Keywords thyroidectomy - hypothyroidism - thyroid hormones
Introduction
Hemithyroidectomy, or thyroid lobectomy, is indicated for benign and malignant thyroid
disease, including cytologically indeterminate nodule, atypia of undetermined significance/follicular
lesion of undetermined significance (AUS/FLUS), follicular/Hürthle cell neoplasm (FN/HCN),
and cases in which there is a suspicious of malignancy.[1 ]
[2 ] In contrast to total thyroidectomy, this procedure avoids the occurrence of hypoparathyroidism
and bilateral recurrent laryngeal nerve injury. It also correlates with a lower risk
of postoperative neck hematoma.[2 ]
[3 ] Likewise, thyroid lobectomy provides the possibility of patients not requiring lifelong
hormone replacement therapy.[1 ]
[2 ] Thus, the occurrence of hypothyroidism after lobectomy is an important factor in
decision-making for the individual patient when deciding which surgical procedure
will be performed.[2 ]
The risk of hypothyroidism after hemithyroidectomy varies greatly between studies,
ranging from 22% to 55.8%.[4 ]
[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ] This discrepancy may be caused by differences in the studied populations, criteria
for initiation of L-thyroxine (T4) therapy, and surgical techniques.[6 ]
Consistently reported data demonstrated that the anatomopathological presence of chronic
lymphocytic thyroiditis, higher than normal range of preoperative thyroid-stimulating
hormone (TSH) levels, and positive anti-thyroid peroxidase antibodies (TPOAb) in the
blood are risk factors for the development of postoperative hypothyroidism.[6 ] Nevertheless, the predictive role of other clinical or pathological factors remains
unclear.[6 ]
In fact, preoperative TSH levels are one of the most frequently reported risk factors
among several studies.[4 ]
[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ]
[11 ]
[12 ] A higher than normal range usually indicates deficiency of reserve thyroid function.[10 ]
[11 ] However, the TSH levels that predict postsurgical hypothyroidism are not well established,
given that different cutoff points were used in the studies.
The present study aims to determine the predictive clinical-pathological factors for
thyroid hormone replacement (THR) in patients undergoing hemithyroidectomy. Additionally,
we also aim to assess the role of single serum TSH measurement before hemithyroidectomy
on subsequent postoperative thyroid status.
Methods
Study Population and Design
We performed a retrospective study of patients undergoing hemithyroidectomy from January
2014 to March 2021 at our institution, a tertiary healthcare center, a teaching hospital
in Southern Brazil. Thyroid lobectomy, or hemithyroidectomy, was defined as total
removal of the unilateral thyroid lobe with or without isthmusectomy. The study received
approval of the local ethics committee (CAAE 46964021.2.0000.5335). Patients with
missing histopathological data, incomplete clinical history data, and pregnant women
were excluded from the analyses.
Characterization of Thyroid Function Status in Follow-up Assessments after Hemithyroidectomy
Euthyroidism was characterized as normal levels of serum TSH and free L-Thyroxine
(FT4). Subclinical hypothyroidism was defined as a mild elevation of TSH levels beyond
the upper limit of the reference range, and FT4 as levels within the normal reference
range. Overt hypothyroidism was characterized as an increase in TSH levels above the
reference range and a decrease in FT4 below the reference range.
At our institution, the reference range of TSH is 0.55 to 4.78 μUI/mL. The FT4 values
changed over time, considered normal from 0.7 to 2.0 ng/mL between 2014 and 2016,
and 0.89 to 1.76 ng/mL, since 2017. Patients were defined to be on THR if any dose
of synthetic L-Thyroxine (T4) therapy was prescribed during follow-up.
Assessment Parameters
We analyze the presurgical patient characteristics, including age, surgery duration,
hospitalization time, sex, body mass index (BMI), TSH, free and total T4 levels, presence
of TPOAb, preoperative thyroid ultrasound, final histological results after surgery,
and coexistence of chronic lymphocytic thyroiditis (Hashimoto's thyroiditis).
The data of each TPOAb assay were recorded as “positive” or “negative” based on a
titer above or below the cutoff point. A diagnosis of Hashimoto's thyroiditis was
determined only on the final histological results.
Statistical Analysis
Clinical and laboratory data are demonstrated as the mean ± standard deviation (SD)
or median and percentiles 25 to 75 (P25–75) for continuous variables and absolute
numbers and percentages for categorical variables. To evaluate the association between
categorical variables, the chi-squared test was used. Receiver operating characteristic
(ROC) curve analysis was applied to identify the optimum cutoff value of preoperative
serum TSH for predicting the probability of postoperative TH replacement. A binomial
logistic regression was performed to evaluate the impact of each variable at risk
of postoperative TH replacement. Variables associated with need for TH therapy, at
the significance level of p < 0.20, in the univariate analysis were included in the multivariate analysis. The
odds ratios (OR) and 95% confidence intervals (95%CIs) were calculated.
The disease-free survival curve (time until initiation of T4 therapy) was plotted
using Kaplan-Meier method and the log-rank test was used to determine their significance.
Data analysis was performed using IBM SPSS Statistics for Windows (IBM Corp., Armonk,
NY, United States) software, version 25.0. Values of p < 0.05 were considered statistically significant.
Results
Preoperative Characteristics of Patients
In the present study, a total of 73 patients underwent hemithyroidectomy. Clinical
and laboratory characteristics of the patients are shown in [Table 1 ]. The mean age at surgery was 48.2 ± 16.5 years. Furthermore, 62 patients (84.9%)
were women, and 58 (84.1%) were in euthyroidism. The indication for the procedure
was due to compressive symptoms in 55 patients (75.3%), followed by indeterminate
FNA or suggestive of malignancy in 9 (12.3%), esthetics in 8 (9%) and autonomous nodule
with hyperthyroidism in 4 cases (5.5%). Based on the Bethesda classification, among
the 9 cases that had an exclusive indication due to FNA, 4 were III, 4 were IV, and
one was VI. Benign final histopathology was present in 91.8% of the patients.
Table 1
Presurgical characteristics of patients underwent lobectomy
Age (years) – mean ± SD
48.2 ± 16.5
BMI (kg/m2 ) – mean ± SD
28.4 ± 6.1
Sex – n (%)
Female
62 (84.9)
Thyroid US – n (%)
Heterogeneous parenchyma
30 (48.4)
Homogeneous parenchyma
32 (51.6)
Previous thyroid status – n (%)
Hypothyroidism
4 (5.8)
Hyperthyroidism
7 (10.1)
Euthyroidism
58 (84.1)
Surgical indication – n (%)
FNA suggestive of malignancy
9 (12.3)
Compressive symptoms
55 (75.3)
Hyperthyroidism
4 (5.5)
Esthetics
8 (11.0)
Final histology – n (%)
Benign
67 (91.8)
Malignant
6 (8.2)
Presence of thyroiditis on the anatomopathological examination – n (%)
6 (8.2)
TPOAb – n (%)
Positive
6 (17.6)
Negative
28 (82.4)
Preoperative TSH –median (P25–75)
1.3 (0.74–2.0)
Preoperative FT4–median (P25–75)
1.1 (0.98–1.3)
Preoperative T4T – median (P25–75)
9.4 (8.2–11.7)
Total follow-up time (months) –median (P25–75)
8.5 (4–13)
Abbreviations: BMI, body mass index; FNA, fine needle aspiration; FT4, free thyroxine; P25, percentile
25; P75, percentile 75; SD, standard deviation; T4T, total thyroxine; TPOAb, anti-thyroid
peroxidase antibodies; TSH, thyroid-stimulating hormone; US, ultrasonography.
Frequency and Risk Factors for Thyroid Hormone Supplementation Following Hemithyroidectomy
After a median follow-up time of 8.5 (4–13) months, 29 of 46 patients who were followed
up after surgery required TH replacement; thus, the incidence of T4 use following
thyroid lobectomy was 63%. While 26 patients (89%) developed hypothyroidism within
6 months after hemithyroidectomy. The median interval from surgery to the initiation
of T4 therapy was 6 (3.2–8.8) months.
The differences between the characteristics of patients with and without TH replacement
after surgery is shown in [Table 2 ]. There were no association in age, BMI, sex, sonographic echotexture of the thyroid,
previous thyroid dysfunction, surgical indication, side of hemithyroidectomy, malignant
anatomopathology, thyroiditis, TPOAb positivity, or preoperative FT4 levels between
those who did and did not require thyroid hormone treatment. TSH was the only clinical
parameter associated with the need for postoperative T4 therapy. Overall, those who
required thyroid hormone had a higher preoperative TSH (median: 1.6 [1.0–2.7] μUI/mL)
than those who did not (median: 0.8 [0.5–1.4] μUI/mL) (p = 0.015).
Table 2
Association between clinicopathological factors and thyroid hormone replacement (THR)
after thyroid lobectomy
THR
(n = 29)
Non-THR
(n = 17)
p
-value
Age (years) – mean ± SD
46.9 ± 15.9
49.2 ± 11.7
0.601
BMI (kg/m2 ) – mean ± SD
29.5 ± 5.9
26.7 ± 6.1
0.167
Female sex – n (%)
25 (86.2)
15 (88.2)
1.000
Thyroid US – n (%)
0.183
Heterogeneous parenchyma
16 (61.5)
6 (40.0)
Homogeneous parenchyma
10 (38.5)
9 (60.0)
Previous thyroid status – n (%)
0.447
Hypothyroidism
2 (6.9)
0 (0,0)
Hyperthyroidism
3 (10.3)
3 (17.6)
Euthyroidism
24 (82.8)
14 (82.4)
Surgical indication – n (%)
FNA suggestive of malignancy
4 (13.8)
1 (5.9)
0.637
Compressive symptoms
22 (75.9)
13 (76.5)
1.000
Hyperthyroidism
2 (6.9)
2 (11.8)
0.619
Esthetics
3 (10.3)
2 (11.8)
1.000
Laterality – n (%)
0.148
Right
19 (70,4)
9 (47,4)
Left
7 (25.9)
10 (52.6)
Isthmectomy
1 (3.7)
0 (0.0)
Malignant on the anatomopathological examination – n (%)
4 (13.8)
2 (11.8)
1.000
Presence of thyroiditis on the anatomopathological examination – n (%)
5 (17.2)
0 (0.0)
0.142
TPOAb, n (%)
0.622
Positive
4 (22.2)
1 (8.3)
Negative
14 (77.8)
11 (91.7)
Preoperative TSH, median (P25–75)
1.6 (1–2.7)
0.8 (0.5–1.4)
0.015
Preoperative FT4, median (P25–75)
1.1 (1–1.2)
1.2 (1–1.2)
0.535
Total follow-up time (months), median (P25–75)
10.0 (5–13)
6.0 (3–12)
0.411
Abbreviations: BMI, body mass index; FNA, fine needle aspiration; FT4, free thyroxine; P25, percentile
25; P75, percentile 75; SD, standard deviation; TPOAb, anti-thyroid peroxidase antibodies;
TSH, thyroid-stimulating hormone; US, ultrasonography.
Predictive of Preoperative TSH Levels
In univariate analysis, the only factor significantly correlated with TH replacement
was preoperative TSH serum (OR: 2.43; 95%CI: 1.06–5.57; p = 0.035). The risk of TH replacement increases by 2.43 times, as preoperative TSH
levels increase by 1 μUI/mL. In the adjusted multivariate analysis for hospitalization
time and laterality of the procedure, which included variables at the significance
level of p < 0.20, presurgical TSH was an independent predictor of postoperative T4 supplementation
(OR: 2.34; 95%CI: 1.02–5.37; p = 0.046). To establish the role of TSH levels in postsurgical TH replacement the
TSH were analyzed into the following groups: ≤ 1.0, 1.0 to 1.9, 2.0 to 2.9, and ≥
3.0 μUI/mL. The percentage of patients with and without TH replacement in each group
is shown in [Figure 1 ].
Fig. 1 The percentage of patients with and without THR (Non-THR), according to preoperative
TSH. Abbreviations: THR, thyroid hormone replacement; TSH, thyroid-stimulating hormone.
TH supplementation was more frequent in those with increasing presurgical TSH levels
(p = 0.029). Given that the TSH level was defined as the most important risk factor
for TH supplementation, we determine that a specific preoperative TSH cutoff level
is greater than or equal to 1.21 μIU/mL. The area under the ROC curve (AUC) is 0.727
(95%CI: 0.568–0.887; sensitivity, 71.4%; specificity, 73.3%; p = 0.015), as shown in [Figure 2 ].
Fig. 2 The ROC curve of the TSH with cutoff at 1.21μIU/mL. The AUC is 0.727, 95% CI is 0.568
to 0.887, and p is 0.015. Abbreviations: AUC, area under curve; ROC, receiver operating characteristic; TSH, thyroid-stimulating
hormone.
The risk of TH supplementation after hemithyroidectomy increases 2.5 times in patients
with preoperative TSH greater than or equal to 1.21 μIU/mL compared to those below
1.21 μIU/mL (OR: 2.53; 95%CI: 1.09–5.88; p = 0.031). Additionally, the median time to initiation of T4 therapy after hemithyroidectomy
was 14.6 (9.3–20) months in patients with preoperative TSH below 1.21 μIU/mL, and
5.2 (2.6–7.9) months in patients with preoperative TSH greater than or equal to 1.21
μIU/mL (p = 0.013), as shown in [Figure 3 ].
Fig. 3 Cumulative rate of THR over time according to cutoff TSH value. Abbreviations: THR, thyroid hormone replacement; TSH, thyroid-stimulating hormone.
Discussion
Our results confirm that preoperative TSH levels are an independent factor in predicting
THR after lobectomy. Interestingly, even patients with TSH levels within the lower
normal range might need levothyroxine supplementation. A presurgical TSH level ≥ 1.21
μIU/mL was correlated with the risk of post hemithyroidectomy T4 replacement.
The other variables (age at operation, sex, BMI, heterogeneity in preoperative ultrasound,
positive TPOAb, lymphocytic thyroiditis at final histology, and presurgical T4 levels)
are not associated with TH replacement at follow-up.
Our data shows that the overall incidence of TH supplementation following thyroid
lobectomy is of 63%, which is relatively higher than that reported in previous studies
(5.6–55.8%).[6 ]
[8 ] The higher incidence observed in our cohort may be due to the nonstandardized levothyroxine
supplementation protocol by different assistants. In fact, some studies have demonstrated
that postoperative hypothyroidism, including subclinical, can occur in 64% of patients
undergoing lobectomy.[13 ] However, without immediate T4 replacement, approximately 68% of patients spontaneously
recover thyroid function.[13 ] In fact, after hemithyroidectomy, most patients will remain in euthyroidism and
immediate start of T4 may lead to TSH suppression.[14 ]
Some studies have demonstrated that, in patients with benign pathology, the rate of
T4 use was lower compared to those with malignancy.[4 ]
[5 ] In order to reach the optimal TSH goal (< 2.0 μIU/mL) to be compliant with the American
Thyroid Association's recommendation for patients with differentiated thyroid carcinoma,
50 to 73% of patients with malignant histological results need postoperative levothyroxine.[1 ]
[12 ]
[15 ] Nonetheless, 92% of the histological results in our study were benign, which indicates
that even in benign pathologies the need for TH replacement is significant. Additionally,
a recent retrospective study reported a higher rate of T4 initiation after lobectomy
for benign disease than prior studies.[16 ]
Some clinical and pathological factors may influence the need for T4 supplementation
following hemithyroidectomy. Preoperative TSH level, positive TPOAb, and chronic lymphocytic
thyroiditis have been associated with postoperative hypothyroidism.[6 ]
[17 ] Similar to previous studies, we have demonstrated that presurgical serum TSH levels
are an independent risk factor for postoperative hypothyroidism, with approximately
double the risk of T4 replacement for every unit of TSH increase over 1 μIU/ml.[8 ]
[11 ]
[18 ] In our sample, preoperative TSH remained an important factor despite the lack of
association with the other variables.
Defining a specific presurgical TSH cutoff level instead of considering only the highest
levels can be very useful in preoperative patient counseling regarding the risks of
T4 replacement after surgery. Nonetheless, different cutoff levels of TSH have been
applied in the studies, some being established by the authors. We established the
specific cutoff level associated with the risk of THR after lobectomy by using ROC
curves. In our study, presurgical TSH levels of at least 1.21μIU/mL were associated
with hormone treatment following lobectomy, with about 2.5-fold higher risks. Interestingly,
our cutoff was lower compared to previous studies, most of which preferred 2.0 μIU/mL.
A presurgical TSH level greater than 2.0 μIU/mL was associated with a risk ratio of
2.955 (95%CI: 2.399–3.640; p = 0.000) for hypothyroidism after lobectomy compared to those under 2.0 μIU/mL.[17 ]
In recent studies, preoperative serum TSH > 2.172 μIU/mL was demonstrated as an independent
risk factor for T4 replacement after surgery (OR = 8.02; 95%CI: 4.87–13.20; p < 0.001).[19 ] The cutoff values defined in other studies ranged from 1.4 to 2.5 mIU/L.[10 ]
[11 ]
[12 ]
[13 ]
[20 ]
Similar to previous studies, most patients of our cohort started replacement with
T4 early in the postsurgical period; almost 70% of them within 3 months, and about
90% within 6 months.[8 ]
[19 ] Interestingly, the time to initiation of T4 therapy in patients with preoperative
TSH < 1.21mIU/L was longer, demonstrating that late onset postoperative hypothyroidism
of 1-year or more after lobectomy can happen, indicating a possible longer follow-up
for thyroid function evaluation.
Several previous studies have demonstrated that higher presurgical TSH levels combined
with lymphocytic infiltration of the thyroid tissue are associated with postoperative
hypothyroidism.[4 ]
[6 ]
[8 ]
[17 ] However, we found that anatomopathological findings on thyroiditis was not significantly
associated with the need for postoperative T4 supplementation. These results should
be viewed with caution because of the small number of thyroiditis patients with histological
description in our cohort. This may be related to the inconsistency in pathological
reporting or due to selection bias recommending total thyroidectomy for patients with
related clinical history or preoperative ultrasonography findings. Nonetheless, this
factor can be reliably assessed after final histological evaluation and is not suitable
for thyroid function prediction before lobectomy.
In the same way we did not find a difference in TPOAb levels between patients who
required or not TH supplementation. Previous studies have shown that TPOAb-positive
patients had a relevant risk (about 50%) of postsurgical hypothyroidism in comparison
with negative ones.[6 ] On the other hand, this association was not confirmed in a recent meta-analysis.[17 ] Indeed, the preoperative measurement may be used as a simple tool to estimate the
risk of hypothyroidism following surgery, but it is not universally recommended in
preoperative evaluation of partial thyroidectomy patients.
There are several limitations to this study. It's a retrospective study performed
at a single tertiary referral center. Our academic medical center, despite a high
volume of thyroidectomies, still recommends lobectomy for a small number of patients;
in addition, some patients had no postsurgical follow-up, which may overestimate the
prevalence of TH replacement. Another possible limitation is the lack of standardization
of THR, which prevented us from assessing the proportion of patients with transient
hypothyroidism. On the other hand, the data reflect the real-life of clinical practice.
Conclusion
In conclusion, thyroid hormone supplementation is common after lobectomy. In our cohort,
many cases had benign pathology, patients with preoperative TSH level > 1.21μIU/mL
are at risk of levothyroxine supplementation. Prospective studies with a larger number
of participants applying the same follow-up protocol are important to clarify the
role of other clinical factors in risk of THR following hemithyroidectomy.
Bibliographical Record
