optimal i therapy of thyrotoxicosis snmmi annual meeting, … · 2019-09-26 · optimal 131i...

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



• 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.



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!



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



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



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



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)”

http://www.annals.org/

http://www.annals.org/

http://www.acponline.org/




• The most important finding should be this:

32

±1

0%

63

±1

8%

37

±7

%

39

±1

0%


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!

optimal i therapy of thyrotoxicosis snmmi annual meeting, … · 2019-09-26 · optimal 131i...

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