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THYROXINE SUPPRESSION THERAPY IN NODULAR THYROID DISEASE PowerPoint PPT Presentation


THYROXINE SUPPRESSION THERAPY IN NODULAR THYROID DISEASE. Rhonda Carter, MD Resident Grand Rounds December 15,1998. CASE PRESENTATION.

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THYROXINE SUPPRESSION THERAPY IN NODULAR THYROID DISEASE

Rhonda Carter, MD

Resident Grand Rounds

December 15,1998


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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: NoneMeds: NoneNKDA

Soc: No Etoh/tobFH: asthma, DMROS: N/C


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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


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THYROID FUNCTION TESTS

Total thyroxine7.4 (5.5-11.8) ug/dl

Thyroid uptake24.8 (24-34) %

Free thyroxine index6.1 (4.8-10.3)

TSH2.19 (0.40-5.5) mcu/ml


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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?


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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


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NODULAR THYROID DISEASE

  • Includes solitary nodules and multinodular glands

  • More common in:

    • women

    • elderly patients

    • history of neck irradiation

    • areas of iodine deficiency


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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


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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


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RESULTS OF FNA

  • Satisfactory

    • Benign

    • Indeterminate

    • Malignant

  • Unsatisfactory

    • Nondiagnostic


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RESULTS OF FNA

  • Benign

    • Benign nodule

      • Nodular adenomatous hyperplasia

      • Follicular adenoma

      • Colloid nodule

    • Hashimoto’s thyroiditis

    • Subacute thyroiditis

    • Cyst


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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


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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:

    • Benign69%

    • Indeterminate10%

    • Malignant 4%

    • Nondiagnostic17%

      • repeat aspiration yields diagnosis 50%


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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


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TSH

  • Reference range 0.5 - 5.0 mcU/ml

  • Our lab0.4 - 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


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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


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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


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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


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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


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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


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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


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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


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SOLITARY THYROID NODULES


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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


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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


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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)


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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


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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


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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


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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


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    COMPLICATIONS OF SUPPRESSIVE THERAPY

    • Possible cardiac complications

      • Atrial fibrillation

      • Cardiac hypertrophy

      • Diastolic dysfunction

    • Possible skeletal complications

      • Decreased bone mineral density


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    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


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    Sawin et al., 1994


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    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


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    Ching et al., 1996


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    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


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    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


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    Fazio et al., 1995


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    Fazio et al., 1995


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    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


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    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


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    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.


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    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


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    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.


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    SKELETAL COMPLICATIONS

    No studies have shown an increase rate of bone fractures among patients on thyroxine therapy.


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    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.


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    RECOMMENDATIONS FOR THERAPY


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    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.


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    SPECIAL THANKS

    • Michael Sollenberger, MD

    • Ann Feely, MD

    • Christine Brandon


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