Alterations in Serum Thyroid–Related Constituents After Thyroid Fine-Needle Biopsy: A Systematic Review

Abstract

Background:

Thyroid fine-needle biopsy (FNB) is a simple, reliable, inexpensive, and generally safe diagnostic procedure in the management of thyroid nodules. Local pain and minor hematomas are the most common clinical complications, and hemorrhage and fibrosis the most common histological alterations after thyroid FNB. FNB can also trigger biochemical alterations in serum, since it may destroy thyroid follicles. In this review we summarized the biochemical alterations in serum that occur after diagnostic thyroid FNB, aiming to review information that would be potentially useful in interpreting thyroid tests in patients who recently had a thyroid FNB.

Summary:

Computerized advanced search for primary evidence was performed in the PubMed (Public/Publisher MEDLINE) electronic database not limited by publication time and English language. An increase in serum thyroglobulin (Tg) ranging from 35% to 341% occurs in 33–88% of patients subjected to FNB. Serum Tg concentrations typically return to baseline about 2–3 weeks after FNB. The abrupt release of Tg after FNB may induce the production of autoantibodies to Tg and thyroid hormones in a minority of patients. There is little information on the effect of FNB on autoantibodies to thyroid peroxidase. No changes seem to occur in thyroid-stimulating hormone, total thyroxine, free thyroxine, free triiodothyronine (T3), or reverse T3, while controversy exists for T3.

Conclusions:

The degree of increase in serum Tg after FNB is highly variable and not a predictor of whether the biopsied nodule is benign or malignant. The increase or development of Tg autoantibodies that occurs in some patients does not appear to be of clinical significance. Development of autoantibodies to thyroid hormones may be more likely in patients whose biopsied nodule is benign than malignant, but further studies are required to confirm this. If changes in serum thyroid–stimulating hormone or thyroid hormones are noted in a patient with a history of a recent fine-needle aspiration, they should be investigated since they are not likely to be related to the biopsy.

Introduction

F ine-needle biopsy (FNB) is considered to be the most accurate and cost-effective diagnostic tool for the preoperative investigation of thyroid nodules, and it has been proposed as the procedure of choice (1 –4). The cytological results after FNB are generally divided into benign, malignant, indeterminate, and nondiagnostic. The use of FNB has almost halved the percentage of patients undergoing thyroidectomy and has doubled the yield of malignancy in patients who finally undergo surgery, thereby decreasing the cost of medical care (5,6). Technically, FNB can be performed with aspiration using a syringe (fine-needle aspiration [FNA]) or without aspiration (fine-needle capillary [FNC]) and can be guided only by palpation (palpation-guided FNB [P-FNB]) or by ultrasound (ultrasound-guided FNB [US-FNB]) (7).

Although FNB is an invasive procedure, it is considered simple, reliable, safe, and well accepted by the patients. Post-FNB local pain and minor hematomas are the most common clinical complications, while serious clinical complications, such as massive hematomas (8), are rare (9,10). Post-FNB hemorrhage and fibrosis are the most common histological alterations observed in surgical specimens if thyroidectomy follows, but some worrisome histological alterations mimicking thyroid malignancy may also be observed (11). FNB can also trigger biochemical alterations, since it may destroy thyroid follicles, resulting in thyroglobulin (Tg) release into the circulation. In this review we have tried to summarize all of the biochemical alterations in serum that occur after diagnostic thyroid FNB. A major aim was to review information that would be potentially useful in interpreting thyroid tests in patients who recently had a thyroid FNB.

Methods—Literature Search

Computerized advanced search for primary evidence was performed in the PubMed (Public/Publisher MEDLINE) electronic database. The search was not limited by publication time or restricted to English literature. Medical Subject Headings database was used as a terminological search filter. From the combination of terminological (Medical Subject Heading terms) and methodological search filters (“PubMed clinical queries”), relevant journal articles were retrieved (12). The bibliographic search was extended to the “Related Articles” link next to each selected article in PubMed and its references. Finally, automatic alerts were activated in PubMed (“My NCBI”) to add relevant articles published after the initial search. A search for a relevant systematic review or meta-analysis in both the PubMed and the Cochrane Library retrieved no result. Eight relevant articles were found in this systematic search. All articles were prospective cohort studies, some of which with a control arm, and are summarized in Table 1. According to the definitions of the American Association of Clinical Endocrinologists, they were of level 2 or 3 of evidence, leading respectively to grade B or C of recommendations (13).

Table 1.

Biochemical Alterations After Thyroid Fine-Needle Biopsy

References a	Study type/level of evidence b	N/F	Controls/F	Age (years) c	Technique	Needle's gauge (G)	Serum measurements (methods)	Sampling time	Main results	Additional information
Lever et al., 1983 (19)	Prospective cohort/2	25/22	7/7 (palpation); 3/3 (surgery)	17–76	P-FNA	20–26	Tg, TSH, TT4, TT3 (RIA); FTI (calculated)	0, 5–30 minutes	1) Tg ↑ in 11 patients 2) Mean Tg ↑ 35% 3) TT4 ↑ and FTI ↓ in only 1 patient 4) TSH, TT3 ↔ 5) Tg marked ↑ in all patients in surgery group and in none in palpation group	All patients initially euthyroid and negative for TgAb. Controls subjected to vigorous external manual palpation or thyroid surgery.
Catania et al., 1985 (18)	Prospective cohort/2	15/13	No	24–60	US-FNA	22	Tg, TgAb (RIA)	0, 3, 30, 60, 120, 180 minutes (Tg); 0, 15, 30, 60 days (TgAb)	1) Tg ↑ in 11 patients 2) Mean Tg ↑ 136% at 30 minutes 3) Mean Tg remain unchanged from 30 to 180 minutes 4) TgAb remained negative in all patients	All patients initially euthyroid and negative for TgAb. All patients subjected to thyroidectomy at the end of the study.
Lin, 1987 (20)	Prospective cohort/3	49/na	No	na	P-FNA	22	Tg, TT4, TT3, rT3 (RIA)	0, 10 minutes	1) Tg ↑ in 16 patients 2) Mean Tg ↑ 182% 3) TT4, TT3, rT3 ↔	All patients initially negative for TgAb. 2 patients initially hyperthyroid.
Sussi et al., 1987 (22)	Prospective cohort/3	15/12	No	42	P-FNA	22	Tg (RIA)	0, 3, 60 minutes	1) Tg ↑ in 12 patients 2) Mean Tg ↑ 78% (3 minutes) and 341% (60 minutes)	Unknown if patients initially euthyroid or negative for TgAb.
Bayraktar et al., 1990 (16)	Prospective cohort/3	12/9	No	26–59	P-FNA	22	Tg (RIA)	0, 5–60 minutes	1) Tg ↑ in 7 patients 2) Mean Tg increase 63%	All patients initially euthyroid and negative for TgAb. All patients subjected to thyroidectomy at the end of the study.
Benvenga et al., 1997 (17)	Prospective cohort/2	214/175	No	na	P-FNA	na	Tg, TgAb, (IRMA); THAb-IgM, THAb-IgG (RIPT)	0, 1–3 hours, 3, 15 days (Tg); 0, 1–3 hours, 3, 15 days, 1, 3 months (THAb-IgM); 0, 15 days, 1, 3, 6, 12 months (TgAb, THAb-IgG, TPOAb)	1) Tg ↑ in 115 (of 156 TgAb- negative) patients 2) Mean Tg increase 66% (1–3 hours) and 35% (3 days) 3) Tg return to baseline by 15th day 4) TgAb remained negative in 145 and converted to positive in 11 (of 156 TgAb negative) patients (1 year) 5) THAb converted to positive in 9 (of 214 patients)	400 patients with scintigraphically cold nodule initially enrolled. Not all patients initially euthyroid. All patients initially negative for THAb. 156 patients initially negative for TgAb.
Luboshitzky et al., 2006 (21)	Prospective cohort/2	25/25	25/na (palpation); 15/na (no intervention)	28–80	P-FNA	na	Tg (IRMA)	0, 60 minutes, 15 days	1) Tg ↑ in 22 patients 2) Mean Tg ↑ 303% (60 minutes) 3) Tg returned to baseline by 15th day 4) Tg ↑ in 4 patients in the palpation group (ns) and in none in no intervention group (ns)	All patients initially euthyroid and negative for TgAb and TPOAb. Controls subjected to vigorous external manual palpation or no intervention (no fine- needle biopsy, no palpation).
Alpay et al., 2007 (15)	Prospective cohort/3	25/19	No	22–66	P-FNA	18	Tg, TSH, TT4, TT3, fT4, fT3 (na)	0, 1, 30 minutes	1) Mean Tg ↑ 16% (1 minute) and 37% (30 minutes) 2) Mean TT3 ↑ 18% (1 minute) and 14% (30 minutes) 3) TSH, TT4, fT4, fT3 ↔	All patients initially euthyroid and with solid nodules. Unknown if patients initially negative for TgAb. Unknown the number of patients who increased Tg and TT3. No interpretation of TT3 ↑ by the authors.

References are presented in publication date order.

According to the definitions of the American Association of Clinical Endocrinologists (13).

Mean age if range was not available.

↑ , Increase; ↓ , decrease; ↔ , no alteration; F, females; FNA, fine-needle aspiration; fT3, free triiodothyronine; fT4, free thyroxine; FTI, free T4 index; IRMA, immunoradiometric assay; N, number of patients; na, not available; ns, not significant; P-FNA, palpation-guided FNA; RIA, radioimmunoassay; RIPT, radioimmunoprecipitation technique; rT3, reverse triiodothyronine; Tg, thyroglobulin; TgAb, Tg autoantibodies; THAb, thyroid hormone autoantibodies; TPOAb, thyroid peroxidase autoantibodies; TSH, thyroid-stimulating hormone; TT3, total triiodothyronine; TT4, total thyroxine; US-FNA, ultrasound-guided FNA.

FNB and serum Tg

As far as trauma to the thyroid is concerned, it was reported as far back as 1982 that thyroid surgery was generally followed by an increase in serum Tg (14). Subsequently, it was noted that even minor insults to the thyroid, such as an FNB, were also followed by increases in serum Tg. In fact, in all eight articles relating to this, increases in serum Tg after FNB were reported in some patients with the reported percentage of patients in whom the increase was significant (ranging from 33 to 88) (15 –22). Initially, it was postulated that the degree of increase in serum Tg could discriminate benign and malignant lesions. This hypothesis was not confirmed, however, and there was no relationship between the changes in serum Tg after FNB and the final histological diagnosis (18,19). Among individuals the rise in serum Tg after FNB is quite variable in most studies. The mean increase ranges between 35% and 341% (Table 1). Enormous increases up to 1500% (18) or 3000% (21) or even 12,500% (17) compared with basal levels have been reported. Tg peaks quickly (between 30 minutes and 3 hours after FNB) and slowly returns to baseline within the next 2 weeks (17,21). The variability in the increase in serum Tg occurs not only within studies, but also between studies. This may be due to differences in the time after FNB that serum was sampled, but it also seems related to differences in the criteria for an increase or decrease. In some studies “increased” or “decreased” is defined to be values that are higher or lower, respectively, than the interassay coefficient of variation for the method used. In other studies the definition was any increase or decrease compared with baseline values, and in still other studies the definition was unclear. As is well known, there are a wide variety of methods used to measure serum Tg in clinical settings and this was also the case for studies on the effects of FNB on serum Tg (Table 1).

No correlation was found between post-FNB Tg alterations and the age of the patient (21), Tg levels at baseline, the volume of aspirate, the needle size, the nodule diameter (19), the nodule echogenicity (cystic or solid) (18), or the number of passes (19,20). However, in one study there was no increase in serum Tg in patients who had only one pass for their FNB (n = 7), whereas 16 of the other 42 patients in this study who had 2–5 passes during the FNB procedure had an increase in serum Tg (20). In one study (19) the degree of rise in serum Tg after FNB was related to the performer of the procedure, but this study did not report differences in technique that might explain this. It is possible that the lack of expertise or a more aggressive or clumsy handling of the needle might lead to more extensive destruction of the thyroid follicles, thereby increasing Tg release into the circulation.

In summary, an increase in serum Tg is common after FNB as well as thyroidectomy. Serum Tg concentrations typically return to baseline about 2–3 weeks after FNB. If the patient has had a total thyroidectomy and serum Tg levels decline to undetectable, the surgery is complete and there are no metastases. Whereas it is current practice to follow serum Tg in patient who have had total thyroidectomy for thyroid cancer, there is usually no need to check serum Tg after FNB. If such patients do develop signs and symptoms of a disorder in which serum Tg is useful, as is the case for differentiating between thyroiditis and thyroid hormone ingestion, it should be remembered that the results for serum Tg are likely to be unreliable if the patient has had an FNB within the previous 2–3 weeks.

FNB and serum autoantibodies to thyroid antigens

Autoantibodies to Tg

Tg autoantibody (TgAb) measurements should accompany Tg measurements since assays for Tg are unreliable in the presence of TgAb (21). Only a few studies, however, have reported TgAb measurement after FNB (17,18). In the earliest study, none of the patients who were TgAb-negative before FNB were reported as becoming TgAb positive after FNB (18). In this study, however, the patients were only sampled up to 2 months after FNB, so the development of TgAb at later times, which hypothetically might have been related to FNB, could not be ruled out. In contrast, in a latter study (17), 7% of the 156 patients who were initially TgAb-negative became TgAb-positive when studied for 1 year, but not 15 days, after FNB. In the 57 patients who were TgAb-positive in this study 12% (n = 7) had higher TgAb titers 1 year after FNB than before FNB and 4 of them showed a clear time-dependent pattern of TgAb increase after FNB. It should be noted, however, that there was no matched control group of subjects who did not have FNB that could provide information on spontaneous conversion of TgAb-negative to -positive status or vice versa.

It should be noted that the ability of the mature Tg of 660 kDa to stimulate the production of TgAb differs from that of lower molecular weight forms. However, it has been reported that in patients with nodular thyroid disease, only the mature Tg, with a molecular mass of 660 kDa, was noted in serum before thyroidectomy, while many different forms (50–300 kDa) were found after surgery (23). Whether this is the case or not for FNB is not clear.

In summary, it is likely that the abrupt release of Tg after FNB may induce the production of TgAb in a minority of patients. The clinical importance of this is probably minimal, however, not only because of the few patients in whom this occurs but also because human Tg-TgAb complexes do not seem to activate complement in vitro and are therefore unlikely to be harmful in vivo (24). However, TgAb measurements may be misleading as markers of thyroid autoimmunity if performed within at least 1 year after FNB. On the other hand, this is an unsettled issue. Thus, it is not clear if conversion from TgAb-negative to -positive after FNB occurs only in patients predisposed to thyroid autoimmunity. Nor is it known if subjects who convert from TgAb-negative to -positive after FNB remain TgAb-positive.

Autoantibodies to thyroid peroxidase

There is little information regarding the effect of FNB on the generation of thyroid peroxidase autoantibodies. These were measured in one study, but only in those who were thyroid peroxidase autoantibody-positive before FNB (17).

Autoantibodies to thyroid hormones

Autoantibodies to L-thyroxine (LT4) and L-triiodothyronine (LT3) are the rarest thyroid autoantibodies and occur in a small number of patients (0.04%) (17). Studies have been performed to determine if FNB induces the formation of antibodies against LT4 (T4Ab), LT3 (T3Ab), or both LT4 and LT3 (T4T3Ab), which are described as autoantibodies to thyroid hormones (THAb). In a well-designed study, THAb were increased after FNB in 4.2% (n = 9) of the 157 initially THAb-negative patients (17). This prevalence was about 50-fold higher than that reported in consecutive European patients attending thyroid clinics (17). All nine patients first developed IgM antibodies (five T3Ab, three T4Ab, and one T4T3Ab). One month after FNB, four of the nine patients developed IgG antibodies of the same specificity (three T3Ab and one T4Ab). In one of them, the IgG T3Ab persisted for 1 year after FNB. It is of interest that all patients who developed IgG antibodies had Hashimoto thyroiditis. It seems that the primary immune response (IgM antibodies) is followed by a secondary response (IgG antibodies) only in a percentage of the patients, and the secondary response is long lasting in only a minority of the latter.

Benvenga et al. (17) concluded that post-FNB Tg release is sufficient to induce THAb synthesis. This synthesis occurred 10 times more frequently in patients with autoimmune than nonautoimmune thyroid disease (21% vs. 2%). In patients with Hashimoto's thyroiditis, TgAb levels below 400 U/mL before FNB that did not increase after FNB and cytological diagnosis of benign colloid nodule were risk factors for the development of THAb after FNB. A possible explanation for the first risk factor is that high serum levels of TgAb can buffer the released Tg. Therefore, TgAb sequester antigen that might have been able to trigger THAb synthesis. With regard to the second risk factor, the association of THAb with benign colloid but not suspicious or malignant nodules resembles the significantly higher frequency of THAb in benign goiters compared with thyroid cancer (3–11% vs. 0–1%) (25). Since it was previously reported that Tg expression is lower in malignant than in benign thyroid nodules (26) and that cystic fluid of malignant nodules contains less Tg than benign nodules (27), it could be hypothesized that benign nodules are more likely to store and release Tg molecules immunogenic for THAb.

In summary, it is likely that the abrupt release of Tg after FNB may induce the production of THAb in a minority of patients. Although further evidence is required, THAb after FNB could be proposed as a predictor of thyroid nodule benignity, adjunctive to cytological diagnosis and other demographic and ultrasonographic data (28). However, the cost-effectiveness of this approach is questioned, since THAb are converted to positive only in a minority of patients subjected to FNB.

Effect of FNB on serum thyroid hormones

There are limited data regarding the effect of FNB on serum thyroid hormones (Table 1) (15,19,20). No change was found in serum thyroid–stimulating hormone (TSH) (15,19) or in serum reverse T3 (rT3) (20). There were no significant changes in total T4 (TT4) (15,19,20) or free T4 (fT4) (15). One patient had decrease in both TT4 and fT4 index (FTI) (19). There is controversy on the effect of FNB on total T3 (TT3): no change was reported in two studies (19,20), whereas significant increase immediately after and 30 minutes after FNB was reported in a third study (15). However, in the last study, serum free T3 (fT3) was unaffected by FNB (15). The sampling time was similar in the above three studies, but there were differences in the needle size (G) (Table 1). There is no reasonable explanation for this discrepancy. In our opinion, there is no obvious reason that could selectively lead to increase of the TT3 without affecting fT3, fT4, and TT4.

In summary, the little or no T4 and T3 leakage that may appear after FNB is not sufficient to alter serum concentrations of these substances. As a consequence, serum TSH is not affected by FNB. It has been proposed that a post-FNB increase in serum T3 might cause unfavorable cardiovascular effects, especially in patients with heart rhythm disorders (15). T3 may lead to increased adrenergic activity by increasing the number of β-adrenergic receptors (29). Since serum fT3 was not altered in the same study (15), however, there should be no T3-mediated effects on the cardiovascular system after FNB.

Comparison between different techniques

P-FNB versus US-FNB

To date, no comparative study between P-FNB and US-FNB had serum post-FNB biochemical alterations as its primary or secondary endpoint. Limited data can be extracted from the unique article evaluating the impact of US-FNB on Tg and TgAb (18). Mean Tg increased by 136% 30 minutes after US-FNB; this increase is in the middle of increases that have been reported after P-FNB (35–303%). Further, Tg was increased in a similar percentage of patients subjected to P-FNB and US-FNB (Table 1). TgAb remained negative in all patients subjected to US-FNB (18), but converted to positive in 7% of the patients subjected to P-FNB (17). However, the cohort of patients was significantly smaller in the study of US-FNB than in the study of P-FNB (15 vs. 156 patients respectively) and sampling time for TgAb was shorter (3 vs. 12 months, respectively). Therefore, no solid conclusions can be made, so further comparisons between US-FNB and P-FNB are needed.

FNA versus FNC

There are no data regarding the effect of FNC on thyroid related tests in serum (Table 1), so comparison of the effects of FNA and FNC is not possible. However, since there is evidence that FNC is probably associated with less trauma to cells and tissues than FNA (30 –32), one could hypothesize that FNC might lead to lower Tg leakage in the circulation and subsequently to lower alterations in thyroid hormones and autoantibodies than FNA.

FNB versus large-needle biopsy

Similarly, there are no data regarding the impact of large-needle biopsy (LNB) (either large-needle aspiration biopsy or core-needle biopsy) on thyroid biochemical tests in serum. Again, however, since LNB is more traumatic to cells and tissues than FNB (33,34), LNB should be associated with more Tg leakage into the circulation than FNB and likely greater alterations in thyroid hormones and autoantibodies.

Conclusions

Thyroid FNB is a widely used diagnostic procedure with a low rate of complications. The effects of FNB on serum Tg, thyroid hormones, and autoantibodies have not been adequately studied. From the limited data it has been noted that Tg increases quickly after FNB and slowly returns to baseline within 2–3 weeks. The extent of this increase, however, is highly variable and poorly correlated with the histology of the thyroid nodule and its benign or malignant nature. In some patients the abrupt release of Tg after needle biopsy appears to be sufficient to induce the production of TgAb. It is unlikely that this has clinical consequences other than possibly affecting Tg measurements. In a few patients the increase in Tg may lead to the production of THAb. There is a suggestion that this occurrence is more likely in patients with benign than malignant nodules, but this has not been clearly established. There are no clinically significant changes in serum TSH, TT4, fT4, fT3, and rT3 after thyroid needle biopsy. In one of three studies (15), there was an increase in TT3 after needle biopsy. In the other two (19,20) no change was noted.

Footnotes

Acknowledgment

We thank the librarian of Ippokration Hospital of Thessaloniki, Dimitrios Vlahoudis, for his help in retrieving the full text of older articles.

Disclosure Statement

The authors declare that no competing financial interests exist.

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