF-36 HRQoL scores from euthyroid
to hypothyroid state was apparent in the LT3-treated group. Moreover, non-treated
patients were initially had higher SF-36 HRQoL scores (role-physical, bodily pain,
vitality, social functioning and mental health) than LT3-treated group during the
euthyroid state. Likewise, in a study with 29 DTC patients, QoL was reported to
deteriorate after short-term hypothyroidism, especially in physical health and
psychological dimensions, along with increase in patient’s being feeling
depressed and anxious after thyroxine withdrawal [18]. In a cross-sectional study evaluating the SF-36, HADS, BDI and
Profile of Mood States (POMS) in 136 DTC patients on thyroid hormone withdrawal for
RAI compared to the general population, hypothyroid patients were reported to have
significantly impaired HRQoL, higher prevalence of anxiety (62.5%) but not
depression (17.9%) [19]. The authors
concluded that HRQoL is severely impaired in DTC patients under short-term
hypothyroidism, with depression and anxiety as the potential predictors of HRQoL
impairment [19]. In our study, hypothyroid
versus euthyroid state was associated with significant increase in the likelihood of
depression and anxiety and deterioration in HRQoL, while deterioration in social
functioning, role-emotional and mental health specific to hypothyroid state was
evident particularly among female patients.
In a study with 18 DTC patients, impaired mental health, general health and social
function domains of SF-36 and worsening of affective and physical symptoms were
reported during chronic suppressive levothyroxine therapy [20]. The authors concluded that the QoL and
psychometric functionality in patients with DTC is not only affected by thyroxine
withdrawal but also by long-term treatment with chronic suppressive doses of
levothyroxine [20]. Indeed, our findings
revealed the association of higher thyroid hormone levels with increased likelihood
of depression and anxiety during euthyroid state in the non-treated group.
In the current study, non-treated and LT-3-treated DTC patients had similar rates of
possible depression (26.7% and 23.3%; moderate-to-severe in
10.0% and 5.0%, respectively) and anxiety (6.7% and
13.3%, respectively) in the euthyroid period, whereas non-treated DTC
patients showed significantly higher rates of possible depression (50.0% and
25.0%; moderate-to-severe in 23.3% and 8.4%, respectively)
and a non-significant trend for increased anxiety (33.3% and 20.0%,
respectively) in the hypothyroid period. Previous studies revealed that patients
with thyroid cancer have different degrees of depression (range 17.9% to
43.3%) and anxiety (range, 45.1% to 62.5%) [19]
[21]
[22], while in patients
undergoing thyroxine withdrawal, the overall anxiety and depression prevalence was
reported to be 63% and 17%, respectively [19]
[21].
While hypothyroidism is considered to represent an unrecognized risk factor with a
marked potential to severely affect mental health, by increasing the age- and
gender-adjusted risk for critical mood deterioration by seven-fold [23], patients’ psychological
flexibility is also an important factor that negatively correlates with depression
and anxiety and dramatically affects patients’ QoL [21]
[24].
Exact mechanisms underlying the interaction between thyroid function and depression
remain unknown [25]. Although patients with
thyroid disorders are considered to be more prone to develop depressive symptoms,
depression is also suggested to be accompanied by various subtle thyroid
abnormalities, including elevated T4 levels, low T3, elevated rT3, a blunted TSH
response to TRH or positive anti-thyroid antibodies [25]. Notably, T3 and or T4 levels were significantly higher in our
non-treated patients with depression or anxiety in the euthyroid state, whereas
during the hypothyroid state, thyroid hormone levels did not differ significantly
with respect to BDI, HADS-D and HADS-A in both non-treated and L3-treated
groups.
Our findings indicate association of thyroxine withdrawal period with an increased
frequency of depression and anxiety along with a significantly reduced HRQoL. In
this regard, using LT3 treatment strategy during hypothyroidism induction prior to
RAI ablation therapy seems to be a favorable alternative in DTC patients in terms of
avoiding the adverse consequences of no treatment strategy (i. e., emergence
of hypothyroid complications, depression and anxiety, and deterioration in QoL).
However, some studies also indicated no further impact of LT3 treatment strategy over
thyroxine withdrawal in terms of QoL measures [8]
[26]. In a study with 291
patients after total thyroidectomy, ablation preparation using withdrawal of LT3 for
2 weeks was reported to be similar to 4 weeks LT4 withdrawal alone, and not to
prevent development of profound hypothyroidism [26]. In a prospective study with patients having withdrawal of thyroxine
(n=37) or T3 supplementation (n=33) the assessment of HRQoL revealed
the equivocal benefit of two approaches with no significant benefit of LT3
supplementation over thyroxine withdrawal in terms of HRQoL, except for the
emotional domain (QLQ-C30) [8]. Therefore, the
authors have suggested developing other alternate strategies to minimize the impact
on HRQoL of reduction in the duration of hypothyroidism in thyroxine withdrawal
[8].
In addition, on the basis of association of later periods of thyroxine withdrawal
with more severe decline in the HR-QoL, and achievement of required TSH levels
(≥30 mU/l) in majority of DTC patients by the third week,
implementation of a shorter (2 or 3 weeks) thyroxine withdrawal is suggested to
minimize the impact on HRQoL [27]
[28]. Use of rhTSH as opposed to thyroxine
withdrawal has also been suggested to an alternate strategy to prevent overt
hypothyroidism and to diminish the adverse effects of thyroxine withdrawal in DTC
patients, particularly in terms of relatively improved HRQoL [4]
[5]
[17].
Certain limitations to this study should be considered. First, due to single center
design of the present study, generalizing our findings to overall DTC population
seems difficult. Second, lack of data on hemodynamic and cardio-metabolic parameters
is another limitation, which otherwise would extend the knowledge achieved in the
current study.
Conclusion
In conclusion, our findings indicate the association of hypothyroid state induced by
thyroxine withdrawal with an increased frequency of hypothyroid complications and
increased likelihood of depression and anxiety along with a significantly reduced
HRQoL. L3-treatment seems to enable a more favorable transition period from
euthyroid to hypothyroid state without experiencing a deterioration in depression
anxiety or HRQoL. In addition, the interactions between thyroid hormones and
depression/anxiety seem to be stronger in euthyroid state, along with
stronger adverse impact of hypothyroid state on HRQoL among females. In this regard,
LT3 treatment strategy seems to be a favorable alternate to no-treatment strategy in
operated DTC patients (females in particular) prior to RAI ablation therapy in
achieving ablation without the detrimental symptoms of overt short-term
hypothyroidism induced by thyroxine withdrawal, avoiding the associated risk of mood
disorders such as depression and anxiety and the deterioration in HRQoL. Further
large scale longitudinal studies are needed to identify the long-term effects of
different hypothyroidism induction strategies used before RAI ablation therapy in
DTC patients.
