1. Vahab Fatourechi MD Mayo Clinic College of Medicine
Highlights of 2016 American Thyroid Association Hyperthyroidism Guidelines
Vahab Fatourechi MD
Mayo Clinic College of Medicine
Isfahan 2017

4. Points from Previous 2011 Guidelines
For Graves disease if radioactive iodine or surgery is chosen the goal should be hypothyroidism
Methimazole (MMI) is antithyroid drug of choice except for first 3 months of pregnancy
PTU should be used if needed in the first 3 months of pregnancy and switched to MMI in second trimester

5. From 2011 guidelines
Patients with overt Graves’ hyperthyroidism should be treated with any of the following modalities: radioactive iodine, antithyroid medication, or thyroidectomy.

6. Past Trends in the Management of Graves’ Disease in US
1% Surgery
22%
PTU
7% MMI
69% RAI Index case
Solomon B et al J Clin Endocrinol Metab 70:1518

7. Shift Away from RAI Therapy of GD in US
Differences in diagnosis and management of Graves disease in Europe ;’ Japan and United States
Wartofsky et al Thyroid , 1991
Survey of practice priorities in management of Graves disease.
Burch et all JCEM 1012
Anti thyroid drugs- the most common treatment in the United States : a nationwide population based study
Brito et al Thyroid ; Aug 2016

8. Points from Previous Guidelines
Low dose MMI is acceptable for long term therapy of any type of persistent hyperthyroidism in individuals with reduced life expectancy
Most side effects of antithyroid therapy occur in the first 3 months – vasculitis can happen later
MMI has lower side effects than PTU
PTU not to be used in children
Block and replace with T4 not recommended r

9. Ross et al, Thyroid : October 2016
2016 American Thyroid Association Guidelines for Diagnosis and management of Hyperthyroidism
Ross et al, Thyroid : October 2016

10. Thyrotoxicosis Associated with a Normal or Elevated RAI
Graves’ disease (GD)
Toxic adenoma (TA) or TMNG
Trophoblastic disease
TSH-producing pituitary adenomas
Resistance to thyroid hormone (T3 receptor b mutation,THRB)

11. Thyrotoxicosis Associated with a Near-absent RAI Uptake
Painless (silent) thyroiditis
Amiodarone-induced thyroiditis
Subacute (granulomatous, de Quervain’s) thyroiditis
Palpation thyroiditis
Iatrogenic thyrotoxicosis
Factitious ingestion of thyroid hormone
Struma ovarii
Acute thyroiditis
Extensive metastases from follicular thyroid cancer

12. Diagnosis Strong recommendation, moderate-quality evidence
The etiology of thyrotoxicosis should be determined. If the diagnosis is not apparent based on the clinical presentation and initial biochemical evaluation, diagnostic testing is indicated and can include, depending on available expertise and resources, (1) measurement of TRAb, (2) determination of the radioactive iodine uptake (RAIU), or (3) measurement of thyroidal blood flow on ultrasonography. A 123-I or 99mTc pertechnetate scan should be obtained when the clinical presentation suggests a TA or TMNG.

13. Diagnosis
My take:
I obtain a 4 hour or a 24 hour RAI uptake this helps me for diagnosis also for planning for RAI therapy.
I obtain TRAb for prognostic and diagnostic purposes (usually not TSI-more expensive and delayed report)
I do office US to exclude associated nodules that may change management

14. Diagnosis-My take 95 % of clinical GD will have positive TRAB
severity of hyperthyroidism is proportional to level of TRAb , level of RAI uptake and vascularity of thyroid on US
In subclinical mild disease only RAI uptake not being near –absent will help
Very low or absent thyroid blood flow suggests thyroiditis and helpful in particular in Type 2 amiodarone induced hyperthyroidism

15. TSH Receptor Antibody Measurement in Graves Disease (GD)
RECOMMENDATION 21
Measurement of TRAb levels prior to stopping ATD therapy is suggested because it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission.
Strong recommendation, moderate-quality evidence.

16. Antithyroid therapy of Graves Disease (GD)
RECOMMENDATION 22 If MMI is chosen as the primary therapy for GD, the medication should be continued for approximately 12–18 months, then discontinued if the TSH and TRAb levels are normal at that time.
Strong recommendation, high-quality evidence.

17. Weak recommendation Antithyroid Therapy of Graves Disease (GD)
If a patient with GD becomes hyperthyroid after completing a course of MMI, consideration should be given to treatment with RAI or thyroidectomy. Continued low-dose MMI treatment for longer than 12–18 months may be considered in patients not in remission who prefer this approach.
Weak recommendation

18. Continuous Long term MMI therapy of Graves Disease - Iranian Study
Randomized study 104 patients
10 year follow up
MMI was safe
MMI was cheaper
Azizi et al Eur J Endocrinol 2005

19. Continuous Long term MMI therapy of Graves Disease - Iranian Study
N=239 GD
59 MM MMI doses of 2.5–10 mg/d, 71 RAI and T4 therapy
14 yrs. F/U
MMI group did better in neuropsychiatric tests
MMI was safe and effective for the control of GD in 59 patients: Conclusion: MMI group did better in mood and cardiac condition
Azizi et al Arch Iran Med ,Aug 2012

20. Long Term ATD Therapy
A retrospective analysis compared long-term outcomes (mean follow-up period of 6–7 years) of patients who had relapsed after a course of ATDs, who were treated with either RAI and levothyroxine or long-term ATD therapy: Those patients treated with RAI (n = 114) more often had persistent thyroid eye disease, than patients receiving long-term ATD:
Villagrelin et al thyroid 2015

21. Long-term ATD
My take:
Factors that would favor definitive therapy at the end of 18 months are:
Large thyroid size, very high levels of TRAb, patient preference, women planning to get pregnant, choosing surgery if there is severe ophthalmopathy(GO), consideration of other medical problems, consideration of long term follow up possibilities

22. Calcium and Vitamin D assessment
RECOMMENDATION 25
Calcium and 25-hydroxy vitamin D should be assessed preoperatively and repleted if necessary, or given prophylactically. Calcitriol supplementation should be considered
preoperatively in patients at increased risk for transient or permanent hypoparathyroidism.
Strong recommendation, low-quality evidence.

23. Stable Iodine Therapy for Graves Disease
RECOMMENDATION 36
Potassium iodide may be of benefit in select patients with hyperthyroidism due to GD, those who have adverse reactions to ATDs, and those who have a contraindication or aversion to RAI therapy (or aversion to repeat RAI therapy) or surgery. Treatment may be more suitable for patients with mild hyperthyroidism or a prior history of RAI therapy.
No recommendation; insufficient evidence to assess benefits or risks.

24. Stable Iodine Therapy of GD
Among 44 Japanese patients who had adverse reactions to ATD and who were treated with KI alone, 66% were well
controlled for an average of 18 years (range 9–28 years), and 39% achieved a remission after 7 years (range 2–23 years).
Among the responders, the doses used were between 13 and 100 mg and were adjusted depending upon biochemical
response

25. Stable Iodine Alone Therapy for GD
Among 15 non responders, 11 (25% of all
patients) escaped the inhibitory effects of iodine and four patients did not respond at all to KI. None of the patients had side effects.
Ocamura et a JCEM. 2014

26. Stable Iodine for GD My take;
It is unlikely that long term stable iodine therapy will be adopted in practice although it can be used as a bridge in some cases for longer period than the usual

27. Alternative Therapies for Toxic Nodular Goiter
RECOMMENDATION 57
Alternative therapies such as ethanol or radiofrequency ablation of TA and TMNG can be considered in select patients in whom RAI, surgery, and long-term ATD are
inappropriate, contraindicated, or refused, and expertise in these procedures is available.
No recommendation; insufficient evidence to and risks.

28. Radiofrequency (RFA) Ablation for Toxic nodular Goiter
A meta-analysis demonstrated that RFA resulted in larger reductions in nodule size with fewer sessions than laser therapy: Ha el et al JCEM ,2015
A retrospective multicenter report of RFA for TA in 44 patients with a mean follow-up of 20 months . An 82% reduction in nodule volume was achieved, but 20% of nodules remained autonomous on scintigraphy, and 18% of patients remained hyperthyroid. there were no complications:
Sung JY et al Thyroid , 2015.

29. Radiofrequency (RFA) Ablation for Toxic nodular Goiter
A Korean study compared the use of RFA to surgery for nontoxic nodules. RFA was associated with an 85% reduction in nodule size, no patient who received RFA became hypothyroid: Che Y et al Am J neuro Radiol 2015.
RFA preserves normal thyroid function compared to surgery or RAI :Ji Hong et al J Vas Interv Raddiol 2015(307.

30. Alternative Therapies for Toxic Nodular Goiter
My take: ). The use of RFA should be limited to centers where clinicians have received adequate training in the technique
For hyperfunctioning nodules RAI is much safer one can reduce frequency of hypothyroidism by using lower dose of RAI and for very large TA in younger individuals lobectomy by experienced surgeon will be safe
RFA and surgery have the least possibility of permanent hypothyroidism

31. Management of Subclinical Hyperthyroidism (SH)
RECOMMENDATION 73
When TSH is persistently <0.1 mU/L, treatment of SH is recommended in all individuals >65 years of age; in patients with cardiac risk factors, heart disease or osteoporosis; in postmenopausal women who are not on estrogens or bisphosphonates; and in individuals with hyperthyroid symptoms.
Strong recommendation, moderate-quality evidence.

32. Management of Subclinical Hyperthyroidism (SH)
RECOMMENDATION 74 When TSH is persistently <0.1 mU/L, treatment of SH should be considered in asymptomatic individuals <65 years of age without the risk factors listed in recommendation 73. Weak recommendation, moderate-quality evidence.

33. Management of Subclinical Hyperthyroidism (SH)
RECOMMENDATION 75
When TSH is persistently below the lower limit of normal but>0.1 mU/L, treatment of SH should be considered in individuals >65 years of age and in patients with cardiac
disease, osteoporosis, or symptoms of hyperthyroidism.
Weak recommendation, moderate-quality evidence..

34. Management of Subclinical Hyperthyroidism(SH)
RECOMMENDATION 76
When TSH is persistently below the lower limit of normal but >0.1 mU/L, asymptomatic patients under age 65 without cardiac disease or osteoporosis can be observed without further investigation of the etiology of the abnormal TSH or treatment.
Weak recommendation, low-quality evidence.

35. Management of Subclinical Hyperthyroidism (SH)
My take;
Etiology is important In GD possibility of remission exists specially if TRAB is neg or at low level. Younger persons can be observed and older persons may need only beta blockers or low dose ATD
For MN toxic or TA definitive therapy for olders and non-urgent definitive therapy at some point even for younger patients should be considered

36. Hyperthyroidism and Pregnancy
RECOMMENDATION 82
We suggest that women with hyperthyroidism caused by GD who require high doses of ATDs to achieve euthyroidism should be considered for definitive therapy before they become pregnant.
Weak recommendation, low-quality evidence.
Both thyroidectomy and RAI therapy are useful

37. Hyperthyroidism and Pregnancy
RECOMMENDATION 93
Patients who were treated with RAI or thyroidectomy for GD prior to pregnancy should have TRAb levels measured using a sensitive assay initially during the first trimester
thyroid function testing and, if levels are elevated, again at 18–22 weeks of gestation.
Strong recommendation, low-quality evidence.

38. Esophageal/choanal atresia (MMI effect)
Spontaneous rate of 1/2,500 to 1/10,000 births
Reported in 2/241 children of mothers taking MMI during early pregnancy
Di Gianantonia et al. Teratology 2001;64:262

39. Aplasia cutis MMI effect
Occurs spontaneously in 1/2,000 births; reported in association with MMI use in early pregnancy, but frequency is unknown

40. Hyperthyroidism and Pregnancy My take:
There has not ben any evidence that subclinical hyperthyroidism in pregnancy has significant adverse effect. Under treatment of hyperthyroidism is better than aggressive therapy.
TRAb measurement is helpful to differentiate GD from pregnancy associated thyroid function changes
Recently question of some teratogenic effect of PTU has been raised

41. Graves Ophthalmopathy

42. A 60 year old man presents with typical symptoms and signs of Graves’ disease. He is a nonsmoker with a 6 month history of swelling around the eyes, diplopia, pain with eye motion and at rest, tearing, and photophobia. Thyroid is 2.0-fold enlarged. Eyes show extensive periorbital erythema and edema, lid and conjunctival erythema, and chemosis.

43. TSH-receptor autoimmunity in Graves’ disease after therapy with ATDs, surgery or RAI: a 5-year prospective randomized study Laurberg et al. Eur J Endocrinol 158;69:2008

44. Radioiodine + prednisone
Effect of RAI on GO
Initial worsening
Persistent worse
Unchanged
Improved
Patients (%)
Radioiodine
Methimazole
Radioiodine + prednisone
Bartalena et al: NEJM 338:73, 1998 CP 44

45. Graves Ophthalmopathy(GO)
RECOMMENDATION 105
In the absence of any strong contraindication to GC use we suggest considering them for coverage of GD patients with mild active GO who are treated with RAI, even in the absence of risk factors for GO deterioration.
Weak recommendation, low-quality evidence.

46. Graves Ophthalmopathy (GO)
RECOMMENDATION 107
In patients with active and moderate-to-severe or sight threatening GO we recommend against RAI therapy.
Surgery or ATDs are preferred treatment options for GD in these patients.
Strong recommendation, low-quality evidence.

47. Graves Ophthalmopathy (GO)
A comparison of total thyroidectomy vs.subtotal thyroidectomy for patients with moderate-to severe
GO showed that the eye disease improved during 3
years of follow-up in all patients;
Jarhalt j et al thyroid 2015
In another series of 42 patients with progressive GO treated with total thyroidectomy, exophthalmos was stable in 60% of cases and improved in the remainder, suggesting that surgery imay be associated with improvement of GO in some patients
Domoslawski et al 2017

48. Graves Ophthalmopathy (GO)
A study suggests that surgery might lead to a more rapid improvement in GO than ATDs
DeBellis et al Endocrine 2012

49. Graves Ophthalmopathy (GO)
RECOMMENDATION 108
In patients with inactive GO we suggest RAI therapy can be administered without steroid coverage. However, in cases of elevated risk for reactivation (high TRAb, CAS>1 and smokers) that approach might have to be reconsidered.
Weak recommendation, low-quality evidence.

50. Graves Ophthalmopathy (GO)
There is a low rate of GO progression or reactivation following RAI in patients with inactive GO. A series of 72 patients with inactive GO according to the CAS were treated with RAI without concurrent glucocorticoid administration . For those in whom hypothyroidism was prevented by early thyroxine therapy, no deterioration in eye disease was reported.
Perros et al JCEM. 2005

51. Graves Ophthalmopathy-My take;
Ablation of thyroid with RAI may increase TRAB in the first year and may have possible adverse effect on GO that can be prevented by concomitant GC but may have beneficial effect due to elimination of source of antigen beyond first year
I have low threshold to use GC with RAI when there is evidence of GO-even so called inactive- If using RTAI use higher ablative dose

52. Summary of Suggestions of new Guidelines
Use of TRAb for diagnosis of GD and monitoring ATD therapy and timing of stopping therapy
Allows long term ATD therapy in some cases
Suggests pre-surgical assessment of vitamin D adequacy
Suggests avoiding RAI for GD with severe GO

53. Summary of suggestions of New guidelines
Suggests surgery if expertise available for GD with severe GO
Suggests definitive therapy for GD in severe hyperthyroidism in anticipation of
pregnancy
Opens the door for possibility of stable Iodide therapy of GD but does not have recommendation
Opens the door for RF ablation of toxic adenoma but not routinely recommend it

54. Summary of Highlights of New Guidelines
Approves long term anti-thyroid therapy

55. Thank you for your attention
Questions?

56. Recommendation 16: A differential white blood cell count should be obtained during febrile illness and at the onset of pharyngitis in all patients taking antithyroid medication. Routine monitoring of white blood counts is not recommended. 1/+00
Recommendation 17: Liver function and hepatocellular integrity should be assessed in patients taking propylthiouracil who experience pruritic rash, jaundice, light colored stool or dark urine, joint pain, abdominal pain or bloating, anorexia, nausea, or fatigue.
1/+00

57. Thyroid-associated ophthalmopathy after treatment for Graves’ hyperthyroidism with ATDs or 131I Traisk et al. JCEM 94: :

58. Graves Ophthalmopathy (GO)
ATDs may not adversely impact mild active GO, but they do not address severe GO Bartalena et al N E J Med 1998
Alternatively, if ATDs are selected for GD therapy, there are reassuring data that long-term use is relatively safe and
effective at preserving euthyroidism while waiting for GO to enter remission:
Elberts et al Thyroid 2011, and Casey et al Obstet Gynecol 2006

59. Graves Ophthalmopathy (GO)
Smoking history did not impact GO outcome in this cohort. A recent trial from Japan (540) randomized patients without GO or inactive GO (i.e., CAS <3 or
T2-weighted imaging T2SIR £1) to receive either glucocorticoid prophylaxis with low-dose prednisolone (on average 0.28mg/kg per day tapered rapidly over 6 weeks) or no prophylaxis at all. The rate of disease progression in the absence of risk factors was low (4.2%) and not impacted by glucocorticoid therapy. The presence of risk factors for GO (high thyroid stimulating antibody, CAS ‡1) increased that risk, again without a benefit from low-dose steroid prophylaxis. Whether high dose GC would have made a difference in these patients is not known.