Current Algorithms of Diagnosis and Management of Graves’ Disease - Konas Padang 2018.pptx

Grave*s Disease

1. CURICULLUM VITAE Imam Subekti , MD, PhD Medical D octor , FMUI …….…………………….. .. 1983 Internal Medicine Specialist, FMUI ………… .. 1993 Medical staff, Department of IM FMUI ……. 1993 Consultant in Endocrinology and Diabetes. . 2000 Coordinator , Consultant Program, Dept of. Internal Medicine FMUI …………………………. 2006-2011 Head , Division of Endocrinology . .….……. ... . 2008-2011 Head, Department of Internal Medicine . … 2011-2016 Vice chairman, Collegium of Internal Medicine 2015-2018

2. Imam Subekti Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta Current Algorithms of Diagnosis and Management of Graves’ Disease

3. ? Hipertiroidisme Introduction ? Tirotoksikosis Sindrom klinik akibat hormon tiroid  disebabkan aktivitas kelenjar tiroid berlebihan Sindrom klinik akibat hormon tiroid  , bisa disebabkan aktivitas kelenjar tiroid berlebihan atau bukan Nn K, 28 th , datang ke RS berdebar 1 tahun , gemetar , BAB setiap makan , BB  , leher membesar ringan sudah minum obat anti tiroid 3 bln , lalu dihentikan karena merasa enakan .  Hipertiroidisme ? atau Tirotoksikosis ? Gardner DG. The Thyroid Gland. Greenspan's Basic & Clinical Endocrinology. 8th Ed. ed. California: McGraw Hill; 2007.

4. Thyrotoxicosis Hyperthyroidism Hyperthyroidism ≈ Graves’ Disease Toxic Adenoma Toxic Multinodular Struma ‘Silent’ Thyroiditis Subacute Thyroiditis Exogen thyroid hormone Trophoblastic tumor H yperemesis gravidarum TSH hipersecretion Thyroid carcinoma Str o ma ovarii , etc Drug induced thyroiditis Radiation thyroiditis Thyroid adenoma infarction Gardner DG. The Thyroid Gland. Greenspan's Basic & Clinical Endocrinology. 8th Ed. ed. California: McGraw Hill; 2007. ≈ Graves’ Disease

5. Pat h ogenesis Graves ’ disease Weetman AP. N EJM 2000;343(17):1236-48. Character changes of TSH-R (genetic, environment, endogen factors) T- and B-lymphocyte auto-reactivity to thyroid tissue  secretion of antibody to TSH receptor TRAb

6. Suspected Graves’ patients Physical examination Diagnostic test History taking Present history Past/Medication history Family history Guidelines summary: Ross DS et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thytoid . 2016;26(10):1343-421. The Indonesian Society of Endocrinology Task Force on Thyroid Diseases. Indonesian Clinical Practice Guidelines for Hyperthyroidism. 2012;27(1):34-9. Weetman AP. Graves disease. N Engl J Med. 2000;343(17):1236-48 General Neck Cardiac Eyes Thyroid function Thyroid morphology Etiology Diagnostic schema for Graves’ disease

7. Clinical manifestations Diaphoresis T remor D iarrhea Weight loss Increased reflex Increased daily intake O phtalmopathy Struma Palpitation Dermopathy Weetman AP. N EJM 2000;343(17):1236-48.

8. Diagnosis of Graves’ disease What additional diagnostic tests would you suggest? Clinical : Signs and symptoms of thyrotoxicosis TSHs (or TSH) FT4 (or total T4) Radioactive iodine uptake TRAb Thyroid ultrasound Ross DS et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thytoid . 2016;26(10):1343-421.

9. FT4: 7.770 (0.930-1.700) ng / dL TSHs: <0.01 (0.270-4.200) ng / dL Laboratory results Serum TSH measurement has the highest sensitivity and specificity of any single blood test used in the evaluation of suspected hyperthyroidism and should be used as an initial screening test . Diagnostic accuracy improves when both a serum TSH and free T4 are assessed at the time of the initial evaluation. ATA/AACE 2016, PERKENI 2012 ATA/AACE 2016, PERKENI 2012 What additional diagnostic tests would you suggest?

10. Radioactive iodine uptake A radioactive iodine uptake should be performed when the clinical presentation of thyrotoxicosis is not diagnostic of GD In a patient with a symmetrically enlarged thyroid, recent onset of ophthalmopathy, and moderate to severe hyperthyroidism, the diagnosis of GD is sufficiently likely that further evaluation of hyperthyroidism causation is unnecessary ATA/AACE 2016, PERKENI 2012 ATA/AACE 2016, PERKENI 2012 What additional diagnostic tests would you suggest?

11. TSH Receptor Antibody ( TRAb ) An alternative way to diagnose GD is by measurement of TRAb . This approach is utilized when a thyroid scan and uptake are unavailable or contraindicated ATA/AACE 2016, PERKENI 2012 What additional diagnostic tests would you suggest?

12. Patients with thyroid problems Physical examination Diagnostic test History taking Graves’ Disease Treatment Anti thyroid drugs RAI Surgery Adjuncts and alternatives Guidelines summary: Ross DS et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thytoid . 2016;26(10):1343-421. The Indonesian Society of Endocrinology Task Force on Thyroid Diseases. Indonesian Clinical Practice Guidelines for Hyperthyroidism. 2012;27(1):34-9. Weetman AP. Graves disease. N Engl J Med. 2000;343(17):1236-48

13. Treatment Approach : Blocking the production and secretion of thyroid hormone using anti thyroid drugs (ATD) Injured or decrease thyroid tissue mass through radioactive iod ine or operation Eliminate the effect of thyroid hormone in peripheral tissue with beta blocker The choice of medication depends on the severity of hyperthyroidism, age, size of the struma and the existence of comorbidities. ATA/AACE . Guidelines. Endocrine Practice . 2011; 17 :e1-e65 . Graves’ disease: ‘remitting and relapsing disease’

14. Case presentation

15. Kasus 1 Nn K, 28 th , datang ke RS berdebar 1 tahun , gemetar , BAB setiap makan , BB  , leher membesar ringan sudah minum thyrozol 3 bln , lalu dihentikan karena merasa enakan  p endapat anda ? 12bln SMRS Pasien kurang pengetahuan tentang penyakitnya Dokter kurang pengetahuan tentang penyakit Graves Dokter kurang waktu untuk edukasi kepada pasien Struma difus , N: 110x/m TSH: 0.01 (0.35-4.94) T4 : 15.3 (4.87-11.7) T3 : 2.56 (0.58-1.59) Graves toksik Tatalaksana : Edukasi Manajemen ? ✔ × ✔ ✔ ?

16. What treatment would you suggest to this patient? Anti-thyroid drug Radio-iodine irradiation Surgery Patients with overt Graves hyperthyroidism should be treated with any of the following modalities: Antithyroid drug, 131 I therapy, or thyroidectomy ATA/AACE 2016, PERKENI 2012 Kasus 1

17. Anti-Thyroid Drugs (ATDs) The elderly or others with comorbidities Limited life expectancy Unable to follow radiation safety regulations Previously operated or irradiated necks Lack of access to a high-volume thyroid surgeon Moderate to severe active GO Definite contraindications to long-term ATD therapy include previous known major adverse reactions to ATDs. ATA/AACE 2016, PERKENI 2012 What treatment would you suggest to this patient? High likelihood of remission (women, mild disease, small goiter, negative or low titer TRAb )

18. 131- I Females planning a pregnancy in the future Comorbidities increasing surgical risk Previously operated or externally irradiated necks Lack of access to a high-volume thyroid surgeon Contraindications to ATD use. ATA/AACE 2011, PERKENI 2012 What treatment would you suggest to this patient?

19. Surgery Symptomatic compression or large goiters Relatively low uptake of radioactive iodine Malignancy is documented or suspected Large nonfunctioning, photopenic , or hypofunctioning nodule Coexisting hyperparathyroidism requiring surgery Females planning a pregnancy in <4–6 months Moderate to severe active GO What treatment would you suggest to this patient? ATA/AACE 2016, PERKENI 2012

20. Anti-Thyroid Drugs (ATDs) The elderly or others with comorbidities Limited life expectancy Unable to follow radiation safety regulations Previously operated or irradiated necks Lack of access to a high-volume thyroid surgeon Moderate to severe active GO Definite contraindications to long-term ATD therapy include previous known major adverse reactions to ATDs. ATA/AACE 2016, PERKENI 2012 What treatment would you suggest to this patient? High likelihood of remission (women, mild disease, small goiter, negative or low titer TRAb ) High likelihood of remission (women, mild disease, small goiter, negative or low titer TRAb )

21. What drug would you suggest to this patient?

22. Adjuncts and alternatives Beta blocker Provides rapid relief of hyperadrenergic symptoms and signs of thyrotoxicosis Prevents episodes of hypokalemic periodic paralysis in susceptible individuals Prepares thyrotoxic patients for surgery *DOC in treating cardiac arrhythmias Beta blocker Dosage Frequency Propanolol * 10-40 mg 3-4 times per day Atenolol 25-100 mg 1-2 times per day Metoprolol 25-50 mg 2-3 times per day Nadolol 40-160 mg 1 time per day Esmolol IV pump 50-100 ug /kg/min 1. Ross DS et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thytoid . 2016;26(10):1343-421.

23. Kasus 1 Nn K, 28 th , datang ke RS berdebar 1 tahun , gemetar , BAB setiap makan , BB  , leher membesar ringan sudah minum thyrozol 3 bln , lalu dihentikan karena merasa enakan  p endapat anda ? 12bln SMRS Selama 9 bulan terakhir Pasien kurang pengetahuan tentang penyakitnya Dokter kurang pengetahuan tentang penyakit Graves Dokter kurang waktu untuk edukasi kepada pasien Struma difus , N: 110x/m TSH: 0.01 (0.35-4.94) T4 : 15.3 (4.87-11.7) T3 : 2.56 (0.58-1.59) Graves toksik Tatalaksana : Edukasi Thyrozol 10: 2-0-0 tab Keluhan tidak ada lagi , dosis diturunkan bertahap  Thyrozol 1 (10mg)-0-0, Lab TSH: 0.13, T4: 6.7 Kesimpulan : ? Sembuh Sudah remisi ? ✔ × ✔ ✔ × Graves eutiroid 

24. If ATDs is chosen as the primary therapy for GD, the medication should be continued for approximately 12–18 month s, then tapered or discontinued if the TSH is normal at that time. When should we stop the ATDs? ATA/AACE 2011 A patient is considered to be in remission if they have had a normal serum TSH, FT4, and T3 for 1 year after discontinuation of ATD therapy. When patients are considered to be in remission

25. Kasus 1 Nn K, 28 th , datang ke RS berdebar 1 tahun , gemetar , BAB setiap makan , BB  , leher membesar ringan sudah minum thyrozol 3 bln , lalu dihentikan karena merasa enakan  p endapat anda ? 12bln SMRS Selama 9 bulan terakhir Pasien kurang pengetahuan tentang penyakitnya Dokter kurang pengetahuan tentang penyakit Graves Dokter kurang waktu untuk edukasi kepada pasien Struma difus , N: 110x/m TSH: 0.01 (0.35-4.94) T4 : 15.3 (4.87-11.7) T3 : 2.56 (0.58-1.59) Graves toksik Tatalaksana : Edukasi Thyrozol 10: 2-0-0 tab Keluhan tidak ada lagi , dosis diturunkan bertahap  Thyrozol 1 (10mg)-0-0, Lab TSH: 0.13, T4: 6.7 Kesimpulan : ? Sembuh Sudah remisi ? Belum remisi ✔ ✔ × ✔ ✔ × Graves eutiroid 

26. Bartalena , 2011 Risk factors for relapse A patient is considered to be in remission if they have had a normal serum TSH, FT4, and T3 for 1 year after discontinuation of ATD therapy. ‘Relapse’ is used when remission was already achieved

27. Kasus 1 Nn K, 28 th , datang lagi setelah 3 bulan tidak minum obat karena bosan dan tidak bisa teratur karena pekerjaannya serta ada rasa cemas Visit lagi  Pilihan terapi ? Tetap minum obat Iodium RA Operasi Indi cation : Large goiter or retro- sternal → compression Low uptake of RI iodine Drug adverse effect s Recurrent / relapse Indi cation : Relapse after long-term ATD with cardiac problem Severe Graves ’ disease and the remission will get problem Previously operated or externally irradiated neck Drugs’ adverse effect or contraindication to ATD use Contraindication : Pregnant and nursing women × The longer the medication , the longer duration of remission 1-2 years of medication is advisable , remi s si on rate is 30-70% Influenced by long-term low TSH level and high level of TR-Ab Post remission , evalua te every 3 months ( 1st year ) and every year afterwards In the case of relapse after ATD , or contraindication to ATD, or no compliance ATD prefer other modalities therapy , such as radioa c ti ve iodine or surgery

28. Kasus 1 14/5/17 Visit post ops TSH: 0.03, T4: 13.5 Pilihan terapi Iodium radioaktif ? Khawatir ada efek samping bila hamil Operasi ? TSH: 5.67 (0.35-4.94) T4 : 3.5 (4.87-11.7) × Nn K, 28 th , datang lagi setelah 3 bulan tidak minum obat karena bosan dan tidak bisa teratur karena pekerjaannya serta ada rasa cemas n ear total thyroidectomy Hipotiroidism Terapi substitusi Terapi supresi Terapi suplementasi ✔ × × Levo -thyroxin

29. Kasus 2 Ny SB, 48 th , datang ke RS ingin meneruskan pengobatan tiroidnya . Tremor, BB turun , mata bengkak sejak 7 bln JEC: Hipertiroid TSH: 0.008  FT4: 4.94  OT/PT/GGT: N  Konsul ke Ahli Penyakit Dalam : Graves’ toksik , diberikan : PTU 3x100 mg Mual , selera makan  Mata kuning , Lab: OT: 75 (<27) PT: 122 (<34) GGT: 67 (<39) ALP: 293 (<98) Bil T: 10.8 (10.2/0.6) HBsAg (-), HCV (-) Masalah ? 6 bulan SMRS 5 bulan SMRS Bagaimana dengan terapi PTU ? Graves dgn drug induced liver Injury (DILI)

30. Evaluation of adverse effects Risk of agranulocytosis is similar (0.2-0.5%) between MMI and PTU. PTU is associated with transaminase elevation, risk for severe liver injury, and acute liver failure in susceptible individuals Closely monitor for signs and symptoms of liver injury, especially during the first 6 months after initiation: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver injury, and provide supportive care MMI may cause a cholestatic effect 1. Ross DS et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thytoid . 2016;26(10):1343-421.

31. D iferensial Diagnosis disfungsi hati dan ikterus pada pasien hipertiroidisme Thyrotoxicosis per se Conditions associated with: thionamide therapy hepatic congestion from thyrotoxic heart failure hepatic necrosis from systemic embolisation caused by atrial fibrillation autoimmune hepatitis, and primary biliary cirrhosis, which may be associated with Graves’ disease Causes of jaundice unrelated to thyrotoxicosis, such
as viral hepatitis, sepsis, cholangitis, alcohol abuse, and medication such as hormonal contraceptives, acetaminophen, isoniazid, rifampicin, and herbal remedies. CS Bal et al. Indian J Nucl Med. 2010;25(4):131-4. Mohamed OH et al. Journal of Thyroid Research. 2012;2012:1-8. ✔ didasari atas respons hipersensitivitas pasien dalam dosis normal sekalipun

32. Kasus 2 Ny SB, 48 th , datang ke RS ingin meneruskan pengobatan tiroidnya . Tremor, BB turun , mata bengkak sejak 7 bln JEC: Hipertiroid TSH: 0.008  FT4: 4.94  OT/PT/GGT: N  Konsul ke Ahli Penyakit Dalam : Graves’ toksik , diberikan : PTU 3x100 mg Mual , selera makan  Mata kuning , Lab: OT: 75 (<27) PT: 122 (<34) GGT: 67 (<39) ALP: 293 (<98) Bil T: 10.8 (10.2/0.6) HBsAg (-), HCV (-) Masalah ? 6 bulan SMRS 5 bulan SMRS Saat ketemu anda 2 bulan PTU tidak diminum , Mual  , makan  , mata kuning  Bil T: 0.4 (0.2/0.2) OT: 34--36 PT: 56--50 GGT: 50--40 ALP: 109—90 FT4: Kesimpulan : ? Bagaimana langkah berikutnya ? Kurangi dosis Stop dan ganti OAT lain Stop PTU ✔ Bagaimana dengan terapi PTU ? Graves dgn drug induced liver Injury (DILI) Graves pasca DILI × ×

33. Kasus 2 Ny SB, 48 th , Graves pasca mengalami DILI Tatalaksana berikutnya : PTU diberikan kembali Tetap tanpa obat PTU tetap stop, ganti golongan lain ✔ Hepatotoksisitas akibat tionamid jenis yang satu , bisa diatasi dengan cara menggantinya dengan jenis yang lain. Chukwuma OE, et al. PLoS Medicine www.plosmedicine.org . 2006;3(1):0042-5. × ×

34. Summary Diagnosis og Graves’ disease based on clinical thyrotoxicosis and confirmed with TSH/FT4 and TRAb if needed The principal treatment of Graves ’ disease : decrease the production (with ATD), damage the tissue (RAI and surgery) , and eliminate the effect of thyroid hormone (beta-blocker) M aintenance of euthyroidism with smallest dose that can keep clinically and laboratory euthyroid The longer the medication, the longer duration of remission

35. Thank You

36. Patients Physical Examination Diagnostic Test History Taking Graves’ Disease Treatment Anti thyroid drugs RAI Surgery Guidelines summary: Ross DS et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thytoid . 2016;26(10):1343-421. The Indonesian Society of Endocrinology Task Force on Thyroid Diseases. Indonesian Clinical Practice Guidelines for Hyperthyroidism. 2012;27(1):34-9. Weetman AP. Graves disease. N Engl J Med. 2000;343(17):1236-48

37. Adjuncts and alternatives Glucocorticoids (prednisone, methylprednisolone, dexamethasone) Decrease T4-to-T3 conversion and decrease thyroid hormones by yet undiscovered mechanisms Adverse effects of long-term use  unattractive for long-term management Can rapidly lower thyroid hormone levels in thyroid storm 1. Ross DS et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thytoid . 2016;26(10):1343-421.