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Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018
Mark Tulchinsky, MD, FACNM, CCD 1
RADIOACTIVE IODINE
THERAPY FOR
HYERTHYROIDISM
Mark Tulchinsky, MD, FACNM, CCD
Professor of Radiology and Medicine
Division of Nuclear Medicine
Penn State University Hospital
I Love What I do, i.e.
Nuclear Medicine …
No other relevant disclosuresor conflicts of interest
• Treatment Options• Medications• Surgery• 131I Treatment (RAIT)
• Graves’ Disease w/o Orbitopathy• Graves’ Disease with Orbitopathy• Toxic Adenoma• Multinodular Toxic Goiter• Intermittent (recurrent) Thyroiditis• Amiodarone Thyrotoxicosis
Learning ObjectivesRadioactive Iodine (RAI)
Administration for Graves’ Disease: Birthplace of
RadiotheranosticsSaul Hertz, M.D.
(April 20, 1905 – July 28, 1950)
• The first to study RAI in an animal model of hyperthyroidism
• March 31st, 1941, at the age of 35 y, administered the first RAI treatment (RAIT) to a patient with Grave’s disease
• The first to use RAI uptake to inform RAIT, i.e. radiotheranostic principle
Conditions Amenable to RAIT
Condition Etiology
Graves’ disease (~80%) TSH-R-Ab stimulation of thyrocyte
Toxic Multinodular Goiter
Toxic Adenoma
mutation → TSH-R-Ab activation →
autonomous function
Hashimoto’s Thyroiditis in
productive phase (“Hashi-
toxicosis”, overlaps Graves’)
autoimmune disease - a variety of
cell- and antibody-mediated
immune processes
Intermittent/recurrent Thyroiditis* Unknown
Amiodarone thyroiditis Multifactorial
Abbreviations: TSH-R-Ab = thyroid stimulating hormone
receptor autoantibobdy, RAIT = RAI treatment
*RAIT in recovery phase, prevents recurrences
Therapeutic Options for Productive Hyperthyroidism
• Antithyroid Drug therapy (ATDT)
Symptomatic control with beta blockers
Thioureas, aka Thionamides, Anti-
Thyroid Drugs (ATD’s)
Corticosteroids
Stable Iodine (SSKI, etc.)
Rituximab
• Radioactive Iodine Treatment (RAIT)
Alone or with adjuncts (steroids ± other DT)
• Surgery
Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018
Mark Tulchinsky, MD, FACNM, CCD 2
• ATD’s divert oxidized iodide away from thyroglobulin, effectively ceasing thyroid hormone biosynthesis
Inhibition of hormone synthesis depletes
existing stores of iodinated thyroglobulin as
the protein is hydrolyzed and hormone
released, depleting thyroid hormone stores
• ATD’s bind intrathyroidal iodide and facilitate its clearance from the thyroid, depleting thyroid iodine content
• PTU inhibits peripheral T4 to T3 conversion
X = the site of biochemical block by thioureas
PTU & MZ PTU & MZ
Hyperthyroidism Drug TherapyThioureas: Propylthiouracil (PTU) & Methimazole (MZ)
ATD’s do NOT
block I- trapping
Hyperthyroidism Drug TherapyPropylthiouracil (PTU) & Methimazole (MZ)
Major Minor
Rare (0.2%–0.5%) Common (1%–5%)
Agranulocytosis Urticaria or other rash
Very rare (<0.1%) Arthralgia
Thrombocytopenia Fever
Aplastic anemia Transient granulocytopenia
Vasculitis, lupus-like syndrome Uncommon (<1%)
Hypoglycemia (anti-insulin Ab) (MZ) Gastrointestinal upset
Cholestatic hepatitis (MZ) Abnormalities of taste and smell
Fulminant hepatitis (PTU) Arthritis
Hypoprothrombinemia (PTU)
Disadvantages of RAIT When Compared to Long-term ATDT:
Realizations of 1990’s and 2000’s
• RAI may induce or worsen Graves’ Orbitopathy (GO) in 15-33%
• RAIT practice not standardized with erratic clinical & biochemical outcomes
Euthyroid goal (Eu-RAIT)
multiple, fixed or calculated SMALL activities
Hypothyroid goal (Ablation)
Fixed activity (15 mCi), over & under treat a lot
Radiation dose to thyroid, prolonged dosimetry
Activity per g of thyroid, simple & fewest failures
The Thyrotoxicosis Therapy Follow-up Study,
assembled in 1961, comprises 35,000 subjects
treated for hyperthyroidism at over 20 medical
centers in the US and 1 in the UK between 1946
and 1964. This is the largest group of
hyperthyroid patients that has been followed up
for subsequent cancer and other health outcomes.
Thyrotoxicosis Therapy Follow-up Study 1946-1964 Typical Approach to GD in the USA:First Decade of 21st Century
• ATD ± beta blocker for 1-2 years
• Stop therapy to check for remission
• If no remission or patient recurs after short remission → RAIT or Surgery
• Eu-RAIT used in early days, ablation became dominant after 2005 study that showed mortality advantage*
• No standardization of hypo-RAIT technique, approaches vary widely
* Franklyn JA, Sheppard MC, Maisonneuve P. Thyroid function and mortality in
patients treated for hyperthyroidism. JAMA. 2005;294:71-80.
Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018
Mark Tulchinsky, MD, FACNM, CCD 3
Abbreviation: MMI = Methimazole
RAIT n=102 pts MMI n=114 pts
Reviewed
15 mCi
RAIT group
MZ group
Worsened
Unchanged
Improved
Between 1995 and 2013,
Brazil (Campinas & São Paulo):
Villagelin, D. et al. Outcomes in Relapsed
Graves' Disease Patients Following
Radioiodine or Prolonged Low Dose of
Methimazole Treatment. Thyroid 2015.
DOI: 10.1089/thy.2015.0195
What NM Docs Should Know?
• Be proactive in confronting GO concerns
Post RAIT Hypothyroidism→ minimize
Practice RAIT that has predictable outcome
Guide referring about timing for TH replacement
Selective steroid prophylaxis
• Be proactive in improving symptoms before, during, and after RAIT
Pre-treat with ATDT, beta blockers
• Good practice – offer consultation service
• Best practice – offer to consult and manage patients after RAIT
Pre-RAIT Work-Up:99mTcO4
− Scan + 24-Hr 131I Uptake
99mTcO4- Thyroid Uptake =
2.45% (Normal 0.36-1.6%)
-Anterior Anterior
RAO LAO
Chin
SSN
24-Hr 131I uptake = 43%Mild (Early) Graves’ Disease
Document Etiology
Measure Uptake:
±4 Hr. & 24 Hr.
Dominant Cold Nodule?
Document Benign Cause!
Educate Patients (and Referring Doctors) About RAIT at Consultation
• Minimized dietary (LID) and medical Iodine
• Go over radiation precautions, pt. should come for RAIT unescorted, etc.
• Assure pts. – they will leave the facility generally feeling the same as on arrival
• Review meds, provide guidance (monitor HR for beta blocker adjustments, etc.)
• Explain RAIT comes as a capsule (pediatric cap. or liquid, if swallowing difficulties)
• It doesn’t cause nausea – but expectation and/or nervousness sure could!
Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018
Mark Tulchinsky, MD, FACNM, CCD 4
RAIT for ThyrotoxicosisGeneral Considerations
• Absolute contraindication – Pregnancy and other*, document pregnancy test results
• Treating a very toxic patient may result in thyroid storm – pretreat with MZ (4-6 wks.)
• Stop ATD’s for 2 d. (48 hrs), start uptake day 3, measure uptake, scan & RAIT day 4
• Beta-blocker can be continued, HR guided
• Re-starting ATDT post-RAIT, optional
• Iodine (lithium) loading post-RAIT is optional, practiced rarely
*Contraindications: pregnancy, lactation, known or suspected thyroid
cancer, individuals unable to comply with radiation safety guidelines.
HYPERTHYROIDISM:TREATMENT GOAL
• RAIT Goals
Euthyroidism – futile in Graves’ & hypothetically may
increase carcinogenic risk – not recommended
Ablation – predictable, time-saver for pts & dead cells
don’t turn cancerous – recommended (1)
• Approach to Ablation
Fixed dose (15 mCi) – simple, but not as predictable
Radiation dose (cGy) based – multiday dosimetry makes
it impractical, simplified is same as below
Delivered activity per g of thyroid, normalized to 24hr
uptake – simple, practical and rational
1. Bahn RS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management
guidelines of the American Thyroid Association and American Association of Clinical
Endocrinologists. Endocr Pract 2011;17:456-520.
Relationship between thyroid radiation dose and hypothyroidism rate in patients who were <18 years old
Scott A. Rivkees, et al. Influence of iodine-131 dose on the outcome of hyperthyroidism
in children. Pediatrics 2003;111:745-749.
Grave’s Disease RAIT:mCi/g of Thyroid @ 24 hrs.
• Most give 0.12-0.20 mCi of 131I/g of thyroid, normalized to 24 hr. uptake
• Ablation activity (AA) coefficient at PSU is 0.24 mCi/g (developed empirically)
• AA = (gland weight in g x 0.24 mCi/g) / 24 hr. uptake fraction (i.e. 0.5 for 50% uptake)
• Gland weight: cannot palpate it for sure – 30 g; can palpate, but cannot see it – 40 g; can see it when pt. walks in – ≥ 60 g
• “Fudge Factor” – give more to pts. who are older, on anti-thyroid meds, MNG, severe HT, rapid 131I turnover, larger glands
Response to 131I Therapy in Graves’:0.24 mCi per gm of Thyroid
(PSU Experience)
75 30025
Treatment Complications: Early
• Typically None
• Thyroiditis (sore throat) is the most common 1:40
Occurs 1-3 days post therapy
Rarely needs medication
Responds well to NSAIDs
Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018
Mark Tulchinsky, MD, FACNM, CCD 5
Treatment Complications: Early
• Exacerbation of thyrotoxicosis (~1%)
Rare in ATD-pretreated, self limited
Increase/start β-blockers and ± ATD’s
• Thyroid storm (0.3%) – ATD pretreatment diminishes risk
Key manifestation is fever
Mean time to onset 6 days
Treatment of the thyroid storm:
Thermoregulation, physiologic support
Iodine (30 drops of SSKI a day)
PTU (900-1200 mg a day)
β-adrenergic blockade (propranolol, atenolol, etc.)
Late Complication of RAIT
• Ageusia – water swish/swallow after RAI
• Very Rare complications –Sialadenitis/Xerostomia
• Hypoparathyroidism is extremely rare
• Hyperparathyroidism (parathyroid adenoma) – questionable relation to 131I
• There is no evidence of increased secondary primary malignancy incidence
• No evidence of congenital defects
Avoid conception for 6-12 months
Graves’ Orbitopathy (GO), akaGraves Ophthalmopathy, Thyroid-Associated Orbitopathy
(TAO), Thyroid Eye Disease (TED)
Progression is the
natural course of GO
Clinical Incidence: ~ 20% of GD
Imaging Reveals: > 60% of GD
Severe in ≤ 5%
Predisposing factors:
Smoking
Older age
Male sex
Diabetes
Hypothyroidism after RAIT
1 year
What Do We Know About Risk of GO as Relevant to Therapy of GD?
• Known risk factors = remove whichever possible, i.e. smoking, post RAIT TSH elevation/hypo (replace early)
• Higher the T3, the greater GO occurrence-progression probability for all treatments (especially for RAIT) = pretreat with ATD’s
• Higher the TSH-R-Ab & inflammation in thyroid, the greater GO risk => suppress autoimmune response with steroids
• GO progression after RAIT starts early => preventive measures must start early
Initial Experience: Basics
Tallstedt L, et al. Occurrence of ophthalmopathy after treatment for Graves'
hyperthyroidism. The Thyroid Study Group. N Engl J Med. 1992;326:1733-1738.
RAI Group – 39 pts, initial dose
120 Gy → 13/39 worsening / de
novo GO, 18/39 were given more
than 1 dose, 12/18 developed
worsening (10) or de novo (2) GO
Lesson 1: “Gentle” RAIT is
rough on the eye! Ablate
with single administration!
>1RAIT, 67% → ↑GO
1 RAIT, 5% → ↑GO
2011 Survey of Clinical Practice Patterns in the Management of Graves' Disease
J Clin Endocrinol Metab. 2012;97(12):4549-4558. doi:10.1210/jc.2012-2802
Case Presentation
without GO
Case Presentation
with mild GO
Choice of Primary Treatment in GD
Abbreviations: GD = Graves’ disease; CS = corticosteroids
Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018
Mark Tulchinsky, MD, FACNM, CCD 6
Grading Exophthalmos
• No signs of GO
• Mild GO (no proptosis, but has some inflammatory scleral redness, etc.
• Mod. GO: proptosis 21 - 24 mm
• Severe GO: proptosis > 24 mm
If any sign of GO –
refer to ophthalmology
for exophthalmometry
Prevention of Post-RAIT GO:Three-tier, Risk-adjusted Approach
• No GO findings, no risk factors → no prophylaxis
• No GO findings or Mild GO, + risk factor(s)
Prednisone 0.2 mg/kg/d, tapered over the 4-5
weeks, starting on the day of RAIT
• Mild to Moderate GO, + risk factor(s)
Prednisone 0.4-0.5 mg/kg/d, tapered over 3
months, starting on the day of RAIT
• Moderate to Severe GO → no RAIT
Shiber S, et al. Glucocorticoid regimens for prevention of Graves' ophthalmopathy
progression following radioiodine treatment: systematic review and meta-analysis.
Thyroid. 2014;24:1515-1523. DOI: 10.1089/thy.2014.0218
Autonomously Functioning Solitary Thyroid Nodules
• They are 7 - 16 times more common among women and can occur at any age
• True adenoma, colloid nodules or local hyperplasia. Up to 4% may harbor occult cancer that is of doubtful clinical significance
• Nontoxic (euthyroid) or toxic (usually mild)
• Usually 1 - 3 cm in diameter, can enlarge quickly if internal hemorrhage occurs
≤2 cm size usually doesn’t make enough TH to
cause hyperthyroidism or suppress normal thyroid
At ~ 2.5 cm extra-nodular thyroid tissue function is
suppressed, ± subclinical hyperthyroidism
At ~ 3 cm hyperthyroidism is expected
RAIT of Autonomous Solitary Toxic Nodules
• An ideal case for 131I treatment. The normal tissue is suppressed and endogenously protected
• Formerly, 30-60 mCi doses were used, which resulted in high incidence of needless hypothyroidism
• Usually, a 160-240 µCi/gm dose is administered (about 10 mCi on average)
• Expect euthyroidism in 91% by 6 months, and 93% by 1 year. 7% may need more than one dose. Hypothyroidism would be very unusual.
• If a nodule edema is a concern (compression), TU pre-treat and/or administer steroids and/or recommend surgery.
RAIT of Multiple Autonomous Toxic Nodules: Multinodular Goiter
• Somewhat more resistant to 131I treatment.
• The dose is greater than for Graves’, 30 mCi dose is usually given (fudge factors –thyroid weight & uptake)
• The hypothyroidism is less common following the treatment
Functioning nodules get ablative dose, then
spared suppressed tissue becomes active, it
may provide adequate euthyroid function
• Poor iodine uptake is common and may require stimulation or higher 131I activities
Multiple Hyper-Functioning Nodules – Toxic Multinodular Goiter
Anterior with Markers Anterior
Chin
SSN
24 hrs. 131I uptake = 38%
Treated with 30 mCi, euthyroid 1 year later
Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018
Mark Tulchinsky, MD, FACNM, CCD 7
Toxic Multi-Nodular Goiter on US with Low 131I Uptake
24 hrs. 131I uptake = 10.5%
Anterior
Could this gland
with low 131I
uptake be
ablated?
Yes, if it is
stimulated first!
What was the uptake stimulant?
4 weeks of Methimazole (MZ), stopped for 2 days,
uptake capsule, day 3 measured/scanned/RAIT-ed
Anterior
24 hrs. 131I uptake = 58%
Huysmans, MD et al. Large, Compressive Goiters Treated with Radioiodine.
Ann Intern Med. 1994;121(10):757-762. doi:10.7326/0003-4819-121-10-199411150-00005
Patient 17 before (A) and 1 year (B) after treatment with 5.6 GBq (150 mCi) of Iodine-131. Note the
distended neck veins and edematous face as signs of compression of the superior vena cava before
therapy (A) and their improvement 1 year after therapy (B). Published with permission of the patient.
Copyright © American College of Physicians. All rights reserved.
Thioureas for minimum of 4 wks.
Day 0
Stop
Thiourea
Drug
Day 1 Day 2
Start
Uptake
Day 3
I-131
Dose
Thyroid Uptake Stimulation:Thioureas Pre-Treatment
PSU Experience
All 19 patients, 100%, were cured from
hyperthyroidism in pre-treated patients.
70.5% of control group patients were cured.
The difference was statistically significant.
Tulchinsky, M. et al. Stimulating Low Uptake Multinodular Goiter with Anti-thyroid
Drugs Prior to I-131 Therapy: A Better Therapeutic Response? Abstract Presented at
2002 SNM Annual Meeting.
Uptake (24 hr) Improvement Following Stimulation
80%
70%
60%
50%
40%
30%
20%
10% 13.8%
43.6%
Tulchinsky, M. et al. Stimulating Low Uptake Multinodular Goiter with Anti-thyroid
Drugs Prior to I-131 Therapy: A Better Therapeutic Response? Abstract Presented at
2002 SNM Annual Meeting.
ATD’s pre- and post-RAIT
• Discontinuation of ATD’s for 2 days after ≥2-3 mo. of treatment or pre-treatment
Boosts RAIU, especially important in MNG
with low baseline uptake
• Kyrilli A, Tang BN, Huyge V, et al. Thiamazole Pretreatment Lowers the (131)I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J ClinEndocrinol Metab 2015;100:2261-2267.
24-hr
RAIU (%)
42d. on/3d. off ADT LID
32±10* 63±18 37 ±7* 39 ±10* Baseline - before intervention
Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. Thiamazole Pretreatment Lowers the 131I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J Clin Endocrinol Metab, June 2015, 100(6):2261–2267
• Included: 22 pts with MNG, subclinical HT, RAIU < 50%, no compressive symptoms, random group assignment:
10 pts low iodine diet (LID) group (age 70.7±7 y, 8 F)
12 pts Thiamazole (MTZ) group (age 66.5±14 y, 10 F)
MTZ continued for 42 d, stopped for 3 days before
start of RAIU re-measurement
• Authors: “The MTZ-enhanced RAIU led to a 31% decrease in the required median 131I activity needed to treat the patients, from 16.0 mCi (Interquartile range: 12.3–34.5) at baseline to 11.0 mCi (Interquartile range: 8.3–14.0) after treatment (p<0.001)”
Optimal 131I Therapy of Thyrotoxicosis SNMMI Annual Meeting, 6/26/2018
Mark Tulchinsky, MD, FACNM, CCD 8
Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. Thiamazole Pretreatment Lowers the 131I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J Clin Endocrinol Metab, June 2015, 100(6):2261–2267
• The most important finding should be this:
32
±1
0%
63
±1
8%
37
±7
%
39
±1
0%
Aglaia Kyrilli et al. and Rodrigo Moreno-Reyes. Thiamazole Pretreatment Lowers the 131I Activity Needed to Cure Hyperthyroidism in Patients With Nodular Goiter. J Clin Endocrinol Metab, June 2015, 100(6):2261–2267
Stimulation with Recombinant Human Thyroid-Stimulating Hormone (rhTSH)
• Single dose of 0.01 – 0.03 mg IM
• Iodine is given 24 hours later
• Uptake improves by about 2 fold
• Pros
Quick prep
• Cons
High prevalence of HT CV side effects
High Cost
This is not an FDA approved use of rhTSH
Romao R, et al. High prevalence of side effects after recombinant human thyrotropin-
stimulated radioiodine treatment with 30 mCi in patients with multinodular goiter and
subclinical/clinical hyperthyroidism. Thyroid 2009;19:945-51.
Amiodarone-Induced Thyrotoxicosis (AIT):Type 2, Normalized off Amiodarone
• n = 15 pts, withdrawal period, 5-147 (33±34) mo., all had RAIU > 10% @24hrs
• Aim, prevent recurrent AIT All euthyroid before RAIT
• I-131, 10-20 (15.6±5) mCi
• Outcome, 14 hypo- and 1 euthyroid
• Early, mild hyper in 2 pts
• Amiodarone reintroduced in 14 pts
• 12 pts had arrhythmia controlledHermida JS, Jarry G, Tcheng E, et al. Radioiodine ablation of the thyroid to allow the
reintroduction of amiodarone treatment in patients with a prior history of amiodarone-
induced thyrotoxicosis. Am J Med. 2004;116:345-348.
Amiodarone-Induced Thyrotoxicosis (AIT):Type 2, on Amiodarone
• n = 4 pts, only 1 was withdrawn, RAIU <4% @24hrs
• Aim – ablation. All thyrotoxic at RAIT
• Thyroid volume by Ultrasound, 1 g/mL → g
• RAI activity, 0.08 mCi/g/24hr-RAIU-ratio
• I-131: 29, 35, 50, 80 mCi
• Outcome, 3 hypo- and 1 euthyroid
Gursoy A, Tutuncu NB, Gencoglu A, Anil C, Demirer AN, Demirag NG. Radioactive
iodine in the treatment of type-2 amiodarone-induced thyrotoxicosis. J Natl Med Assoc.
2008;100:716-719.
Conclusions:
• RAIT is safe and effective initial therapy for hyperthyroidism, including Graves’ disease, multi-nodular toxic goiter, etc.
• RAIT has lower mortality than ATD
• RAIT induced Graves’ Orbitopathy is preventable
• RAIT is effective and safe in reducing the size of toxic and substernal goiter, but it may require iodine uptake stimulation
• The most cost-effective and the safest stimulation maneuver to raise RAIU is thioureas pre-treatment
Thank you for your attention!