(02) update on mgmt of graves - f.nabhan - osu …02) update...nabhan 2 robert graves 1797-1853...

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Update on the Management of Graves Disease

Fadi Nabhan, MDClinical Assistant ProfessorDivision of Endocrinology

Objectives

Pathophysiology and Clinical Presentation

Approach to Diagnosis

Management

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Robert Graves

1797-18531797-1853

Robert Graves

“violent and long continued palpitation in females….in one the beating of the heart gcould 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 herslept or tried to shut her eyes, the lids were incapable of closing”

1797-18531797-1853

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Graves Disease

Classic Triad:

Thyrotoxicosis Goiter Eye Disease

Activated T Cells

B Cells

+

TSH R

TSH R Abs

6

Thyroid Follicular Cell

HyperthyroidismHypertrophy

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Genetic Factors

Environmental Factors

Immune Tolerance

InfectionIodine IntakeSmokingStress

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


Iodine Sufficient Areas: 50 80% of all causes of Iodine Sufficient Areas: 50-80% of all causes of Thyrotoxicosis


Epidemiology



More Frequent in Women than Men 5:1


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Epidemiology



More Frequent in Women than Men 5:1

Peak in the 5th and 6th decade but can occur at any age


Clinical Presentation

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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%

13

Increased appetite 10-65%

Diarrhea 10-30%

Menconi et al. Autoimmunity Reviews 13 (2014) 398–402

50%

60%18-32 years

33-44 years

45-60 years

Number Of

Patients

20%

30%

40%

5 or more Symptoms

3-4 Symptoms

0-2 Symptoms

10%

Boelaert, K. et al. J Clin Endocrinol Metab 2010;95:2715-2726

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50%

60%18-32 years

33-44 years

45-60 years

Over 61 years

Number Of

Patients

20%

30%

40%

y

5 or more Symptoms

3-4 Symptoms

0-2 Symptoms

10%

Boelaert, K. et al. J Clin Endocrinol Metab 2010;95:2715-2726

Age Related Change in Graves Disease Hyperthyroid Symptoms

More Common In The OlderOlder

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' DiseaseGraves 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 SwellingPeriostitis

Fatourechi et al. J Clin Endocrinol Metab. 2002 Dec;87(12):5435-41.

Differential Diagnosis

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Thyrotoxicosis

Exogenous

Thyrotoxicosis

Endogenous Exogenous

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Exogenous

Extrathyroidal

Thyrotoxicosis

Endogenous

Struma Ovarri

Thyrotoxicosis


Extrathyroidal Thyroid

Struma Ovarri

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Thyrotoxicosis



Struma OvarriIncreased Release

Thyroiditis

Thyrotoxicosis



Struma OvarriIncreased

ProductionIncreased Release

Thyroiditis

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Thyrotoxicosis





ThyroiditisPrimary Secondary

Thyrotoxicosis






TSH Producing Tumors

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Thyrotoxicosis






Graves DiseaseToxic Nodular Goiter

Iodine Induced


Laboratory Findings

Suppressed TSH

Elevated T4 and/or T3

32

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Thyrotoxicosis







Iodine Induced


Thyrotoxicosis







Iodine Induced

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Thyrotoxicosis

Typical presentation of Graves disease

No need for further testing

35

(ATA/AACE Guidelines Bahn R, et al Thyroid 2011; 21:593)

g


Thyrotoxicosis

Radioactive Iodine Uptake and Scan

Clinically not diagnostic of Graves

36

p


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Thyroid Radioiodine Uptake and Scan

Thyrotoxicosis

HIGH UPTAKE

Graves Disease

LOW UPTAKE

Thyroiditis Graves Disease

Toxic Nodular Goiter

Thyroiditis

Expanded Iodine Pool

Surreptitious Thyroid Hormone Ingestiong

Ectopic Thyroid

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Thyrotoxicosis

HIGH UPTAKE

Graves Disease 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 ti 1819 98 1 (90 3 100)2nd generation 1819 98.1 (90.3-100)

3rd generation 1976 99.2 (97.3-100)

Tozzoli R. Autoimmun Rev. 2012;12:107–113


Thyrotoxicosis

TSH Receptor A tib di

Radioactive Iodine Uptake and Scan

OR??

Clinically not diagnostic of Graves

44

Antibodies Uptake and Scan

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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

45

Barbesino and Tomer. J Clin Endocrinol Metab. 2013;98 (6):2247–2255

Thyroid Ultrasound and color flow Doppler

Hypoechoic

Color flow Doppler is increased

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Thyroid Ultrasound

Normal Doppler Graves’ Doppler


Thyroid Ultrasound and color flow Doppler

Hypoechoic

Color flow Doppler is increased

Should be done to evaluate cold nodules seen on iodine scan

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Management

Approach to Management

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C t l f H th idiControl of Hyperthyroidism Trying to Preserve Thyroid Function

With Aim at Remission


C t l f H th idi

Anti Thyroid Drugs

Control of Hyperthyroidism Trying to Preserve Thyroid Function


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Definitive Treatment of HyperthyroidismWith Result in Hypothyroidism

Anti Thyroid Drugs





Anti Thyroid DrugsRadioactive Iodine

OrSurgeryg y

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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

PTU MMI

Minor 5-20% 5-20%

Agranulocytosis 0.2-0.5% 0.2-0.5%. Dose dependent

Hepatic Failure <0.1% Cholestatsis

59

Vasculitis ANCA + Very rare

Comparison between PTU and MMI Side Effects

PTU MMI

Minor 5-20% 5-20%

Agranulocytosis 0.2-0.5%First 100 days

0.2-0.5%. Dose dependent

Hepatic Failure <0.1% Cholestatsis

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Vasculitis ANCA +Increases with time

Very rare

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Therefore: Always use Methimazole except in limited psituations…..

61

When Can PTU be used?

PTU is drug of choice in first trimester


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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


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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 l l t d > fi f ld th li it flevels elevated > fivefold the upper limit of 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 theobtained during febrile illness and at the onset of pharyngitis

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Monitoring

No consensus concerning the utility of periodic monitoring of white blood cell gcounts and liver function tests

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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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No difference if treatment exceeds 18 months

Duration of Treatment and Probability of Remission

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

Methimazole10-30 mg a

day

Taper to maintenance 5-

10 mg a day

Continue for about 18 months

73

Time

Taper further and then Stop if not

H th id

How Antithyroid Drugs Are Used

Methimazole10-30 mg a

day

Taper to maintenance 5-

10 mg a day

Continue for about 18 months

Hyperthyroid

Measure Receptor Abs and stop if

negative

OR

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Time

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Relapse

Repeat Antithyroid Drugs

RAI I-131 Surgery

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Relapse

Repeat Antithyroid Drugs

RAI I-131 Surgery

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May use low dose Methimazole long

term?

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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)

OROR

Calculating the activity based on the size of the thyroid and iodine uptake

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Radioactive Iodine Dose

Administering a fixed activity (10-15 mCi)

OROR

Calculating the activity based on the size of the thyroid and iodine uptake

Fixed dose is easier and no definitive evidence ofFixed dose is easier and no definitive evidence of superiority of calculated dose

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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

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Chances of Success after Radioactive Iodine

Severity of Hyperthyroidism

Size of Goiter

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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

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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

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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

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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

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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

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Surgical Complications

Hypocalcemia (permanent <2%)

Recurrent laryngeal nerve injury (permanent <1%)

Post- operative bleeding

Complications related to general anesthesia.

95





Anti Thyroid DrugsRadioactive Iodine

OrSurgeryg y

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Choice of TreatmentChoice of Treatment

I-131Or

Surgery

I-131Or

Surgery

Anti Thyroid Drugs

Anti Thyroid Drugs

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Probability of RemissionProbability of RemissionHigh Low

Choice of TreatmentChoice of Treatment

I-131I-131SurgerySurgery

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High Surgical Risk High Surgical Risk

Compressive GoiterSevere Eye Disease?

Compressive GoiterSevere Eye Disease?

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PATIENT PREFERENCE!!

99

Pattern of Therapy by Physicians

Survey of Endocrine Society, American Thyroid Association and AACE Members

730 R d t730 Respondents

ATDs: 53.9%

I-131: 45%

Surgery: 0.7%

Versus a similar study in 1991, there is greater use of y , gATDs and Lower Use of I-131

100

Burch HB, Burman KD, Cooper DS. J Clin Endocrinol Metab. 2012 97:4549-4558

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101

Burch HB, Burman KD, Cooper DS. J Clin Endocrinol Metab. 2012 97:4549-4558

Potential Future Therapy

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T Cells

B Cells

+

TSH R

TSH R Abs

Th id F lli l C ll

103



T Cells

B Cells

+

Rituxumab

TSH R

TSH R Abs

104



Adopted from Rebecca Bahn Expert Rev Clin Pharmacol. Nov 2012; 5(6): 605–607

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T Cells

B Cells

+

Rituxumab

TSH R

TSH R Abs


Abs blockBinding to Receptor

105




T Cells

B Cells

+

Rituxumab

I d AMP l l

TSH R

TSH R Abs

Th id F lli l C ll

Abs blockBinding to Receptor

SML (Small Molecule Ligand)

106

Increased c AMP levels Thyroid Follicular Cell



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THANK YOU!

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(02) update on mgmt of graves - f.nabhan - osu …02) update...nabhan 2 robert graves 1797-1853...

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