thyroxine suppression therapy in nodular thyroid disease
TRANSCRIPT
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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: None Meds: None NKDA
Soc: No Etoh/tob FH: asthma, DM ROS: 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 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
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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:
– Benign 69%
– Indeterminate 10%
– Malignant 4%
– Nondiagnostic 17%
• 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 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
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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
%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
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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
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
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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
+ 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
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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
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
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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
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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
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
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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.
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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
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)
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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