Download Update On Mgmt Of Graves

Update on the Management of Graves Disease
Fadi Nabhan, MD
Clinical Assistant Professor
Division of Endocrinology
Objectives
 Pathophysiology and Clinical Presentation
 Approach to Diagnosis
 Management
Nabhan
1
Robert Graves
1797-1853
Robert Graves
 “violent and long continued
palpitation in females….in
g of the heart
one the beating
could be heard from distance
from the bed….enlargement
of thyroid gland”
 “ It was observed that….the
eyeballs were apparently
enlarged, so that when she
slept or tried to shut her
eyes, the lids were incapable
of closing”
1797-1853
Nabhan
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Graves Disease
 Classic Triad:
 Thyrotoxicosis
 Goiter
 Eye Disease
Activated
T Cells
+
B
Cells
TSH R Abs
TSH R
Thyroid Follicular Cell
Hyperthyroidism
Hypertrophy
6
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Genetic
Factors
Immune Tolerance
Environmental
Factors
Infection
Iodine Intake
Smoking
Stress
Mechanism of
Disease
Epidemiology
 It affects 0.5% of the population
Brent G. N Engl J Med 2008; 358:2594-2605
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Epidemiology
 It affects 0.5% of the population
 Iodine Sufficient Areas: 50-80%
50 80% of all causes of
Thyrotoxicosis
Brent G. N Engl J Med 2008; 358:2594-2605
Epidemiology
 It affects 0.5% of the population
 Iodine Sufficient Areas: 50-80%
50 80% of all causes of
Thyrotoxicosis
 More Frequent in Women than Men 5:1
Brent G. N Engl J Med 2008; 358:2594-2605
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Epidemiology
 It affects 0.5% of the population
 Iodine Sufficient Areas: 50-80%
50 80% of all causes of
Thyrotoxicosis
 More Frequent in Women than Men 5:1
 Peak in the 5th and 6th decade but can occur at
any age
Brent G. N Engl J Med 2008; 358:2594-2605
Clinical Presentation
Nabhan
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Clinical Presentation
Symptoms
Frequency
Nervousness
80-95%
Palpitation
65-99%
Sweating
50-90%
Heat intolerance
40-90%
Wight loss
50-85%
Dyspnea
65-80%
Fatigue
45-80%
Oligomennorrhea
11%
Increased appetite
10-65%
Diarrhea
10-30%
Menconi et al. Autoimmunity Reviews 13 (2014) 398–402
13
18-32 years
60%
33-44 years
45-60 years
50%
40%
Number
Of 30%
Patients
20%
10%
0-2
Symptoms
3-4
Symptoms
5 or more
Symptoms
Boelaert, K. et al. J Clin Endocrinol Metab 2010;95:2715-2726
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18-32 years
60%
33-44 years
45-60 years
50%
Over 61 y
years
40%
Number
Of 30%
Patients
20%
10%
0-2
Symptoms
3-4
Symptoms
5 or more
Symptoms
Boelaert, K. et al. J Clin Endocrinol Metab 2010;95:2715-2726
Age Related Change in Graves Disease
Hyperthyroid Symptoms
More Common In The
Older
 Weight Loss
 Decreased Appetite
 Atrial Fibrillation
 Depression
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Features of Goiter in Graves Disease
 Diffuse enlargement
 Non nodular
 Bruit
17
Graves Eye Disease
- 50% of patients.
- 3-4% have severe disease.
- Usually occur with
hyperthyroidism or within 6-12
months of that
- Rarely can occur in absence
of hyperthyroidism
Bartalena L, Tanda ML. N Engl J
Med 2009;360:994-1001.
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Dermopathy of Graves' Disease
Graves Dermopathy
Cheng S, Liu C. N Engl J Med
2005;352:918-918
Thyroid Acropathy
Clubbing
Fatourechi et al. J Clin Endocrinol Metab. 2002 Dec;87(12):5435-41.
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Thyroid Acropathy
Soft Tissue Swelling
Periostitis
Fatourechi et al. J Clin Endocrinol Metab. 2002 Dec;87(12):5435-41.
Differential Diagnosis
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Thyrotoxicosis
Exogenous
Thyrotoxicosis
Endogenous
Nabhan
Exogenous
12
Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Struma Ovarri
Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Thyroid
Struma Ovarri
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Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Thyroid
Increased
Release
Struma Ovarri
Thyroiditis
Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Struma Ovarri
Thyroid
Increased
Production
Increased
Release
Thyroiditis
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Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Struma Ovarri
Primary
Thyroid
Increased
Production
Increased
Release
Thyroiditis
Secondary
Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Struma Ovarri
Primary
Thyroid
Increased
Production
Secondary
Increased
Release
Thyroiditis
TSH Producing Tumors
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Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Struma Ovarri
Thyroid
Increased
Production
Primary
Graves Disease
Toxic Nodular Goiter
Iodine Induced
Secondary
Increased
Release
Thyroiditis
TSH Producing Tumors
Laboratory Findings
 Suppressed TSH
 Elevated T4 and/or T3
32
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Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Struma Ovarri
Thyroid
Increased
Production
Primary
Increased
Release
Thyroiditis
Secondary
Graves Disease
Toxic Nodular Goiter
Iodine Induced
TSH Producing Tumors
Thyrotoxicosis
Exogenous
Endogenous
Extrathyroidal
Struma Ovarri
Thyroid
Increased
Production
Primary
Secondary
Increased
Release
Thyroiditis
Graves Disease
Toxic Nodular Goiter
Iodine Induced
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Approach to Diagnosis
Thyrotoxicosis
Typical presentation of Graves disease
No need for further
g
testing
(ATA/AACE Guidelines Bahn R, et al Thyroid 2011; 21:593)
35
Approach to Diagnosis
Thyrotoxicosis
Clinically not diagnostic of Graves
Radioactive Iodine
p
and Scan
Uptake
(ATA/AACE Guidelines Bahn R, et al Thyroid 2011; 21:593)
36
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Thyroid Radioiodine Uptake and Scan
Thyrotoxicosis
HIGH UPTAKE
 Graves Disease
 Toxic Nodular Goiter




Nabhan
LOW UPTAKE
Thyroiditis
Expanded Iodine
Pool
Surreptitious
Thyroid Hormone
g
Ingestion
Ectopic Thyroid
19
Thyrotoxicosis
HIGH UPTAKE
 Graves Disease
 Toxic Nodular Goiter
Graves Disease--Thyroid Scan
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TSH Receptor Antibodies
Graves Disease
Sensitivity
Range
1st generation
3634
79.8 (52.2-94)
2nd generation
1451
96.4 (87-100)
3rd generation
1630
97.2 (95-100)
Tozzoli R. Autoimmun Rev. 2012;12:107–113
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Control
Specificity
Range
2nd generation
ti
1819
98 1 (90
98.1
(90.3-100)
3 100)
3rd generation
1976
99.2 (97.3-100)
Tozzoli R. Autoimmun Rev. 2012;12:107–113
Approach to Diagnosis
Thyrotoxicosis
Clinically not diagnostic of Graves
TSH Receptor
A tib di
Antibodies
OR??
Radioactive Iodine
Uptake and Scan
44
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Clinical Utility of TSH R Abs
 Radioactive Iodine is contraindicated
 Prognostic marker for probability of Remission
with use of antithyroid medication
 In pregnancy as a prognostic marker for fetal
thyroid disease
Barbesino and Tomer. J Clin Endocrinol Metab. 2013;98 (6):2247–2255
45
Thyroid Ultrasound and color flow Doppler
 Hypoechoic
 Color flow Doppler is increased
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Thyroid Ultrasound
Normal Doppler
Graves’ Doppler
Brent G. N Engl J Med 2008; 358:2594-2605
Thyroid Ultrasound and color flow Doppler
 Hypoechoic
 Color flow Doppler is increased
 Should be done to evaluate cold nodules seen
on iodine scan
Nabhan
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Management
Approach to Management
Nabhan
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Approach to Management
C t l off Hyperthyroidism
Control
H
th
idi
Trying to Preserve Thyroid Function
With Aim at Remission
Approach to Management
C t l off Hyperthyroidism
Control
H
th
idi
Trying to Preserve Thyroid Function
With Aim at Remission
Anti Thyroid Drugs
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Approach to Management
C t l off Hyperthyroidism
Control
H
th
idi
Trying to Preserve Thyroid Function
With Aim at Remission
Definitive Treatment of Hyperthyroidism
With Result in Hypothyroidism
Anti Thyroid Drugs
Approach to Management
Nabhan
C t l off Hyperthyroidism
Control
H
th
idi
Trying to Preserve Thyroid Function
With Aim at Remission
Definitive Treatment of Hyperthyroidism
With Result in Hypothyroidism
Anti Thyroid Drugs
Radioactive Iodine
Or
Surgery
g y
27
Antithyroid Drugs
Cooper DS. N Engl J Med 2005;352:905-917.
Actions
 Have been used since 1940s
 Inhibit thyroid hormone synthesis
 They may have clinically important
immunosuppressive effects.
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Antithyroid Drugs
 Which Drug?
 Dose
 Monitoring
 Duration of Treatment
Comparison between PTU and MMI
PTU
MMI
Frequency of
Administration
Twice or three times
daily
Once daily
Compliance
Lower
Higher
Inhibits Conversion
of T4 to T3
Yes
No
58
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Comparison between PTU and MMI Side
Effects
Minor
Agranulocytosis
Hepatic Failure
Vasculitis
PTU
MMI
5-20%
5-20%
0.2-0.5%
0.2-0.5%. Dose
dependent
<0.1%
Cholestatsis
ANCA +
Very rare
59
Comparison between PTU and MMI Side
Effects
Minor
Agranulocytosis
Hepatic Failure
Vasculitis
PTU
MMI
5-20%
5-20%
0.2-0.5%
First 100 days
0.2-0.5%. Dose
dependent
<0.1%
Cholestatsis
ANCA +
Increases with time
Very rare
60
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 Therefore: Always use
Methimazole except
p in limited
situations…..
61
When Can PTU be used?
 PTU is drug of choice in first trimester
(ATA/AACE Guidelines Bahn R, et al Thyroid 2011; 21:593)
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APLASIA CUTIS CONGENITA (Use of
Methimazole)
When Can PTU be used?
 PTU is drug of choice in first trimester
 Treatment of thyroid storm
 Patients who are unable to tolerate MMI due to
minor reactions and refuse to other modalities of
therapy
(ATA/AACE Guidelines Bahn R, et al Thyroid 2011; 21:593)
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Dose
Nakamura H. J Clin Endocrinol Metab. 2007 Jun;92(6):2157-62
Monitoring
 Baseline ling CBC and liver profile
 A baseline absolute neutrophil count
<500/mm3 or liver transaminase enzyme
l
levels
l elevated
l
t d > fivefold
fi f ld the
th upper limit
li it off
normal are contraindications to initiating
therapy
66
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Monitoring
 A differential white blood cell count should be
obtained during febrile illness and at the
onset of pharyngitis
67
Monitoring
 No consensus concerning the utility of
periodic monitoring
g of white blood cell
counts and liver function tests
68
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Monitoring Thyroid Function Tests
 Assess thyroid function tests every 4 weeks until
euthyroid.
 TSH lags behind T4 changes
 Once the patient is euthyroid, check tests every
2-3 months.
69
Duration of Treatment and Probability of
Remission
Cooper DS. J Clin Endocrinol Metab.2003 Aug;88(8):3474-81
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Duration of Treatment and Probability of
Remission
No difference if treatment exceeds 18 months
Cooper DS. J Clin Endocrinol Metab.2003 Aug;88(8):3474-81
Factors that Increase Chance of
Remission
 Disappearance of TSH-receptor antibodies during
therapy
 Mild hyperthyroidism
 Smaller goiter
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How Antithyroid Drugs Are Used
Methimazole
10-30 mg a
day
Taper to
maintenance 510 mg a day
Continue for
about 18
months
Time
73
How Antithyroid Drugs Are Used
Taper further and
then Stop if not
H
Hyperthyroid
th
id
Methimazole
10-30 mg a
day
Taper to
maintenance 510 mg a day
Continue for
about 18
months
OR
Measure Receptor
Abs and stop if
negative
Time
74
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Relapse
Repeat Antithyroid
Drugs
RAI I-131
Surgery
75
Relapse
Repeat Antithyroid
Drugs
RAI I-131
Surgery
May use low dose
Methimazole long
term?
76
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Radioactive Iodine
 It has been used for treatment of
hyperthyroidism for six decades
 Goal is to render patient hypothyroid
78
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Radioactive Iodine Dose
 Administering a fixed activity (10-15 mCi)
OR
 Calculating the activity based on the size of the
thyroid and iodine uptake
79
Radioactive Iodine Dose
 Administering a fixed activity (10-15 mCi)
OR
 Calculating the activity based on the size of the
thyroid and iodine uptake
 Fixed dose is easier and no definitive evidence of
superiority of calculated dose
80
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Success of Radioactive Iodine Treatment
 80-90% after one dose
 Treatment can be repeated at a larger dose in
patients who fail first dose
81
Chances of Success after Radioactive Iodine
 Severity of Hyperthyroidism
 Size of Goiter
Nabhan
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Preparation of Radioactive Iodine
Treatment
 Methimazole should be stopped about 3-7 days
before I 131 Tx.
 Use of B Blocker around the treatment
 Negative pregnancy test within 48 hours of
treatment
83
Post Radioactive Iodine Treatment
 Anti thyroid medication can be restarted in 3-7
days and then taper over 4-6 weeks
 Avoidance of pregnancy for 4-6 months
 Check Thyroid function tests every 4 weeks
84
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Risk of Radioactive Iodine Treatment
 Worsening Hyperthyroidism
85
When to do Pre Treatment with Anti
Thyroid Drugs
 Very symptomatic patient
 Have free T4 estimates 2–3 times the upper limit
of normal
 Elderly and Co morbidities such as
cardiovascular disease
86
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Risk of Radioactive Iodine Treatment
 Worsening Hyperthyroidism
 Eye Disease
87
Changes in the Degree of Ophthalmopathy in Patients with
Hyperthyroidism Who Were Treated with Radioiodine, Radioiodine
and Prednisone, or Methimazole.
Bartalena L et al. N Engl J Med 1998;338:73-78.
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Changes in the Degree of Ophthalmopathy in Patients with
Hyperthyroidism Who Were Treated with Radioiodine, Radioiodine
and Prednisone, or Methimazole.
Bartalena L et al. N Engl J Med 1998;338:73-78.
 This is increased in SMOKERS!
90
Nabhan
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Prevention of Ophthalmopathy around
Radioactive Iodine Treatment
Use of Glucocorticoids
 Prednisone at 0.4–0.5 mg/kg/day (? 0.2 mg/kg
sufficient)
 Started 1–3 days after radioactive iodine
treatment
 Continued for 1 month
 Then tapered over 2 months
Nabhan
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Surgery
Surgery
 Normalize T4/T3 with antithyroid drugs
 Consider using potassium Iodide
 Near-total or total thyroidectomy is the
procedure of choice
 Total thyroidectomy has a nearly 0% risk of
recurrence
Nabhan
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Surgical Complications
 Hypocalcemia (permanent <2%)
 Recurrent laryngeal nerve injury (permanent
<1%)
 Post- operative bleeding
 Complications related to general anesthesia.
95
Approach to Management
Nabhan
C t l off Hyperthyroidism
Control
H
th
idi
Trying to Preserve Thyroid Function
With Aim at Remission
Definitive Treatment of Hyperthyroidism
With Result in Hypothyroidism
Anti Thyroid Drugs
Radioactive Iodine
Or
Surgery
g y
48
Choice of Treatment
I-131
Or
Surgery
Anti
Thyroid
Drugs
High
Low
Probability of Remission
97
Choice of Treatment
Surgery
Compressive Goiter
Severe Eye
Disease?
I-131
High Surgical Risk
98
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PATIENT PREFERENCE!!
99
Pattern of Therapy by Physicians
Survey of Endocrine Society, American Thyroid
Association and AACE Members
730 Respondents
R
d t
ATDs: 53.9%
I-131: 45%
Surgery: 0.7%
Versus a similar study
y in 1991,, there is g
greater use of
ATDs and Lower Use of I-131
Burch HB, Burman KD, Cooper DS. J Clin Endocrinol Metab. 2012 97:4549-4558
100
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Burch HB, Burman KD, Cooper DS. J Clin Endocrinol Metab. 2012 97:4549-4558
101
Potential Future Therapy
Nabhan
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T
Cells
+
B
Cells
TSH R Abs
TSH R
Th
Thyroid
id Follicular
F lli l Cell
C ll
Hyperthyroidism
Hypertrophy
103
T
Cells
+
B
Cells
Rituxumab
TSH R Abs
TSH R
Thyroid Follicular Cell
Hyperthyroidism
Hypertrophy
104
Nabhan
Adopted from Rebecca Bahn Expert Rev Clin
Pharmacol. Nov 2012; 5(6): 605–607
52
+
T
Cells
B
Cells
Rituxumab
Abs block
Binding to
Receptor
TSH R Abs
TSH R
Thyroid Follicular Cell
Hyperthyroidism
Hypertrophy
105
Adopted from Rebecca Bahn Expert Rev Clin
Pharmacol. Nov 2012; 5(6): 605–607
+
T
Cells
B
Cells
Rituxumab
Abs block
Binding to
Receptor
TSH R Abs
TSH R
I
Increased
d c AMP levels
l
l
SML (Small
Molecule Ligand)
Th
Thyroid
id Follicular
F lli l Cell
C ll
Hyperthyroidism
Hypertrophy
106
Nabhan
Adopted from Rebecca Bahn Expert Rev Clin
Pharmacol. Nov 2012; 5(6): 605–607
53
THANK YOU!
107
Nabhan
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