THYROXINE SUPPRESSION THERAPY IN NODULAR THYROID DISEASE Rhonda Carter, MD Resident Grand Rounds December 15,1998
CASE PRESENTATION HPI: 32 y.o. Indian-American female w/o sig. PMH presented with a complaint of a “lump in her neck” that had been slowly enlarging for one year. Denied history of thyroid disease, dyspnea or dysphagia but was concerned about cosmetic appearance. Denied any hair/skin changes, heat/cold intolerance, weight changes, palpitations or menstrual irregularities. She did have occasional constipation. PMH: None Meds: None NKDA Soc: No Etoh/tob FH: asthma, DM ROS: N/C
Physical Examination Gen: WDWN Indian female, NAD VS: Wt. 138lbs, HR 68, BP 96/60, T98.5, RR 16 HEENT: no exopthalmos or lid lag Neck: diffuse nontender goiter, smooth, approx. twice normal size, no nodules/thrills/bruits Lungs: CTA Heart: RRR w/o MRG Abd: BS+, soft, NTND Ext: no edema Neuro: DTRs 2+ throughout Skin: warm, dry
THYROID FUNCTION TESTS Total thyroxine 7.4 (5.5-11.8) ug/dl Thyroid uptake 24.8 (24-34) % Free thyroxine index 6.1 (4.8-10.3) TSH 2.19 (0.40-5.5) mcu/ml
QUESTIONS • Should this euthyroid patient be given L-thyroxine to suppress her goiter? • In what clinical situations is thyroxine suppression indicated? • Is there any evidence that thyroxine suppression works? • Are there any complications to this therapy? • What are current recommendations regarding duration of therapy and goal TSH levels?
TERMINOLOGY • Thyroxine suppression therapy = • TSH suppressive therapy • administering levothyroxine with the intent to suppress serum TSH levels in an effort to control the growth of abnormal thyroid tissue
NODULAR THYROID DISEASE • Includes solitary nodules and multinodular glands • More common in: • women • elderly patients • history of neck irradiation • areas of iodine deficiency
PREVALENCE • Framingham, Massachussetts, 1950s • >5,000 people studied by National Heart Institute for CAD & HTN • Palpable thyroid nodules found in • 1.5% of men • 6.4% of women • 27% incidence of thyroid nodules by ultrasound • 250,000 new nodules and 12,000 new thyroid malignancies diagnosed each year • 4-5% of nodules are malignant
FINE NEEDLE ASPIRATION • Initial diagnostic test • Simple in-office procedure • Indicated in • all solitary thyroid nodules • dominant nodules within a multinodular gland • suspicion of malignancy • growing nodules
RESULTS OF FNA • Satisfactory • Benign • Indeterminate • Malignant • Unsatisfactory • Nondiagnostic
RESULTS OF FNA • Benign • Benign nodule • Nodular adenomatous hyperplasia • Follicular adenoma • Colloid nodule • Hashimoto’s thyroiditis • Subacute thyroiditis • Cyst
RESULTS OF FNA • Indeterminate • Hurthle cell neoplasm • Follicular neoplasm • Findings suggestive but not diagnostic of malignancy • Malignant • Papillary carcinoma • Medullary carcinoma • Anaplastic carcinoma • Metastatic carcinoma • Lymphoma
Gharib et al., 1993 • Reviewed literature on FNA of thyroid • Pooled data from • seven large patient series • total of 18,183 biopsies • Rates of cytologic diagnoses: • Benign 69% • Indeterminate 10% • Malignant 4% • Nondiagnostic 17% • repeat aspiration yields diagnosis 50%
FNA RESULTS • Patients with malignant aspirates are of course referred to surgery • Patients with indeterminate aspirates have a 30% chance of malignancy and should be referred to a surgeon as well • For patients with benign cytology there are two choices • observation • TSH suppressive therapy
TSH • Reference range 0.5 - 5.0 mcU/ml • Our lab 0.4 - 5.5 mcU/ml • Third generation assays can detect a TSH of 0.01 mcU/ml • Low TSH (0.01 - 0.4 mcU/ml) • Suppressed <0.01 • Replacement dose thyroxine -- 1.6 - 1.7 ug/kg/day • Suppressive dose thyroxine -- >2 ug/kg/day
PATHOPHYSIOLOGY • The theory behind suppressive therapy • TSH regulates both function and growth of thyroid cells • Administering L-thyroxine to suppress TSH will decrease growth of thyroid cells • Other growth factors act on thyroid cells • Growth stimulating immunoglobulins, epidermal growth factor, insulin-like growth factors, interleukin-1, interferon-gamma, transforming growth factor-beta • Mutations of ras oncogenes in benign & malignant nodules • ? TSH increases responsiveness of thyroid to other growth factors
THYROXINE SUPPRESSION THERAPY • Greer and Astwood, 1953 • uncontrolled report of 50 patients treated with thyroid extract • two-thirds experienced regression of their goiters • Lead to widespread clinical use • No randomized trials until 1980s and 1990s
THYROXINE SUPPRESSION THERAPY • Five clinical situations in which thyroxine suppression is used for thyroid disease • Treatment of solitary thyroid nodules • Treatment of diffuse or nontoxic multinodular goiter • Prophylactic post-op therapy after partial thyroidectomy • In patients with history of neck irradiation • In patients with a history of thyroid cancer
SOLITARY THYROID NODULES • Of the few randomized trials studying TSH suppression for nodules, only three have been placebo-controlled and included ultrasound determination of nodule size. • Gharib et al., 1987 • Papini et al., 1993 • La Rosa et al., 1995
Gharib et al., 1987 • First randomized placebo-controlled trial • 53 patients with colloid nodules • 23 received levothyroxine • 25 received placebo • 6 month duration • Nodule volume decreased • from 3.0 ml to 2.5 ml in thyroxine group • from 2.6 ml to 2.4 ml in placebo group • No statistically significant difference (P>0.10) • Study limited by inclusion of cystic & mixed cystic/solid nodules (19%) and short follow-up period
Papini et al., 1993 • 12-month placebo-controlled randomized trial • 101 euthyroid patients with colloid nodules • 51 received thyroxine to suppress TSH to below normal (ave. 0.06) • 50 received placebo • A decrease in nodule size determined by palpation but not by ultrasound (P = 0.82) • 6.2 ml to 5.8 ml -- thyroxine group • 6.2 ml to 6.4 ml -- placebo group • 20% of patients in treatment group had a >50% decrease in nodule size • Only 6% of patients in placebo group had >50% decrease
La Rosa et al., 1995 • Most nodules follicular adenomas or nodular hyperplasia, minority colloid nodules • Randomized controlled trial of 55 patients, 12-month follow-up • 23 received thyroxine, TSH <0.3mcU/ml • Mean nodule volume decreased 3.5-2.1 ml, 40% reduction (P>0.001) • 22 received placebo • Mean nodule volume increased 3.5-3.9 ml (P>0.2) • 9/23 thyroxine group (39%) had >50% decrease nodule size • 0/22 placebo group had >50% decrease nodule size • Then d/c’d thyroxine in treatment group and reexamined 4 months later • 26% increase in nodule volume off therapy
SOLITARY THYROID NODULES Kuma et al., 1994 • Studied fate of untreated thyroid nodules • 134 patients followed for nine years • 43% shrank or disappeared • 23% enlarged • 34% no change
DIFFUSE/MULTINODULAR GOITER • A spectrum of disease • Over time two things happen • diffuse goiters become more nodular • nodules become more autonomous • Hansen et al., 1979 • older nonrandomized study of diffuse goiters • 45 patients given 150 ug L-thyroxine for 12 months • ultrasound determination of thyroid volume • 30% of patients obtained normal size of thyroid • median thyroid volume increased after therapy stopped
Berghout et al., 1990 • Only randomized placebo-controlled trial of TSH suppression on diffuse and multinodular goiters • 26 patients received L-thyroxine • 26 patients received placebo • A positive response was defined as a decrease in thyroid volume of 13% • A positive response was found in • 58% of thyroxine group • 5% of placebo group • Conducted in the Netherlands, an area of borderline iodine sufficiency • Urinary iodide 139 ug/day (150-300ug/day)
POST-OP THYROXINE • Many patients need thyroxine post partial thyroidectomy due to hypothyroidism • For years, many clinicians gave thyroxine post-op to euthyroid patients to prevent goiter recurrence • Bistrup et al, 1994 conducted a prospective study of 100 patients with nine years follow-up • 40 patients received thyroxine • goiter recurrence in 14.5% • 60 patients no treatment • goiter recurrence in 21.8% • P = 0.52
HISTORY OF NECK IRRADIATION • Patients with a history of neck irradiation benefit from prophylactic suppressive therapy following partial thyroidectomy • Fogelfeld et al., 1989, nonrandomized prospective study, 11-yr f/u • 511 patients post partial thyroidectomy for benign disease • all had history of radiation to tonsils/adenoids during childhood • 25/299 (8.4%) recurrent nodules in thyroxine group • 72/201 (35.8%) recurrent nodules in placebo group • P>0.05 • no difference in cancer frequency
HISTORY OF THYROID CANCER • TSH suppression therapy is indicated to decrease recurrence of differentiated thyroid cancer • Papillary and follicular • Initial therapy is surgery • Post-op thyroxine given not only for replacement, but TSH suppression • TSH may serve as a growth factor for residual tumor cells • No randomized controlled trials have been conducted
HISTORY OF THYROID CANCER Mazzaferri, 1987 • large retrospective study of 693 patients • 10-year follow-up period • 17% recurrence rate in thyroxine group • 34% recurrence rate in untreated group (P<0.0006) • Level of TSH suppression needed not known • Some authors keep serum TSH <0.1 for five years post-op • Varies with stage of cancer • TSH <0.1 is within range associated with tissue manifestations of hyperthyroidism
COMPLICATIONS OF SUPPRESSIVE THERAPY • Possible cardiac complications • Atrial fibrillation • Cardiac hypertrophy • Diastolic dysfunction • Possible skeletal complications • Decreased bone mineral density
ATRIAL FIBRILLATION Sawin et al., 1994 • 10-year prospective study • 2007 patients over age 60 in the Framingham Heart Study • Showed increased risk of atrial fibrillation in patients with low serum TSH • Established low serum TSH as an independent risk factor for atrial fibrillation
CARDIAC HYPERTROPHY • Only cross-sectional studies have been done Ching et al., 1996 compared: • 11 patients on thyroxine with TSH values <0.5 • 23 patients with endogenous hyperthyroidism • 25 controls with TSH values in normal range • Showed a statistically significant increase in interventricular septal thickness and left ventricular mass index in thyroxine treated patients • Left ventricular mass index was similarly increased in patients with endogenous thyrotoxicosis
Ching et al., 1996 • Thyroxine treatment was associated with 18.4% increase in LV mass index • ? Development of LVH without increased HR, BP, or EF is secondary to a direct trophic effect of thyroid hormone on myocardial tissue
DIASTOLIC DYSFUNCTION Fazio et al., 1995 • Small, cross-sectional study • Also found echocardiographic evidence of increased LV mass index • Found possible evidence of diastolic dysfunction • Showed a beneficial effect of beta-blockade on thyroxine treated patients • Echocardiograms obtained in • 25 patients on thyroxine with TSH values <0.05mcu/ml • 20 control subjects with normal TSH values
SKELETAL COMPLICATIONS • Long-term TSH suppressive therapy may lead to decreased bone mineral density • Endogenous hyperthyroidism is a known risk factor for osteoporosis • Ross et al., 1987, published a small cross-sectional study showing decreased BMD in patients on thyroxine for 10 or more years • Several other cross-sectional studies either supported or refuted his findings • No randomized-controlled trials
Uzzan et al., 1996 • Large meta-analysis of over 41 cross-sectional studies between 1982 and 1994 • Included 1250 patients • Showed a 7% decrease in BMD of lumbar spine and distal radius and a 5% decrease in BMD of the femoral neck in postmenopausal women on thyroxine therapy • No significant effect was found in men or premenopausal women
Schneider et al., 1994 • Studied 196 women on thyroxine suppression therapy and 795 controls receiving bone mineral density measurements in an osteoporosis study • Controlled for calcium intake, smoking, body mass index and other factors which influence bone mineral density • Thyroxine group had lower BMD levels than controls at four sites.
Schneider et al., 1994 • Decreased BMD in patients on >1.6 ug/kg/day thyroxine at all four sites • 7.8% decrease in BMD in hip • No significant difference in BMD in patients on less than 1.6 ug/kg/day compared with controls • P<0.05 all sites • TSH not measured
Schneider et al., 1994Effect of Estrogen Replacement • Women on estrogen replacement and thyroxine had denser bones at all four sites than women on thyroxine alone (P<0.01) • There was an 8.1% increase in BMD of hip in women taking T4 + E2 compared to T4 alone • However, E2 + T4 had lower BMD than E2 alone • Postmenopausal women on T4 should be on E2 and may need lower thyroxine doses.
SKELETAL COMPLICATIONS No studies have shown an increase rate of bone fractures among patients on thyroxine therapy.
RECOMMENDATIONS FOR THERAPY General guidelines: • Patients with TSH <1.0 should not be placed on thyroxine. • Patients at risk for atrial fibrillation or osteoporosis should not have TSH suppressed below the low-normal range.
CONCLUSION • A trial of L-thyroxine therapy is indicated in certain clinical situations. • Randomized controlled trials to study possible cardiac and skeletal effects are needed. • In most cases, clinicians should aim for TSH values in low normal range.
SPECIAL THANKS • Michael Sollenberger, MD • Ann Feely, MD • Christine Brandon