GRAVES DISEASE

INCIDENCE
Most common form of thyrotoxicoses 6 times more common in women Most prevalent in young adults Extrathyroid manifestations include: 1.Exomphalos 2.Pretibial myxedemea 3.Dermopathy 4.Acropachy 5.Vitiligo

PATHOGENESIS AND PATHOLOGY

Autoimmune disorder Thyroid stimulating antibodies(TsAB) or immunoglobulins are directed at the TSH receptor on thyroid follicular cell.

TSH bonding(TsSB) or (TSI)

(AGONIST ACTION) Block TSH Receptor

MACROSCOPICALLY
Gland is diffuse and smoothly enlarged. Gland hyper vascular.

MICROSCOPICALLY

Gland is hyper plastic Epithelium is columnar with minimal colloid present Nuclei exhibit MITOSIS Papillary projection of hyper plastic epithelium Aggregates of lymphoid tissue Vascularity increased Hyperplasia of acini Acini lined by columnar epithelium Many of them are empty and others contain vacuolated colloids, givin characteristic SCALLOPED Patteruadjacent to thyrocytes.

Clinical Features

Graves Disease a diffuse toxic goiter appearing at the sam time as hyperthyroidism, usually occurs in young women frequently associated with eye signs The syndrome is of primary thyrotoxicosis 1.Graves disease is characterized by classical Goitre Thyrotoxicosis Exopthalmos 2.Most significant symptoms are Loss of weight despite good appetite Recent preference for cold Cc onset palpitations

3.Other Symptoms

Tiredness Emotional Lasibility Heat Tolerance Weight Loss Excessive appetite Palpitation
Excitability of Pt Presence of goiter Exopthalmos Tachycardia Cardiac Erthmia

4.Most Significant Signs

5.Other Signs
Hot/Mosit palms Thyroid bruit Lidley/retractions

6.Family H/O automimmune thyroid disease-50% cases Graves Disease/Hashimotos thyroiditi 7.Decreased fertility/amenorrhea/miscarriage 8.On examination Goitre Diffuse Vascular Large/small Firm/soft Thrill + Bruit + Onset abrupt Remissions & exacerbations not frequent 9.Hyperthyroidism is more severe than in secondary thyrotoxicosis but cardiac failure is rare.

10.Manifestations of thyrotoxicosis not due to hyperthyroidism Opthalmoplegia Orbital proptosis Pretibial myxedema 11.Cardiac rhythm Fast heart rate which persists during sleep is characteristic during sleep.cardiac errythmias then superimpose on serious tachycardia as the disease progresses. Stages of development of thyrotoxic errythmias i. Multiple Extrasystole ii. Paroxysmal arterial tachycardia iii.Paroxysmal arterial fibrillation iv.Persistant arterial fibrillation not responsive to digoxin.
12. Myopthy- weakness of proximal limb muscles.

13. Eye Signs i. Exopthalmos May be unilateral. True Ex- Proptosis of eye, caused by infiltration of retrobulbar tissues with fluid & round cells with varying degree of spasm of upper eye lid. ii. Lid Spasm-LPs muscle is partly innervated by sympathetic fibres. This results in widening of palpetoral fissure so that the scelra may be seen clealy above the upper margins of corne(DALRYMPESs) iii. Lid Lag (VON GRAEPES SIGN) iv. Extraocular muscle weakness(Particularly elevators-IO) Results in diplopia v. Supra/Infraorbital swelling

vi. Stellwag Sign-Absence of N blinking-so person has starring

look. vii. Joffroy Sign-Absence of wrinkling on forehead. viii. Lack of convergence of eyeballs.(MOEBIUS SIGN) ix. Giffords Sign-Difficulty in inverting the upper eyelid in primary toxic goitre.Differenciates from exopthalmos of other causes. x. Naffziger Sign-With P+ in sitting position & neck fully extended,protruded eye ball can be visualized when observed from behind. xi. Severe exopthalmos Eyelid edema,chemosis,conjuctival injection Diplopia,opthalmoplegia(weakness of elevator muscles-IO) Corneal ulcer Papilloedema Also C/D malignant exopthalmos(MISNOMER)

Cardiac Manifestation Tachycardia Ectopies Pulsusparadoxus Wide pulse pressure/Apex Pulse Arythmias-defect Pretibial Myxedem(MISNOMER) It is usually bilateral,symmetrical,shiny red thickened,dry skin with coarse hair in feet and ankle. Due to deposition of myxomatous tissues(mucin-like deposits) in skin and subcutaneous plane. 16. Thyroid acropachy is clubbing of fingers and toes in primary thyrotoxicosis.
14. 15.

INVESTIGATIONS 1) Thyroid Function Test

Type Of Disease
Conventional Hyperthyroidis m T3 Hyperthyroidis m Subclinical Hyperthyroidis Serum T3 & m

T4
Increased

T3
Increased

TSH
Decreased or not detectable Decreased or not detectable Decreased or not detectable is very low or

Increased

T4 levels are very high.TSH undetectable. Sometimes only T3 level is increased as C/D T3 toxicosis. Herein T3 toxicosis,free T3 istimation is important.

2) USG

3) TsAB TSI

-Solid and cystic lesions. - Can also differenciate nonpalpable nodules -Thyroid stimulating Antibody -Thyroid stimulating immunoglobin estimation.

4) Isoptope Scan Main stay of investigation of discreet thyroid swelling to determine the functional activity relaive to the surrounding gland according to isotope uptake. But in Graves Disease there is diffuse uptake throughout the gland. An uptake of 45-90% is observed usually but practically has no value.
5) Chest X-Ray & X-Ray Neck When there is clinical C/O,tracheal deviation or compression for former & X-ray neck for retrosternal extensions.

6) Indirect Laryngoscopy Used preoperatively to determine the mobility of the vocal cords although usually for Medicolegal than clinical reasons. 7) ECG -To look for cardiomyopathy -Atrial Fibrillation -Ectopic beats 8) Total count and neutrophil count are very essential as a baseline investigation before starting antithyroid drugs(Agranulocytosis) 9) Serum Calcium Estimation

TREATMENT
Principles Of Treatment 1) Make the patient Enthyroid by antithyroid drugs & maintain this for prolonoged period in hope permanent. Re-emmision can occur i.e. that production of TsAb ceases. 2) It should be noted that anti-thyroid drugs cannot cure a toxic nodule because here over active thyroid tissue is autonomous & recurrence of hypethyroidism certainly occurs if oxygen is discontinued. 3) Anti-thyroid drug may worsen exopthalmos. Therefore, careful observation with steroid supplementation can be considered.

I)
a)

Antithyroid drugs
Carbimazole(most commonly used) MOA = Acts by blocking thyroid peroxidase & prevents oxidation of iodide. Dose = 5-10mg 8hourly ADR = agranulocytosis, GI intolreance, Skin rashes, Joint pains,liver damage. Pharmacoanomalies = Orally absorbed carbimazole

Methimazole

T - bhrs Can cross Placenta

b)Propyl thiouracil MOA = Same as carbimazole Also inhibits peripheral conversion of T4 to T3. Dose = 50-150 mg TDS Pharmacokinetics = Doesnt cross placenta,hence used in pregnant females. ADR = Same as carbimazole c) Other drug not commonly used = Methimazole = 5-20mg TDS with same MOA as carbimazole. d) Propanolol 40mg TDS (Non selective blockers) Dose = Propanolol 40mg TDS Nadolol 160 mg OD MOA = Rapidly elevates manifestations of thyrotoxicosis that are due to sympathetic activity. - Palpitations - Temors - Nervousness - Severe Myopathy - Sweating

Indications -thyrotoxic crisis -while awaiting response to carbimazole or I131 to cure sympathetic manifestation of thurotoxicosis e) Lugods Iodine (5% I2 +10% KI) Advantages - Increases vascularity of the gland - Makes it more firm & easier to handle during Sx. - Immediate Preoperative preparation 10 days before Sx Dose 10-30 drops/day x 10days prior to Sx. f) Block & Replacement Therapy It is giving carbimazole + L thyroxine carbimazole. Inhibits T3/T4 with maintainence dose of 0.1mg of L-Thyroxine

Advantages - It reducesiatrogenic thyroid insufficinecy Advantages of Anti-thyroid Drugs - Avoids Sx and its complications - Avoids radio iodine therapy

Disadvantages 1) It is impossible to predict which patient is likely to go into permanent remission although - large gland size - severity of disease - TsHAS levels Are indicators of poor prognosis.

2) Some goitres enlarge and become very vascular during Re,probably due to TSH Ras stimulation. 3) Agranulocytosis or aplastic anaemia. (Dangerous drug Rxn)

Liver Damage
Sore throat is the earliest presentation of agranulocytosis.

- Drug is stopped - TLC count done - Confirm agranulocytosis, - l/v 10-20 benzyl penicillin to prevent infection - It requires blood transfusion - To control toxicity, T.Propanolol 40mg TDS - Rarely need bone transplantation

Plau

Start with high dose 10 mg carbimazole TDS/QID

till P+ becomes biochemically euthyroid

Start low dose 5mg maintainance BD/TDS for 6-24 months

Alternative technique(Block and Replacement therapy)

- Permanent Cure(Levels of TSH RHb usually fall during Rx) is seen in 50% patients with drugs. - Anti thyroid drugs can be combined with sedation and rest. Indications of anti thyroid drugs i. Tocixity in pregnant women, propylthiouracil is preffered ii. Toxicity in children and young adults iii. Before Sx to make P+ euthyroid iv. Soon after starting Radioactive I131 therapy x 6-12 weeks (effect of RT start only in 6-12 weeks) v. Thyrotoxic action II) Treatment of Severe Exopthalmos i. Advice to sleep propped up ii. To wear dark spectacles or eye patches.

iii. Massive doses of prednisone is helpful. iv. Intr orbital injections of steroid are dangerous because of

- venous congestion - Total thyroid asslation has not proved effective. v. When eye is danger, orbital decompression is required(DYSTHYROID EXOPTHALMOS) Antithyroid drugs may worsen exopthalmos and the patient should be observed once thyroid drugs are started as steroid supplementation may be required.
vi. I/V antibiotics to prevent secondary infection vii. Guanethydine eye drops

Steroid eye drops Antibiotic eye drops viii. Lateral tarsorrkaphy ix. Local Radiation Therapy

Surgery Indications of Surgery i. Failure of drug Rx in primary thyrotoxicosis in young pt.(<45 yrs) ii. Autonomous toxic module iii. Multi nodular goitre iv. When malignancy cannot be R/O Clinical suspicion = Age/male sex/hard texture/fixity/RCN palsy/Lymphadenopathy/recurrent cyst. v. Cosmesis/Patiarts WISHES Rational for Sx i. Sx cures by reducing the mass of overactive tissue

Cure is probable if the thyroid tissue is decreased below a critical mass.This may result in reduction of TSH RAB or it may be that TSH Rab,however high levels can produce limited hypertrophy and hyperplasia when mass of thyroid tissue is small. Advantages of Sx Cure is rapid and cure rate is high.
ii.

Disadvantages i. Recurrent thyrotoxicosis(5%) ii. Post operative thyroid insufficiency(20-45% of cases) Hyper thyroidism is better than recurrent thyrotoxicosis. It can be Rc by L thyroxine 0.1mg OD life long iii. Complications of thyroid Sx

Surgery For Thyrotoxicosis 1. Pre-operative preparation Patient is biochemically euthyroid Clinical signs of improvement

Wt gain Lowering pulse Serial estimation of thyroid profile

Carbimazole must be given(last dose) on the evening before Sx. If patient is on B blocking agent Propanol 40mg TDS Nadolol 160mg OD To be taken early morning on the day of Sx.

 If rapid control of hyper thyrotoxicosis is required, it is achieved by a) Carbimazole 30-40 mg

DRUG OF CHOICE

When euthyroid(8-12 weeks)

5mg 8 hrly OR b) Propanolol 80mg TDS Nadolol 320 mg OD B Blockers donot interfere with synthesis of thyroid hormones & hormone level remains high during Rx.Hence for a week post operatively must be supplemented as half life of L-Thyroxine is 7 days.Hence,carbimazole should also be continued x 7days after Sx.

OR c) Iodides- Lugols iodine consumed L carbimazole/B blockers Iodides - Decrease vascularity - Transient remission Gives an additional measure of safety incase the early morning dose of B Blocker is mistakenly ommited on the day of Sx. 2) Surgery Subtotal Thyroidectomy (2x subtotal losectomy + Isthmusectomy) Anaesthesia = GA Position Patient is supine on operation table with table tilted up 15 at the head end to reduce venous engorgement. A gel pad or sand bag is placed transeversly to the shoulder & neck extended(with care in particularly elder) to make the thyroid gland - More prominent - Apply tension on skin,platysma and muscles which make dissection easier

INCISION A gently curved skin crease incision is made between the notch of the thyroid cartilage & supra sternal notch. PROCEDURE i. Skin is cut and platysma flaps are raised. ii. Divide deep cervical fascia iii. Strap muscles are retracted. iv. 30% middle thyroid vein,ligated and divided v. Sup. Pole- arteries(branches of suprathyroid A. are ligated) individually ligated. vi. Inferior thyroid arteries are not routinely ligated to preserve blood supply to para thyroids if is to be ligated, then must be very close to thyroid gland. vii. RLN should be identified in its course in operative field.

viii. Parathyroid are protected by careful inspection of the

goitre before resection to retain the glands. Diathemy not used in this area. If parathyroid is damaged, auto transplanted immediately in several fragments with SCM muscle. Leave 4-5 gm on each side. ix. Absolute hemostasis secured. x. Deep cervical fascia, subcutaneous skin closed with suction drain in thyroid bed. xi. Post Operative Complications 1. Haeomrrhage Due to slipping of ligature on superior thyroid artery, occasionally from thyrod remanent or from thyroid vein may be responsible. Very rarely needs exploration in theatre & secure the bleeding vessels.

2.Respiratory Obstruction i. Collapse of trachea(seabbards trachea),ready for emergency Tracheostomy or late extusation. ii. If after hematoma, evacuation, respiration does not improve, Intusation and steroids later on may require permanent tracheostomy. iii. Other cause could be bilateral RLN injury-collapse of vocal cords. iv. Temporary measure-Needle tracheostomy (12G)-diameter 2-3 mm is highly satisfactory. 3. RLN Palsy May be unilateral or bilateral. It can be Transient or Permanent Occurs in 3% nerves at risk Recovers in 3 weeks to 3 months

Rare if nerve identified at Sx.

4. Thyroid Insufficiency Occurs within 2 years but sometimes delayed for 5 years. 5. Parathyroid Insufficiency Due to removal of the parathyroid glandsor infarction through damage to parathyroid end artery. Incidence <0.5% Most cases present 2-5 days Rarely 2-3 weeks Very patient asymptomatic Rc calcium supplements 6. Wound Infection 7. Hypertrophied or Keloid Scar 8. Stitch Granuloma

9. Thyrotoxic Crisis This is an acute exacerbation of hyperthyroidism. It occurs if a thyrotoxic patient has been inadequately prepared for thyroidectomy and is now extremely rare. Symptomatic and supportive Rx is for Dehydration - Hyperpyrexia - Restlessness Rx i. I/V Fluids ii. Cooling patient with ice iii. Administration of oxygen iv. Diuretics for cardiac failure v. Digoxin for uncontrolled atrial fibrillation

vi. Sedation

vii. I/V Hydrocortisone

viii. Specific Rc

Carbimazole 10-20 mg 6 hourly Lufols I2, 10 drops 8 hourly ix. Sodium I2 1gm I/V x. Propanolol 40mg QID adversly will block B adrenergic effect

Can be given I/V 1-2mg

POST OPERATIVE CARE 1. If voice is N or cough unequivocally occlusive, it is not mandatory to carry out indirect laryngoscopy as routine before leaving hospital. Any persisting voice change at subsequent view should prompt visualization of cords. 2. About 25% patients develop transient hypocalemia Rx Ca Glucuronate I/V, then oral Ca. Screen for parathyroid insufficiency 4-6 weeks after Sx. 3. Biochemical thyroid failure should not be indication for Rx with L-Thytoxine during the first year. 4. If patient develops clinical hypothyroidism, thyroxine should be withheld if possible during the first 6 months after Sx. 5. Recurrent thyrotoxicosis(5%) R/U therefore should be till life. Rc-Radio I2 or anti thyroid drugs in females who intend to have children

6. Thyroid Failure(20-45%) L-thyroxine 0.1mg OD-TDS.

Radio Iodine Therapy

IV) i. ii. iii. iv.

Indications Primary thyrotoxicosis after 45yrs of age In autonomous toxic nodule In recurrent thyrotoxicosis In some countries used in younger individuals MOA = Radioiodine destroys the cells and causes complete ablation of the thyroid gland. I131 is concentrated by thyroid, incorporated in colloid units. Radiation from within follicles only penetrate0.5-2mm of tissue.Therefore N surrounding tissue is spared. The thyroid follicular celss are affected from within,undergo Pkynosis & necrosis followed by fibrosis. Response to first dose is slow, 8-12 weeks. Accurate dosing is difficult. If there is no clinical improvement, 2nd dose can be given after 12 weeks.2 or less than 2 doses are required.

DOSE Usual dose 5-10 millicurie or 160 microcurie per gram of thyroid. It takes 3 months to get full response(6-12 weeks) Therefore give anti-thyroid drugs To give therapeutic doses, patient should be admitted and isolated for 7 days to prevent irradiation.

It is given soon orally, mixed with milk after manufacturing without much delay to have optimal effect/Advise not to urinate in open surroundings.

Advantages No Sx No prolonged therapy Once hyperthyroidism is controlled, cure is permanent. Disadvantages i. Isotope facilities not available everywhere. ii. Proper F/U is not available. iii. Hypothyroidism
About 75-80% develop thyroid insufficiency at 10years. - Rx L-Thyroxine 0.1mg OD This due to sublethal damage to those cells not actually destroyed by minimal Rx and this eventually causes failure of cellular reproduction. Therefore ,indefinite F/U is essential.
-

iv. Large dose- thyroid failure within 6 Months

Small Dose Patient Euthyroid but life long survillience to detect thyroid insufficiency vi. C/I during pregnancy-Feotal thyroid also destroyed(cretinism) vii. Not suitable for young patients- Risk of life long Rx by L-Thyroxine-Hypothyroidism.
v.

Genetic damage/teratogenic potential is feared but there is no evidence for it.

V) Special Problems in Rx a. Pregnancy Radioactive iodine is absolutely C/I- cretinism in newborn Danger of Sx is misscarriage, but in competent hands, second trimestic is small Careful administration of anti thyroid drugs(propyl Thiouracil) less transferred across placenta because more plasma protein bound b. Post partum hyperthyroidism Pregnancy leads to exacerbation of variety autoimmune disease in PPP c. Children

Radio iodine CI because theoretical risk of inducing thyroid carcinoma. Recurrence after Sx is high because thyroid cells are highly active in young. Best is to start antithyroid drugs until late teens,failing which total or near total thyroidectomy by an expert Sx.

d) Severe cardiac damage resulting from

hyperthyroidism(THYROCARDIAC) - cardiac opinion - B Blockers - Radio I2 is Rx of choice with anti thyroid drug till radio I2 effect. e) High titres of thyroid anti bodies Best Rx with anti thyroid drugs, but if medical Rx fails then Sx or Radio iodine Steroid may help to reduce pain swelling. f) Proptosis of recent onset Patient Rx with antiantithyroid drugs + steroids until proptosis become static x 6months

Then followed by Sx.(Subtotal thyroidectomy)

Differential Diagnosis 1. Thyrotoxicosis factita Hyperthyroidism may be induced by taking thyroxine but if only dosage exceeds N requirement 0.15-0.25 mg/day. 2. Jod Basedow thyrotoxicosis (Large doses of iodine given to endemic hyperplastic goitre) 3. Subacute/Acute de Querrcains thyroiditis - mild hyperthyroidism 4. Secondary carcinoma of thyroid Hyperthyroidism in neonates 5. Neonatal thyrotoxicosis Babies born to hyperthyroid mothers who have had thyrotoxicosis,high TSH RAS present both in mother and child because TSHRAS crosses placental barrier. Rx Observation as hyperthyroidism gradually subsides in 3-4 weeks as TSHRAS titres fall in serum.