1. 13th Asian Association of Endocrine Surgeons Congress “Current Practices New Directions”
26th -28th March 2012
Singapore
Graves' Disease
Prof. Ranil Fernando
Dept of Surgery
Faculty of Medicine
University of Kelaniya
Sri Lanka

2. Graves' Disease Historical aspects
Robert James Graves
Caleb Hillier Parry
Graves’ R J. observed affection of the thyroid gland in four females with what he thought was a cardiac problem
Graves described this condition in London Medical and Surgical Journal This entity became known as Graves Disease
It is an Immunogenic hyperthyroidism

3. Graves' Disease Background
In 1956 a humoral factor was discovered that caused Graves' Disease, later it was shown to be an antibody to the TSH receptor
Rapid progress has been made in:
understanding the molecular interaction between autoantibodies and the TSH receptor
identifying the genes that contribute to the predisposition to disease
developing an animal model of Graves' Disease
identifying the long-sought orbital antigen in ophthalmopathy

4. Graves' Disease Current Status
Graves' Disease affects approximately 0.5% of the population and is the underlying cause of 50 to 80% of cases of hyperthyroidism in the west
In Sri Lanka autoimmune thyroiditis is also equally common cause of hyperthyroidism, possibly a consequence of iodization
The common age group is 40 and 60 years
The female-to-male ratio among patients with Graves' Disease is between 5:1 and 10:1.
The concordance rate for Graves' Disease among monozygotic twins is 35%

5. Graves' Disease Risk Factors for Graves' Disease
Genetic susceptibility
Stressful life events
Infections
Recent childbirth
Family history of thyroid disease, especially in maternal relatives, is associated with an increased incidence of Graves' Disease and a younger age at onset
Genetic loci have been identified, conferring susceptibility to Graves' Disease alone or to both Hashimoto's thyroiditis and Graves' Disease - (e.g. chromosome 20q11.2)

6. Graves' Disease Graves' Disease is characterized by
A diffuse goitre (usually soft goitre)
Eye signs - (unilateral/bilateral)
Sympathetic overdrive
Graves ophthalmopathy
Other features of thyrotoxicosis
Stigmata of autoimmunity
Can make a clinical diagnosis when the
patient walks into the clinic

7. Graves' Disease Clinical Picture in Sri Lanka
Graves' Disease in Sri Lanka has a female
preponderance 6:1
Common between ages of
Youngest - 4 years (incidence in children is 1-5%)
Last 150 patients with goitres seen in the clinic
- 20 had hyperthyroidism
- 4 had overt features of Graves' Disease
Late disease is yet seen
Is Graves Disease different in endemic and non endemic areas?

8. Graves' Disease The diagnosis
The diagnosis of Graves' disease is based on clinical features and biochemical assay
Elevated T4 & suppressed TSH is characteristic
Receptor antibody levels are not routinely required for diagnosis or to monitor disease activity
Imaging
Us Scan
Isotope Scan only if there is doubt
FNAC - mandatory if there are nodules

9. Graves' Disease Graves' ophthalmopathy (GO)
Graves' ophthalmopathy is thought to result from a complex interplay of genetic and environmental factors
Various genes, including those coding for HLA determine a patient's susceptibility and its severity
Once established, the chronic inflammatory process takes on a momentum of its own
There are 3 subtypes
ocular myopathy
congestive myopathy
mixed congestive and myopathic ophthalmopathy

10. Graves' Disease Graves' ophthalmopathy (GO)
GO is likely to be due an autoimmune reaction involving sensitised T lymphocytes and autoantibodies directed against a specific orbital or thyroid-and-orbital shared antigens
Thyroid-stimulating hormone receptor (TSHR), are expressed in the orbital fibroblasts and pre-adipocytes
The key elements are:
binding and activation of orbital fibroblasts by autoantibodies
complex interactions of fibroblasts with T cells and the deposition of extracellular matrix molecules
proliferation and differentiation of fibroblast subsets into either fat-laden adipocytes scar-forming myofibroblasts result in the increased orbital connective tissue volume and remodeling

11. Graves' Disease Graves' ophthalmopathy (GO)
Thyroid. 2008 September; 18(9): 959–965

12. Graves' Disease Graves' ophthalmopathy (GO) Tests for Ophthalmopathy
GO is often mild and self-limiting, and probably declining in frequency, with only 3–5% of cases posing a threat to eyesight
20% may not have eye signs and 10% of people with eye signs may not have Graves' disease
Tests for Ophthalmopathy
The measurement of eye prominence by means of an exophthalmometer
Formal visual-field testing, as well as orbital imaging, is needed in patients with severe eye disease
Patients with clinically significant symptoms or findings should be referred to an ophthalmologist

13. Graves' Disease Management of Graves' disease
Most are managed by pharmacological methods - by endocrinologists
The symptoms are alleviated and the production of thyroxine is blocked using sympathetic blockers and
Thianamides
months of treatment is usually recommended
Remission of 50% or more is quoted
The autoimmune process recedes and patients will remain in remission. No further therapy is needed
Others will relapse and further treatment including surgery must be considered

14. Graves' Disease Role of Surgery 3 main indications for Surgery
For failed medical therapy or complications of antithyroid drugs
Compressive symptoms in larger goitres/nodules
Suspicion of malignancy

15. Graves' Disease Other indications
Pregnant women requiring high doses of
antithyroid drugs
Patients who decline treatment with radioiodine
or prefer surgery
Surgery is also considered in patients with larger
toxic goitres as other modalities are less likely
to succeed

16. Graves' Disease Does Graves disease increase the risk of thyroid
carcinoma?
There is some evidence that it does

17. Graves' Disease Thyroid Nodules in Graves disease
Patients with Graves Disease are 2- 3 times more
likely to have a thyroid nodule
About 20 % of these nodules are malignant
Are they more aggressive than euthyroid counterparts ?
- some think so
Belfiore A, Russo D, Vigneri R et al (2001) Graves' Disease, thyroid nodules and thyroid cancer Clin Endocrinol (oxf) 55:

18. in Graves' patients with
Graves' Disease
Graves Disease & thyroid Cancer
% Cancer
Reference
No. patients studied
in Graves' patients
in Graves' patients with
clinical nodules
Shapiro et al., 1970
172
8·7
Dobyns et al., 1974
100
0·4 13
Hancock et al., 1977
457
1·5
Wahl et al., 1982
178
1·1
Farbota et al., 1985
117
5·1
Behar et al., 1986
194
5·2
Pacini et al., 1988 86
6·9
22·2
Ozaki et al., 1990
743
2·6
Clinical Endocrinology Volume 55:6; 711–718, December 2001

19. in Graves' patients with
Graves' Disease
Graves Disease & thyroid Cancer
% Cancer
Reference
No. patients studied
in Graves' patients
in Graves' patients with
clinical nodules
Belfiore et al., 1990
132
9·8
45·8
Hales et al., 1992
886
1·8
5·8
Terzioglu et al., 1993 33
6·0
Chou et al., 1993
674
1·5
Miccoli et al., 1996
140
9·3
Pomorski et al., 1996
704
0·4
Pellegriti et al., 1998
450
4·7 (clinical)
3·3 (occult)
Carnell and Valente, 1998
468
1·3 10
Cantalamessa et al., 1999
315
0·3
2·3
Kraimps, 2000
557
3·8 15
Clinical Endocrinology Volume 55:6; 711–718, December 2001

20. Graves' Disease Occult Carcinoma in Graves' disease
Incidental thyroid cancers are detected in 3% -16.6% of apparently benign goiters  
The Cooperative Thyrotoxicosis Follow-up Study found that thyroid cancer was twice as common in Graves' disease patients than in euthyroid individuals
Dobyns BM, Sheline GE, Workman JB, Tompkins EA, McConahey WM, Becker DV
J Clin Endocrinol Metab Jun;38(6):976-98
The clinical course of these tumours is unknown
Other have shown them to be more aggressive

21. Graves' Disease Occult Carcinomas in benign disease in Sri Lanka
Incidence of occult carcinoma is 5/ %
Mean age - 52 (SD±13.3) years
Range- 32 to 67 years
Male : Female = 1:4
All detected by histology- post operatively
Indication for surgery n
Primary thyrotoxicosis 1
Multi nodular non toxic goitre 3
Multi nodular toxic goitre
R Fernando, DSG Mettananda, L Kariyakarwana.
Ceylon Med J. 2009 Mar;54(1):4-6

22. Graves' Disease
Occult Carcinoma

23. Graves' Disease
Role of surgery
Only 10% – 15% will require surgery

24. Graves' Disease Surgery in Graves disease
Thyroidectomy for the treatment of Graves' disease
has a history of more than 100 years
Most of the early thyroidectomies were for Graves' disease
Theodore Kocher & Thomas Dunhill
were great exponents of surgery for Graves' disease
The good outcome has been clouded by complications
and the need to be on life long thyroxine therapy
No clear consensus has been reached (perhaps - never!)

25. Graves' Disease Which Procedure ? No Consensus Total Thyroidectomy
Subtotal Thyroidectomy ( difficult to define)
Near Total Thyroidectomy ( less than 1gr of tissue left behind)
Hartley Dunn Procedure ( 7gr remnant left on one side)
Total Thyroidectomy is becoming the preferred choice
(some evidence)

26. Graves' Disease Advantages of a total Thyroidectomy - evidence based
Complication rate no higher than a lesser procedure
Higher cure rates
Negligible recurrence

27. Implications of Subtotal Procedure
Graves' Disease
Implications of Subtotal Procedure
May worsen the eye signs?
Recurrence (remnant size) - unpredictable
Complications of re-do surgery
Treats an occult carcinoma inappropriately

28. Graves' Disease Who Should undertake surgery ?
In Sri Lanka thyroid surgery is done by general surgeons, some E.N.T/ Head & Neck surgeons
Consensus is unlikely
Should at least have an interest in endocrine surgery
Should not be undertaken by ‘occasional’ thyroid surgeon
Should do at least 50 thyroidectomies a year (one a week)

29. Graves' Disease Preparation for Surgery Patient must be euthyroid
Lugol’s iodine to reduce vascularity of the gland based on the Wolff - Chaikoff effect once popular, is not used much now
Tends to make the gland hard and difficult to handle during surgery
Do not stop antithyroid drugs

30. Graves' Disease The surgery
Meticulous surgical technique with parathyroid and nerve preservation and capsular dissection
Should be conversant with parathyroid auto transplantation

31. Graves' Disease Drain or No drain ? - No evidence that drain helps
The thyroid glands tend to be larger - due to endemicity?
Average gland weight of toxic glands at surgery is 105gr (168gr for non toxic benign goitres)
Drain or No drain ? - No evidence that drain helps

32. Graves' Disease Surgical Practice in Sri Lanka
Pre tested questionnaire sent to 100 surgeons
replies anonymous
For Graves' Disease
35% performed subtotal thyroidectomy
35% performed total thyroidectomy
13% performed near total thyroidectomy
17% did not offer surgery / consider surgical treatment

33. Graves' Disease Level of experience and choice of procedure
0-14 years years/more Total
Total Thyroidectomy
Near Total Thyroidectomy
Subtotal Thyroidectomy
Younger surgeons are doing more total thyroidectomies

34. Graves' Disease Post Operative Events
Post-operative “thyroid crisis” is a rare phenomenon now
Good pre- operative control eliminates the possibility
Only one patient - controlled with β blockage & supportive therapy
“Hungry Bone Syndrome” - Thyrotoxic-Osteodystrophy
Patient with severe disease tend to be come Hypocalcaemic
due to avid absorption of calcium by the bones post operatively - Needs intravenous calcium supplemented by oral calcium usually - start calcium prophylactically

35. Graves' Disease Management in Children
Unlike in adults current evidence favour ablative therapy
RAI or Surgery
Depends on the parents wishes and the available
expertise

36. Management of Ophthalmopathy
Graves' Disease
Management of Ophthalmopathy
Systemic and intraocular glucocorticoid agents
Anti-inflammatory and immunosuppressive agents
Radiation
Corrective surgical procedures

37. Graves' Disease Summary
Graves 'disease is an organ specific immune disorder
of the thyroid
In adults there is no evidence to support one form of therapy
over the others
Most patients do not require surgery
Incidence of nodules & occult carcinoma in Graves is
an important consideration especially in selecting surgical
options
Graves’ Ophthalmopathy requires special attention

38. Graves' Disease Summary - Surgery
The current evidence indicate that total thyroidectomy is the better option, if surgery is recommended
Those undertaking surgery for Graves' Disease, should aim to achieve the bench mark standards RLN &EBSLN injury rate less than 2%
Protecting the parathyroid glands or auto transplanting when required- rate of permanent hypocalcaemia below 2%
While many surgeons will undertake thyroidectomy an argument could be made for the difficult cases to be referred to a centre with experience and expertise to obtain the best outcome for the patient

39. Graves' Disease Areas that need further study
Genetic factors associated with susceptibility to Graves' disease & the factors that trigger the disease
The clinical picture and course of disease in endemic and non endemic areas of goitre
Pathogenesis of Graves' orbitopathy and dermopathy
The choice of treatment with antithyroid drugs versus radioiodine
The appropriate duration of treatment with antithyroid drugs in order to induce remission, the mechanism of remission
The optimal therapeutic targets in women with Graves' Disease during pregnancy 
Best surgical option

40. Thank you