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