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

%Response/ >50% change

No. of Pts. T4 Placebo Nodule type

Gharib, 1987 53 14 20 Colloid,

Some cystic

Papini, 1993 101 20 6 Colloid

LaRosa,1995 55 39 0 25% colloid

75% foll.aden,

nod.hyperplas

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

Sawin et al., 1994

TSH

No.

subjects % fib 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

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

N = 11

Thyrotoxic

N = 23

Controls

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

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

Fazio et al., 1995

Controls

N = 20

Patients

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 +/- 0.5 1.2 +/- 0.3 <0.001

Isovol. Relax

Time (ms) 78 +/- 12 95 +/- 13 <0.001

Fazio et al., 1995

L-T4 (N = 10)

After 4 months

L-T4+ bisoprolol P

LV mass index

(g/m2)

111 +/- 21 94 +/- 21 <0.01

E/A ratio 1.13 +/- 0.2 1.42 +/- 0.2 <0.01

Isovol. Relax

time (ms)

98 +/- 13 86 +/- 7 <0.01

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

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Dis

t ra

d

Mid

ra

d

Hip

Sp

ine

Controls

<1.6

ug/kg

>1.6

ug/kg

• 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

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Dis

t ra

d

Mid

ra

d

Hip

Sp

ine

-T4/-E2

+T4/-E2

-T4/+E2

+T4/+E2

• 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.

RECOMMENDATIONS FOR

THERAPY

Clinical Situation Generally Indicated

TSH Goal

(normal 0.5-5 mcu/ml)

H/O differentiated thyroid

cancer

Yes Varies with author, stage

Generally <0.5

Post-op after partial

thyroidectomy

No

Only if hypothyroid

After partial

thyroidectomy with h/o

neck XRT

Yes Low normal

(about 0.5)

Solitary nodules No

Diffuse/Nontoxic

Multinodular Goiters

6 – 12 month trial Low normal

(about 0.5)

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