TABLE OF CONTENTS
Prophylactic Postoperative Thyroid Hormone
THYROXINE SUPPRESSION THERAPY
IN
NODULAR THYROID DISEASE
Rhonda Carter, MD
Department of Internal Medicine
Resident Grand Rounds
December 15, 1998
A 32 y.o. Indian-American female without significant PMH presented for a new patient visit with a complaint of a "lump in her neck" that had been present and slowly enlarging for about one year. She had no history of prior thyroid disease and denied any dyspnea or dysphagia, but was concerned about the cosmetic appearance of her neck. She denied any hair/skin changes, heat/cold intolerance, weight loss/gain, tremors, palpitations or menstrual irregularities. She did report occasional constipation.
PMH: None
Meds: None
Allergies: NKDA
Gyn: G2P2A0, s/p BTL, PAPs WNL, menses regular
SH: Denied Etoh/Tob, Divorced, Worked as a daycare worker
FH: +DM, +asthma
ROS: otherwise NC
PHYSICAL EXAM
Gen: WDWN Indian female, NAD
VS: Wt 138 lbs, HR 68, BP 96/60, T98.5, RR 16
HEENT: no exopthalmos or lid lag
Neck: diffusely enlarged nontender thyroid gland, smooth surface, approx. twice normal size, no distinct nodules, no thyroid thrills/bruits
Lungs: CTA
Heart: RRR without MRG
Abd: BS+, soft, NTND
Ext: no tremors/edema
Neuro: DTRs 2+ throughout
Skin: warm, dry
GU: WNL
TFTs: Total thyroxine 7.4 (5.5-11.8) ug/dl
Thyroid uptake 24.8 (24-34) %
Free thyroxine index 6.1 (4.8-1.3)
TSH 2.19 (0.40-5.5) mcu/ml
CLINICAL QUESTIONS:
1. Should this euthyroid patient be given levothyroxine to suppress her goiter?
2. In what other clinical situations is a trial of thyroxine suppression indicated?
3. Is there any evidence that thyroxine suppression works?
4. Are there any complications to this therapy?
5. Are there any current recommendations regarding duration of therapy and goal serum TSH levels?
Throughout this discussion the terms thyroxine suppression therapy and TSH suppressive therapy will be used interchangeably. Both refer to the intentional prescribing of levothyroxine with the intent of suppressing serum TSH levels in an effort to control growth of abnormal thyroid tissue.
Nodular thyroid disease is a common clinical problem. The term nodular thyroid disease is used to include both solitary thyroid nodules and multinodular glands. It is more common in women, in the elderly, in areas of iodine deficiency and following exposure to ionizing radiation. The prevalence of thyroid disease in the U.S. was clearly defined in the population of Framingham, Massachusetts, in the 1950s (1). In over 5000 people studied by the National Heart Institute for coronary heart disease and hypertension, they found palpable thyroid nodules in 1.5% of men and 6.4% of women between the ages of 30 & 59 and an annual incidence of new thyroid nodules of 0.1%. Thyroid nodules are even more commonly detected when the thyroid is examined by ultrasonagraphy (2). A random ultrasound screening in 1991 showed a 27% incidence of thyroid nodules. Approximately 250,000 new nodules and 12,000 new thyroid malignancies are diagnosed each year. These data suggest that 4-5% of nodules are malignant (3).
The diagnostic evaluation of thyroid nodules is beyond the scope of and not the primary focus of this review. However, given the fact that fine needle aspiration biopsy has revolutionized the diagnostic approach to thyroid nodules, this technique deserves special mention. Fine needle aspiration biopsy (FNA) is indicated in all patients with solitary thyroid nodules (4). In patients with multinodular goiters, FNA may be helpful when carcinoma is suspected: cytologic examination should focus on the dominant nodules or those that have a different consistency from other nodules within the gland. And, any previously biopsied benign nodule that appears to be growing should be rebiopsied.
Thyroid FNA is a simple in-office procedure. It is best performed with the patient supine with the neck flexed backward. The skin is cleansed with alcohol. No local anesthesia is needed. A 1.5 inch 25-gauge needle is attached to a 10cc syringe. The use of a pistol-grip syringe holder is optional. When the needle is inserted inside the nodule, suction is applied, and the needle is moved back and forth to sample the nodule. Once aspirate appears in the hub of the needle, suction is released, and the needle is withdrawn. The aspirated material is expelled onto slides. Slides are either air-dried and stained using the May-Grunwald-Giemsa technique or, more commonly, immediately wet-fixed in 95% ethyl alcohol and stained using a modified Papanicolaou method. Two to four aspirations are usually done. A local hematoma is the only usual complication.
Cytologic results of FNA of the thyroid are divided into the following categories:
Satisfactory:
Benign:
Benign nodule
Nodular adenomatous hyperplasia
Follicular adenoma
Colloid nodule
Hashimoto’s thyroiditis
Subacute thyroiditis
Cyst
Indeterminate:
Hurthle cell neoplasm
Follicular neoplasm
Findings suggestive but not diagnostic of malignancy
Malignant:
Papillary carcinoma
Medullary carcinoma
Anaplastic carcinoma
Metastatic carcinoma
Lymphoma
Unsatisfactory:
Nondiagnostic
In 1993 Gharib et.al. published a review of the literature on FNA of the thyroid (5). He pooled data from seven large series of patients with a total of 18,183 biopsy specimens and found the following rates of cytologic diagnoses:
Benign 69%
Indeterminate 10%
Malignant 4%
Nondiagnostic 17%
In patients with nondiagnostic cytologic results, specimens are found to be inadequate for proper cytopathologic interpretation, usually because of the presence of cystic fluid or hemorrhagic material, or because of too few cells present. A repeat aspiration will provide a diagnostic smear in up to 50% of cases. If repeat aspiration yields nondiagnostic findings, further management should be based on clinical suspicion, possibly, including a thyroid scan, with surgical removal of cold nodules. Surgical therapy is of course indicated for a patient with a diagnosis of malignancy. Because of a 30% chance of malignancy in patients with an indeterminate aspirate, these patients should be referred for surgical exploration as well.
The reference range for TSH in most labs is 0.5 - 5uU/ml. In our lab at Wake Forest the normal range is reported as 0.40 - 5.5 uU/ml. Third generation assays (the most sensitive assay that is widely available) can measure TSH down to 0.01 uU/ml. A low TSH usually refers to a TSH below the reference range but still detectable (0.01 - 0.5). A "suppressed" TSH is often taken to mean a TSH which is below the detection limit for that assay. The dose for replacement therapy with levothyroxine for hypothyroidism is generally between 1.6-1.7 ug/kg/day. Suppressive doses have traditionally been greater than 2 ug/kg/day (9).
Now that fine needle aspiration biopsy has simplified the diagnostic approach to thyroid nodules, the issue for most clinicians is what therapeutic approach to take in the approximately 75% of patients whose biopsies are benign. In most patients who have either solitary or multiple benign thyroid nodules, the choice is either observation or thyroid hormone suppression therapy (6).
The theory behind thyroid hormone suppression therapy is that TSH is a stimulator of both thyroid growth and function. It seemed logical that administering doses of thyroxine sufficient to suppress serum levels of TSH would shrink or at least slow the growth of existing nodules and multinodular goiters. TSH is a known regulator of differentiated thyroid follicular cell function. However, the role of TSH as a thyroid growth factor is contested. In recent years, several other growth factors that act on human thyroid cells have been identified: growth stimulating immunoglobulins, epidermal growth factor, insulin-like growth factors, interleukin-1, interferon-gamma, and transforming growth factor-beta. Furthermore, mutations of ras oncogenes are prevalent in both benign and malignant thyroid nodules, and it is likely that nodules containing ras
mutations will be unresponsive to the suppression of TSH (7). However, there is some evidence that TSH may increase the sensitivity of the thyroid to other growth factors. Therefore administering thyroxine in doses sufficient to suppress serum TSH might be useful in the prevention and treatment of thyroid nodules and goiters (8).
In 1953, Greer and Astwood published their report of 50 patients treated with thyroid extract therapy in which two-thirds experienced regression of their goiters (10). This led to the widespread use of thyroxine suppression therapy for thyroid nodules and goiters, although it was not until the late 1980s and 1990s that any randomized controlled trials were conducted to study the efficacy of this therapy.
There are five clinical situations in which thyroxine suppression is used in the treatment of thyroid disease:
1. Treatment of solitary thyroid nodules.
2. Suppression of diffuse or nontoxic multinodular goiter.
3. Prophylactic post-op therapy after partial thyroidectomy.
4. Suppression of nodules in patients with a history of neck irradiation.
5. Suppression therapy in patients with a history of thyroid cancer.
We will look at each of these clinical situations and the evidence regarding TSH suppressive therapy. Treatment of toxic nodular goiter and replacement therapy for hypothyroidism is not controversial and will not be discussed.
Only a handful of randomized trials have studied the effect of TSH suppression on solitary thyroid nodules. Of these, three were placebo-controlled and included objective ultrasound determination of nodule size. In 1987, Gharib et al. published the first randomized placebo-controlled trial of suppressive therapy in 53 patients with colloid solitary nodules (11). Twenty-eight patients received levothyroxine and 25 received placebo for six months. Average nodule volume decreased from 3.0 ml to 2.5 ml in the levothyroxine group and decreased from 2.6 ml to 2.4 ml in the placebo group, but this was not statistically significant (P > 0.10). This study was limited by the relatively short (six month) treatment period and the inclusion of cystic and mixed solid/cystic nodules (19%) which would not be expected to respond to suppression therapy.
In 1993, Papini et al. conducted a 12-month randomized trial of 101 euthyroid patients with single palpable colloid thyroid nodules measured by ultrasound in a double-blind fashion (12). Fifty-one patients were assigned to receive thyroxine in doses sufficient to suppress TSH below the normal range (average 0.06), and 50 patients assigned to receive placebo. In the treatment group, the nodules showed a significant decrease in volume when measured by palpation (2.14 ml vs. 2.86 ml, P<0.05), but not when measured by ultrasound (5.86 ml vs. 6.20 ml, P=0.82). In the placebo group nodule volume did not change significantly (6.48 vs. 6.25, P=0.89). The authors postulated that the apparent reduction in volume by palpation but not by ultrasound measurement might be due to reduction of the thickness of surrounding thyroid tissue still responsive to TSH. However, it is likely due to the fact that only the radiologists were blinded. Although the change in average nodule size was not significant, 20% of the patients in the treatment group experienced a >50% decrease in the size of their nodule, whereas only 6% of the patients in the placebo group experienced a similar reduction.
The most recent study done by La Rosa et al. in 1995 did show a positive effect of suppression therapy (13). Unlike the previous two studies, only a minority of his patients had colloid nodules. Most nodules were follicular adenomas and nodular adenomatous hyperplasia. Twenty-three patients received L-thyroxine sufficient to suppress TSH to <0.3 for 12 months and 22 patients received placebo. Mean nodule volume decreased from 3.5 ml to 2.1 ml (a 40% decrease, P<0.001) whereas mean nodule volume increased from 3.5 ml to 3.9 ml in the placebo group (P>0.2). La Rosa also noted the percent of patients who experienced a >50% reduction in nodule size. Nine of the 23 patients receiving L-thyroxine (39%) and none of the 22 patients receiving placebo had a >50% reduction in nodule size. After the one-year treatment period, the patients in the L-thyroxine group discontinued therapy and were reexamined by ultrasound 4 months later. During this time off thyroxine, nodules, which had decreased during therapy, had an increase in mean volume of 26%.
Although most authors reported their results in terms of change in mean volume size, that may not be the best way to view the data. From what we know about the potential monoclonality and possible oncogene mutations within thyroid nodules it would be expected that some nodules may still be responsive to TSH and some not. Likewise, some would shrink during suppressive therapy and others would continue to grow. Therefore, looking at changes in the mean geometric volume is not the best way to look at the impact of therapy. Rather we should look at the percentage of nodules which showed a clinically relevent decrease in size.
% Response
(>50% change)
No. of Pts. T4 Placebo Nodule Type
Gharib, 1987 53 14 20 colloid, some cystic
Papini, 1993 101 20 6 colloid
La Rosa, 1995 55 39 0 75% parynchymatous
25% colloid
In summary, the three best designed randomized placebo-controlled trials looking at thyroid hormone suppressive therapy for solitary thyroid nodules have found conflicting results. This may in part be due to the inclusion of different types of nodules. Even La Rosa’s results are less impressive when one considers the fate of untreated benign thyroid nodules. In a study in Japan of 134 patients with benign nodules with a 9-year follow-up period, 43% of single nodules shrank or disappeared, 23% enlarged, and 34% remained the same size (14).
Diffuse goiters and multinodular goiters are probably just different points in a spectrum of disease. In the early phase of goitrogenesis, the thyroid may be diffusely enlarged, but with time diffuse goiters tend to grow and become more nodular (4). Also, with time nodules often become more autonomous and euthyroidism may evolve into subclinical or overt hyperthyroidism. Older, nonrandomized studies showed effectiveness of TSH suppresive therapy on diffuse non-toxic goiters. Hansen et al. in 1979 published a study of 45 patients given 150 ug of L-thyroxine for 12 months with ultrasound determination of goiter size (15). Half of his study group experienced a measurable decrease in the size of their goiters with 30% obtaining normal size of the thyroid gland. Furthermore the median thyroid volume returned to pretreatment values three months after therapy was stopped. Several non-randomized studies suggest that this therapy is also effective in patients with multinodular goiters. To date, only one randomized placebo-controlled trial using ultrasound evaluation to determine the effects of thyroxine on diffuse and multinodular goiters has been conducted.
In 1990, Berghout et al. studied the effects of thyroxine treatment on patients with either diffuse or multinodular non-toxic goiters (16). Twenty-six patients were assigned to receive thyroxine and 26 patients received placebo for nine months. Goiter response was measured by ultrasound. A positive response to treatment was defined as a decrease in thyroid volume greater than 13% at nine months. The mean decrease in volume among those responding was 20% of initial size. A response to treatment was found in 58% of the patients in the thyroxine group and in 5% of the placebo group. Furthermore, following discontinuation of treatment, thyroid volume increased in the responders and had returned to base-line values after nine months of follow-up. Although these data are striking, the study was conducted in the Netherlands, which is an area of borderline iodine sufficiency. Berghout reported the 24-hour urinary iodine measurements from the thyroxine group at 139 ug/24 hours. The World Health Organization recommends a daily iodine intake of 150-300 ug. Therefore, Berghout’s results may not be generalizable nor applicable in the U.S., where endemic goiters from iodine deficiency are practically nonexistent.
PROPHYLACTIC POSTOPERATIVE THYROID HORMONE
Postoperative thyroxine may be necessary in patients who become hypothyroid following partial thyroidectomy. But the question which frequently arises is whether euthyroid patients should receive post-op thyroid hormone to prevent recurrence of goiters after a partial thyroidectomy There have been three prospective randomized studies, all from Denmark, comparing thyroxine therapy to no treatment. Of these, only the most recent study by Bistrup et al. (1994), had a prolonged follow-up period (17). Bistrup randomized 100 consecutive patients after partial thyroidectomy for nontoxic goiter to receive thyroxine or no therapy. Forty patients received 100mcg of thyroxine, 60 patients did not. After nine years of follow-up, recurrences were assessed by palpation in 14.5% of the treatment group and 21.8% of the no treatment group (P=0.52). However, TSH levels were not significantly different between the two groups, raising the possibility of inadequate dosing.
In contrast to patients with a sporadic goiter, in whom prophylactic suppression remains unproven, individuals with a history of craniocervical irradiation appear to benefit from TSH suppressive therapy after partial thyroidectomy. Fogelfeld et al. in 1989 published a nonrandomized prospective study of 511 patients who received partial thyroidectomys for benign thyroid disease (18). All had received radiation therapy to the tonsils and adenoids during childhood. Of 299 patients with postoperative thyroid hormone, 25 (8.4%) had recurrent thyroid nodules during an 11-year follow up period. Of 201 patients who did not receive TSH suppressive therapy, 72 (35.8%) developed recurrent thyroid nodules (P>0.05). The frequency of cancer developing over the same period of time did not differ between the two groups.
Differentiated thyroid cancers (papillary and follicular) account for more than 90% of thyroid cancers. The initial treatment is surgery, which cures most patients and, of course, leads to hypothyroidism. The standard treatment post-surgery is not only to administer replacement thyroxine but to administer supraphysiologic doses of thyroxine to suppress TSH secretion, since TSH may serve as a growth factor for any residual tumor cells (19). TSH suppression has no benefit for medullary thyroid cancer.
No randomized trials evaluating the efficacy of TSH suppression in patients with thyroid cancer have been conducted. In a large retrospective study by Mazzaferri in 1987 of 693 patients, the treated group showed a cumulative recurrence rate of 17% at 10 years compared to 34% of those not treated (P <0.0006),(20). The level of TSH suppression needed to prevent recurrent cancer is not known, although some authors have argued keeping the serum TSH <0.1 mcu/ml for at least the first five years post-op (19).
A TSH <0.1 is within the range that has been associated with tissue manifestations of hyperthyroidism, such as atrial fibrillation and osteoporosis. The morbidity of lifelong mild hyperthyroidism is generally felt to be outweighted by the risk of cancer recurrence. To determine whether the morbidity of suppresive therapy outweighs the potential benefits for patients with benign thyroid disease, one must first review the recent data on the long-term effects of suppressive therapy on the cardiac and skeletal systems.
In 1994, Sawin et al. examined prospectively the incidence of atrial fibrillation in relation to serum TSH concentrations over a 10-year follow-up period among 2007 people over age 60 who were participating in the Framingham Heart Study (21). The subjects were classified into four categories:
TSH No. subjects % w/ afib RR P
Low TSH <0.1 61 28 3.1 <0.001
Slightly low 0.1-0.4 187 16 1.6 0.05
Normal 0.4-5.0 1576 11 1 --
High >5.0 183 15 1.4 0.12
The cumulative incidence of atrial fibrillation was 28% among subjects with a low TSH value compared with 11% among subjects with normal values (P=0.005). After adjustments for known risk factors for atrial fibrillation, Sawin showed a relative risk for atrial fibrillation in people with a low TSH of 3.1 compared with those with a normal TSH, and that a TSH <0.1mcu/ml is an independent risk factor for atrial fibrillation.
It has also been suggested that low TSH levels may be related to cardiac hypertrophy. However, the only studies to date have been cross-sectional and included small study groups. In 1996, Ching et al. published a cross-sectional study of heart rate, blood pressure, systolic funtion, and left ventricular chamber size in 11 patients prescribed long term thyroxine suppression therapy after thyroidectomy for differentiated thyroid carcinoma, 23 patients with untreated thyrotoxicosis, and 25 controls (22). All patients on thyroxine had TSH levels in the low-normal or undetectable range (<0.5). No significant difference between pulse and blood pressure between the treated group and controls was detected. The mean ejection fraction was also similar within the three groups. However, a statistically significant increase in interventricular septal thickness and calculated left ventricular mass index in patients treated with thyroxine was observed. The left ventricular mass index was similarly increased in patients with thyrotoxicosis.
Ching, 1996
+thyroxine thyrotoxic controls
n=11 n=23 n=25 P
HR 74 94 76
SBP 116 128 113
EF 66 71 65
IVS(cm) 1.03 0.88 0.84 <0.01
LVMI(g/m2) 101.9 99.3 86.1 <0.01
It was concluded that thyroxine treatment was associated with an 18.4% increase in LV mass index compared with controls, and that the development of LVH in patients without an increase in heart rate, systolic blood pressure or ejection fraction was consistent with a direct trophic effect of thyroid hormone on the myocardium.
Fazio et al. (1995) confirmed in another small, cross-sectional study an increase in LV mass index in patients on TSH suppressive therapy and also found echocardiographic evidence of diastolic dysfuntion, as well as showing a beneficial effect of beta-blockade (23). Fazio studied 25 patients on Synthroid with TSH values <0.05 mcu/ml and 20 control subjects with normal TSH values. Four indices of ventricular filling were determined: 1) maximal early diastolic flow velocity (E, cm/sec); 2)maximal late diastolic flow velocity (A, cm/sec); 3) E/A ratio; and 4) isovolumic relaxation time (ms). Statistically significant differences in all indices of diastolic function are shown below:
Controls Patients
N=20 N=25 P
LV mass index
(g/m2) 80 +/- 18 95 +/- 19 <0.001
Early diast flow
(E, cm/sec) 80 +/- 12 66 +/- 12 <0.001
Late diast flow
(A, cm/sec) 43 +/- 12 53 +/- 10 <0.005
E/A ratio 1.8 +/- .5 1.2 +/- .3 <0.001
Isovol. relax
time(ms) 78 +/- 12 95 +/- 13 <0.001
A subgroup of 10 patients were placed on the beta-blocker bisoprolol for four months and then underwent repeat echocardiogram which demonstrated significant regression of cardiac hypertrophy and improved diastolic dysfunction.
L-T4 L-T4 + bisoprolol P
LV mass index
(g/m2) 111 +/- 21 94 +/- 21 <0.01
E/A ratio 1.13 +/- .2 1.42 +/- .2 <0.01
Isovolum relax
time (ms) 98 +/- 13 86 +/- 7 <0.01
In summary, data from cross-sectional studies show that long-term thyroxine treatment increases myocardial mass and causes diastolic dysfuntion, and that these effects may be improved by beta-blockade. To date, however, there have been no randomized trials to study this.
The other potential complication of long term TSH suppressive therapy is the possibility of decreased bone mineral density. This is a legitimate concern since endogenous hyperthyroidism is a known risk factor for osteoporosis. In 1987, Ross et al. published the first cross-sectional study that showed decreased bone mineral density in women who had taken thyroxine for 10 or more years compared to age-matched controls (24). In the next few years many studies were published which either supported or refuted these findings. In 1996, Uzzan et al. conducted a large meta-analysis of over 41 cross-sectional published studies between 1982 and 1994, that included 1250 patients (25). Uzzan demonstrated a 7% decrease in BMD of the lumbar spine and distal radius, and a 5% decreae in BMD of the femoral neck in postmenopausal women receiving long-term suppression therapy. No significant negative effect was found in premenopausal women or men.
Some evidence exists that estrogen-replacement therapy ameliorates thyroid hormone-associated bone loss in postmenopausal women (26). Schneider, et al. (1994) studied 196 women on long-term thyroid hormone and 795 controls who were enrolled in an osteoporosis study. At the beginning of the study, women were asked about thyroid hormone dose, estrogen replacement therapy, calcium intake, smoking and other factors which might influence BMD. After controlling for these other osteoporosis risk factors, Schneider found that thyroid-hormone users had lower BMD levels that nonusers at four sites; distal radius, midshaft radius, lumbar spine and hip. In the hip, they found a 7.8% decrease in BMD of the hip in patients who were on thyroxine at doses >1.6 ug/kg/day, or greater that standard replacement dose. There was no significant difference between controls and women on lower doses of thyroid hormone. It is important to point out, however, that no TSH measurements were made, which is a major flaw in the study.
When Schneider looked at the effect of oral estrogen replacement therapy on BMD he found women taking estrogen and thyroid hormone had significantly denser bones at all four sites than women taking thyroid hormone without estrogen.
The authors found an 8.1% increase in BMD of the hip in women taking thyroid hormone and estrogen compared to women taking thyroid hormone alone and they asserted that estrogen replacement was protective against any osteoporotic effects of thyroxine. However, if you only study the population of women on estrogen replacement, those on thyroxine did have lower BMD than those not on thyroxine. So, all one can conclude from this is that women on long-term suppresive therapy should definitely be on estrogen replacement, or that postmenopausal patients should be placed on a lower dose of thyroxine if possible.
To date there have been no studies demonstrating an increased rate of bone fractures among patients on thyroxine therapy.
In light of the evidence reviewed above, and given recent concerns about complications of long-term TSH suppressive L-thyroxine treatment, what are some general recommendations for therapy? Remember, the normal range for serum TSH is about 0.5-5 mcu/ml and the lower range of detectability of a third generation assay is 0.01mcu/ml. There is no question that patients with a history of differentiated thyroid cancer need to be on thyroxine suppressive therapy. It has been common practice to place these patients on enough L-thyroxine to suppress their TSH to <0.01mcu/ml. However, in recent years because of the low risk of recurrent thyroid cancer and due to concerns regarding bone and cardiac effects, many clinicians have opted to aim for a TSH measurement below the normal range but still detectable (9). In patients who have had a partial thyroidectomy for benign reasons, it is generally not indicated to place them on prophylactic thyroxine post-op unless they become hypothyroid(17). The exception is in patients with a history of radiation to the neck. In this case, TSH suppressive therapy has been shown to decrease nodule recurrence in any remaining thyroid tissue (18). The exact range of TSH that one should aim for is uncertain. Some authors recommend slightly below normal (0.1-0.5 mcu/ml) and others recommend the low normal range (about 0.5).
Because of a general lack of evidence regarding efficacy and the natural history of many thyroid nodules to spontaneously resolve, most authors no longer advocate TSH suppressive therapy for benign solitary thyroid nodules (3). All new nodules and any nodule that appears to be growing should receive FNA biopsy.
Although the supporting evidence is not great, most authors still recommend a trial of suppressive therapy for some patients with diffuse or multinodular goiter because some patients will get a good response. In general, patients with small or diffuse goiters or goiters which have been present for only a short time will obtain the most benefit from TSH suppression (4,6). Goiters due to autoimmune thyroiditis will also usually decrease in size on thyroxine. However, the majority of such patients will be or become hypothyroid and require thyroxine anyway. Anyone whose baseline TSH is <1 should not be placed on L-thyroxine because they likely have an autonomously functioning goiter, and there is a risk of inducing hyperthyroidism in these patients. Anyone with known osteoporosis or significant risk factors for atrial fibrillation should not have their TSH suppressed below the low-normal range.
The remaining patients with diffuse or nontoxic multinodular goiters can be given a 6 to 12 month trial of thyroxine therapy with the goal of decreasing TSH to 0.1-0.5 mcu/ml. If such patients experience a decrease in goiter size, then the thyroxine dose can be decreased to keep TSH at the low end of the normal range and continued indefinitely. All postmenopausal women given TSH suppressive therapy need estrogen replacement, and some would argue that TSH should not be suppressed below the low end of the normal range in these patients.
TSH Goal
Clinical Situation Generally Indicated (normal 0.5-5)
H/O Thyroid C/A yes Varies with author,
generally <0.5
Post-op after partial no
thyroidectomy only if hypothyroid
Post-op after patial
thyroidectomy w/
H/O neck XRT yes Low normal
(about 0.5)
Solitary nodules no
Diffuse/Nontoxic In some patients Low normal
Multinodular Goiters If TSH > 1 (about 0.5)
There are certain clinical situations in which a trial of L-thyroxine therapy to reduce the size of a nontoxic goiter, or to prevent thyroid nodule recurrence is appropriate. However, randomized controlled trials have shown that this therapy is not as beneficial as preliminary studies of case series had suggested. Randomized controlled trials to study the possible cardiac and skeletal effects are needed. In most cases, clinicians should aim for TSH values in the low normal range.
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