Current Concept in Graves

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Abbreviations
usu occ dev p/w w/n usually occasionally developed present with with in change

Introduction
Most common hyperthyroidism in dev world (60-80%)
20-50 years Genetic + Environment If no Rx, Psychosis, Tachyarrhythmia, Cardiac failure

Introduction
Known as Exophthalmic goitre Robert James Graves, who described the condition in 1835; 1st described by Parry in 1825 Common
Women (F:M ; 5-10:1) Smokers Autoimmune diseases FH of thyroid autoimmunity
Robert James Graves, M.D., F.R.C.S. (1796 20 March 1853)

Etiology
TSI stimulate TSH-r follicular cell growth (T3, T4)
TSI indirectly measure by TBII assay HLA-DRB1-08, DRB3-0202, CTLA-4, CD25, PTPN22
Risk factor
Stress Smoking

Aggravating factor
Sudden I- intake after HAART or Alemtuzumab Recent childbirth Infection

Clinical Features
Usu acute, reflecting sudden TSI but may be indolent Classical symptoms of hyperthyroidism
Wt loss Heat intolerance Irritability Insomnia

Cosmetic
Goitre, eye changes Hair loss

Sweatiness Diarrhea Palpitations Muscular weakness Menstrual irregularity.

Clinical signs
Diffuse goitre
Fine resting tremor Tachycardia Hyperreflexia Lid lag

Warm and smooth skin

Proximal myopathy Atrial fibrillation Thyroid bruit

Apathetic hyperthyroidism
Elderly are more likely to p/w subtle symptoms such as depression and wt loss
AF or CHF

Graves Ophthalmopathy
Clinically apparent in 30-50%
> 70-80% by orbital imaging (EOM enlargement) TSH-R shared autoAg in EOM Usu, simultaneously or w/n 18 months, although occ may precedes or follows the onset of hyperthyroidism by many years

 Late disease; irreversible fibrosis Exophthalmos, Chemosis, Periorbital edema, Exposure keratitis, Excessive tearing, Photophobia, Lid lag, EOM (vertical/lateral gaze), diplopia Acute in VF/VA, diplopia or the inability to close the eyelids consult ophthalmologist

Graves dermopathy
Most uncommon manifestation
usu appears later 99% have Graves orbitopathy Hyaluronic acid , Chondroitin sulfates lymphatic obstruction

Investigations
Serum TSH is a sensitive Less commonly, Graves disease may display subclinical hyperthyroidism or T3 toxicosis TSH-R Ab +ve in 90%
TSH-receptor binding Ig (TBII) Stimulating antibodies (TSI)

TBII
risk of relapse after a course of thionamides risk of neonatal Graves' disease

Investigations
Ab to TPO, Tg are not specific, may also be detected in
Hashimoto's thyroiditis type I diabetes mellitus 525% of the general population

 Tc-labelled thyroid scintigraphy

distinguishes Graves' disease from thyroiditis or an autonomously hyperfunctioning nodule

Radionuclide uptake may be affected by

amiodarone within the past 12 months iodine load (usually by intravenous radiocontrast dye within the past month Thyroxine or high-dose thioamide therapy for prolonged periods.

In such patients, thyroid U/S may be useful.

Thyroid ultrasound
prevalence of thyroid CA is not increased in Graves' disease
Suspicious features
Hypoechogenicity irregular edges microcalcification

Effects of Hyperthyroidsim
BMD EKG
CT scan of the neck

Treatment

Treatment
risks of psychiatric illness, cardiac disease, arrthymia and sudden cardiac death three treatment
thionamides (antithyroid drugs) radioactive iodine (RAI) therapy Surgery

Surgery has the highest long-term remission rate (95%)

Thionamides
since the 1940s propylthiouracil (PTU) and methimazole (MMI) Carbimazole is a prodrug of MMI blocking the synthesis of thyroid hormone PTU inhibiting peripheral conversion of T4 to the more active T3 may also possess immunosuppressive and antiinflammatory properties

Thionamides
MMI has a longer intrathyroidal half-life allowing for once-daily dosing PTU is usually administered three or four times daily case reports of fulminant hepatitis and liver failure in young adults treated with PTU

Thionamides
potential side effects
rash, arthralgia ANCA-positive vasculitis hepatitis agranulocytosis

rare idiosyncratic reaction affects 0.10.3% no recommendation for the routine measurement of the white cell count

Thionamides
Elevations in hepatic transaminase levels may either be a direct effect of thyrotoxicosis or related to medication use PTU may cause hepatocellular inflammation MMI typically results in cholestatic dysfunction

Thionamides
The dose of thionamides should be individualized de pending on the initial severity aim of normalization of T4 and T3 followed by serum TSH MMI of 1530 mg is usually adequate monitoring of thyroid function tests after 4 weeks and then 2- to 3-monthly thereafter weaned to a maintenance daily dose of 5 mg

Thionamides
PTU would be from 50 to 150 mg three times daily combining thionamides with thyroxine (the block-and-replace regimen) allow a higher dose and longer duration of thionamide Systematic reviews have not demonstrated any improvement in remission rates in patients taking the block-and-replace regimen as compared with a standard regimen

Thionamides
long-term remission rate is generally about 50% no evidence that treatment duration should be determined by changes in the titre of TSHreceptor antibodies. greater remission rates in those treated for 18 versus 6 months no difference in remission rates in those treated for 24 versus 12 months

Thionamides
most authors recommend a 1218-month course after establishing a state of euthyroidism clinical assessment and thyroid function tests within 3 months, followed by annual testing, to assess for relapse definitive therapy with radioiodine or surgery in the event of relapse Patients high risk to surgery or radioiodine, or elderly , significant comorbidities, continue longterm treatment with thionamides may be appropriate

Other Drugs
Nonselective beta-blocker drugs are useful adjuncts for rapid symptomatic relief propranolol is believed to block the peripheral conversion of T4 to the more active hormone T3 and has greater effect on tremor than other more B-1 selective blockers

Other Drugs
Glucocorticoids also inhibit peripheral conversion of T4 to T3 and reduce thyroid hormone secretion use in patients with severe hyperthyroidism and thyroid storm combination with thionamides, cholestyramine assists in reducing serum T4 and T3 concentrations lithium blocks thyroid hormone release but rarely used due to toxicity

RAI Treatment

RAI Treatment
following an unsuccessful course of thionamides or as initial therapy Thionamides should be discontinued several days before the admini stration of RAI persistent hyperthyroidism patient poses serious risks thionamides may be restarted shortly after RAI in order to control the hyperthyroidism while awaiting effect

RAI Treatment
Following a dose of RAI
approximately 80% of patients eventually become hypothyroid 10% remain euthyroid 10% will need a second or third ablative dose

dose of RAI may be fixed or determined on the basis of the gland's radionuclide uptake and volume

RAI Treatment
Side effects of RAI include transient sore throat and radiation thyroiditis 1% transient increase in thyroid hormone production and may be treated with a thionamide elderly, pre-existing cardiac disease, severe thyrotoxicosis, should receive thionamide therapy prior to RAI, as this possibly reduces the risk of radiation thyroiditis.

RAI Treatment
Several studies have suggested an association between RAI and exacerbation or development of thyroid eye disease may possibly be due to the increased production of TSH-receptor auto-antibodies or an increase in circulating antigenic stimuli some experts consider severe thyroid eye disease to be a contraindication to RAI

RAI Treatment
Current practice is to treat patients with severe active eye disease with prednisolone 3050 mg daily, commencing on the first day of RAI and weaning over 68 weeks.
abstain from intercourse for 24 hours and wait a minimum of 6 months before attempting pregnancy

Surgery

Surgery
effective risks associated with
general anaesthesiarecurrent laryngeal nerve palsy transient or permanent hypoparathyroidism

third-line therapy

Surgery
useful for
patients who decline or cannot tolerate treatment with thionamides or RAI Large or compressive goitres suspicious nodules

Management of Graves' Disease in Pregnancy

PTU is safer in pregnancy due to the association of MMI with a rare birth defect, aplasia cutis recommendations PTU be used during the first trimester and then switched to MMI in the second and third trimesters to minimize the risk of hepatitis many centres, PTU is still used throughout pregnancy

Management of Graves' Disease in Pregnancy

As pregnancy is an immunomodulatory state Graves' disease tends to improve or remit as gestation progresses thionamide therapy to be weaned or ceased As thionamides cross the placenta, close monitoring of maternal thyroid function tests to minimize the risk of foetal hypothyroidism aim of maintaining TSH concentrations in the lower third of the normal range

Management of Graves' Disease in Pregnancy

TSH-receptor antibodies cross the placenta and levels should be measured in the third trimester as high levels correlate with risk of neonatal Graves' disease ultrasonography to monitor foetal development and check for the presence of foetal goitre may be useful

Management of Graves' Disease in Pregnancy

foetal goitre may be due to either overtreatment with thionamides or foetal Graves' disease warned of the likelihood of relapse of their Graves' disease in the postpartum period

Novel Agents
Rituximab, a monoclonal CD20 antibody, may induce a sustained remission in patients who have low TSH-receptor antibody levels as well as ameliorating the signs of thyroid eye disease However, its utility is limited by both cost and toxicity. novel small-molecule ligands bind to the TSHreceptor remain preliminary studies

Special Thanks