GRAVES DISEASE

PRESENTING TEAM: ENDOCRINOLOGY UNIT.

PRESENTER: DR. NWAGBARA CT. DATE: 6TH FEBRUARY, 2013.

OUTLINE

Introduction Epidemiology Pathophysiology Clinical features Differential diagnosis Investigations Treatment Conclusion References

INTRODUCTION

Graves disease, named after Robert J. Graves, MD, 1830, is an autoimmune disease characterized by hyperthyroidism, ophthalmopathy and dermopathy. Thyroid stimulating immunoglobulins (TSIs) bind to and activate thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicle to increase sythesis of thyroid hormones.

Sometimes Graves disease is associated with other autoimmune conditions like; - Pernicious anemia - Vitiligo - Diabetic mellitus type 1 - Autoimmune adrenal insfficiency - Systemic sclerosis - Myasthenia gravis

- Sjogren syndrome - Rheumatoid arthritis - Systemic lupus erythematosis

Epidemiology

Prevalence of hyperthyroidism in the general population is 1.2%

0.7% subclinical hyperthyroidism 0.4% Graves Disease most common etiology; note there is overlap with the subclinical group

Graves Disease is more common in females (7:1 ratio)

The Classic Triad of Graves Disease

Hyperthyroidism (90%) Ophthalmopathy (20-40%)

proptosis, ophthalmoplegia, conjunctival irritation 3-5% of cases require directed treatment localized myxedema, usually pretibial especially common with severe ophthalmopathy

Dermopathy (0.5-4.3%)

There is also a close association with autoimmune findings (e.g. vitiligo) and other autoimmune diseases (e.g. ITP)

PATHOGENESIS

In Graves disease,B and T lymphocytemediated autoimmunity are known to be directed at 4 well-known thyroid antigens: thyroglobulin, thyroid peroxidase, sodiumiodide sympoter, and thyrotropin receptor. However, the thyrotropin receptor is the primary autoantigen of Graves disease and is responsible for the manifestation of hyperthyroidism.

Pathogenesis contd

Direct proof of an autoimmune disorder that is mediated by autoantibodies is the development of hyperthyroidism in healthy individual by transferring thyrotropin receptor antibodies in serum from patients with graves disease and the passive transfer of the thyrotropin receptor antibodies to the fetus in pregnant women.

Pathogenesis contd

The thyroid gland is under continuous stimulation by the circulating autoantibodies against the thyrotropin receptor, and pituitary thyrotropin secretion is suppressed because of the increased production of thyroid hormones. The stimulating activity of thyrotropin receptor antibodies is found mostly in the immunoglobin G1 subclass.

Pathogenesis contd

These will lead to stimulation of iodine uptake, protein synthesis and thyroid gland growth. Several autoimmune thyroid disease susceptibility gene have been identified: CD40, CTLA-4, thyroglobulin,TSH receptor and PTPN22.

Pathogenesis

An autoimmune phenomenon presentation determined by ratio of antibodies

Graves Disease

+
Thyroid TSH Receptor

Thyroid Stimulating Ab (TSAb)

Thyroid Stimulation Blocking Ab (TSBAb) Autoimmune Hypothyroidism (Hashimotos)

Thyroglobulin Ab

Thyroid peroxidase Ab (anti TPO)

Symptoms

General: fatigue , general weakness Dermatologic: warm, moist, fine skin; sweating; fine hair; onycholysis; vitiligo; alopecia; pretibial myxedema. Neuromuscular: tremors, proximal muscle weakness, easy fatigability, periodic paralysis in persons of susceptible ethnic groups. Skeletal: back pains, increased risk of fracture.

Symptoms contd

Cardiovascular: palpitations, dyspnoea on exertion, chest pains, edema. Respiratory: dyspoea Gastrointestinal: increased bowel motility with increased frequency of bowel movement. Ophthalmologic: tearing, gritty,sensation in the eye, photophobia, protruding eye, diplopia, visual.

Symptoms contd

Renal: polyuria, polydipsia Hematologic: easy bruising. Metabolic: heat intolerance, weight loss despite increase or similar appetite, worsening DM control. Endocrine/reproductive: irregular menstrual periods, amenorrhea, gynecomastia, impotence. Psychiatric: restlessness, anxiety, insomnia

Physical findings

Eyes: - Lid lag, - lid retraction - proptosis - periorbital edema - chemosis

Graves Ophthalmopathy

Antibodies to the TSH receptor also target retroorbital tissues

T-cell inflammatory infiltrate -> fibroblast growth Severe: exposure keratopathy, diplopia, compressive optic neuropathy

Strong link with tobacco

Classification of eye changes (NOSPECS)

0. No signs no symptoms Only signs (lid-retraction and lag), no symptoms Soft tissue involvement (symptoms & signs) Proptosis (>20mm by Hertels exopthalometer) Extra ocular muscle involvement Corneal involvement Sight loss (optic nerve involvement)

Ophthalmopathy in Graves

Periorbital edema and chemosis

Exopthalamos in Graves Disease

Lid Lag in Graves Disease

Dermopathy

Usually occurs over the dorsum of the legs or feet and is termed localized or pretibial myxedema. It is usually a late phenomenon The affected area is usually demarcated from the normal skin by being raised and thickened and having a peau d orange appearance ;it may be pruritic and hyperpigmented. The most common presentation is non pitting oedema, but lesions maybe plaque like, nodular or polypoid. Clubbing of the fingers and toes accompanies and is termed thyroid acropachy

Myxedema of Graves

Activation of fibroblasts leads to increased hyaluronic acid and chondroitin sulfate

Asymmetric, raised, firm, pink-to-purple, brown plaques of nonpitting edema

Thyroid Acropathy

Clubbing and
Osteoarthropathy

Physical findings contd

Neck: - thyroid gland enlargement - thyroid bruits - thyroid nodules may be palpable

Diffuse Graves disease

Graves Goitre

Physical findings contd

CVS: - murmur - hyperdynamic precordium - S3, S4 heart sounds - ectopic beats - irregular heart rates and rhythm

Differential Diagnosis

Toxic Multinodular Goiter Toxic Adenoma Thyroiditis

silent (Hashimotos) painless, often post partum subacute (de Quervains) painful, post viral drug-induced amiodarone, lithium, interferon

Thyrotoxicosis factitia

Differential diagnosis

Anxiety Pheochromocytoma Hydatidiform mole Ectopic thyroid tissue(struma ovarii) Pituitary macroadenomas Pituitary microadenomas Hyperemesis gravidarum

Laboratory Evaluation

Suppressed TSH (<0.05 uU/ml) Elevated Free T4 and/or Free T3

T3:T4 > 20 - Graves Disease - Toxic MN Goiter
T3:T4 < 20 - Non-thyroid illness - Thyroiditis - Exogenous thyroxine

Its Good to be Free

Thyroxin is 99% bound to thyroid binding globulin (TBG), albumin, and transthyretin

Elevated TBG in viral hepatitis, pregnancy, and in patients taking estrogens and opiates Decreased TBG binding with heparin, dilantin, valium, NSAIDs, lasix, carbamazepine, ASA Measuring Free T4 instead of total T4 avoids this problem all together

Laboratory Evaluation

Direct measurement of TSH receptor antibodies (TSAb and TBAb)

Can help with Graves diagnosis in confusing cases (as high as 98% sensitivity) Can predict new-onset Graves in the post-partum period

Anti TPO Antibody and anti Tg Antibody

Can be mildly elevated in Graves Usually most active in Hashimotos

Diagnostic Imaging

Radioactive Iodine Uptake

Provides quantitative uptake (nl 5-25% after 24h) Shows distribution of uptake
Distinguishes high-uptake from low-uptake Faster scan only 30 minutes Identifies nodules Doppler can distinguish high from low-uptake

Technetium-99 Pertechnetate Uptake

Thyroid ultrasonography

Treatment

Immediate Medical therapy and Long term therapeutic options

Immediate Medical Therapy

Thionamides inhibit central production of T3 and T4; immunosuppressive effect

Methimazole once daily dosing PTU added peripheral block of T4 to T3 conversion; preferred in pregnancy Side effects: hives, itching; agranulocytosis, hepatotoxicity, vasculitis

Beta-blockade decrease CV effects, also it inhibits the peripheral conversion of T4 to T3. High-dose iodine Wolff-Chaikoff effect

Long-term Therapeutic Options

Continued Medical Management

Low dose (5-10mg/day of methimazole) for 12 to 18 months then withdraw therapy Lasting remission in 50-60%
Discontinue any thionamides 3-5 days prior Overall 1% chance of thyrotoxicosis exacerbation Hypothyroidism in 10-20% at 1 yr, then 5% per yr Lasting remission in 85%

Radioiodine Ablation

Titration Regimen

titrate the dose of antithyroid drug, giving carbimazole (or methimazole) 20 mg two or three times daily, and then lowering the dose every 3 to 4 weeks or so, based on free T4 measurements, until a maintenance dose of 5 to 10 mg once daily is achieved. Equivalent starting and maintenance doses of propylthiouracil are 100 to 200 mg three times daily and 50 mg once or twice daily. Maximum remission rates occur after 18 to 24 months of treatment.

Block and Replace Regimen

start with the same dose of antithyroid drug but then to add thyroxine 100 g daily after 3 to 4 weeks when free T4 levels are usually becoming normal, rather than lowering the dose of drug. Thereafter the patient is maintained on 40 mg carbimazole or methimazole once daily (alternatively, 100 to 150 mg propylthiouracil three times daily) and thyroxine, the latter being adjusted if necessary 4 weeks after starting to achieve normal free T4 levels.

Long-term Therapeutic Options

Total Thyroidectomy

Indications: suspicion for malignant nodule, comorbid need for parathyroidectomy, radioactive ablation contraindicated, compressive goiter Recent metaanalysis showed this is the most cost effective if surgery is < $19,300. Prep with 6 weeks thionamides, 2 weeks iodide Hypoparathyroidism and/or laryngeal nerve damage in <2% Lasting remission in 90%

Treatment of Ophthalmopathy

Mild Symptoms

Eye shades, artificial tears

Oral steroids typical dosage from 30-40mg/day for 4 weeks Oral versus IV steroids Orbital Decompression surgery

Progressive symptoms (injection, pain)

Impending corneal ulceration, loss of vision

Treatment of Dermopathy

Milder cases do not require therapy other than Rx of thyrotoxicosis For severe cases, therapy with topical steroids applied under an occlusive plastic dressing for 3 -10 weeks Also pulse glucocorticoid therapy may be tried

Graves disease & Pregnancy

Risks: fetal anomalies, spont abort, preterm labor, fetal hyperthyoridism, thyroid storm in labor. No RAI ever Rx options: ATD or 2nd trimester thyroidectomy PTU drug of choice Avoid MTZ in first trimester due to scalp defects Aim to keep FT4 levels in hi normal range Use of iodides should be avoided because of the risk of neonatal goitre and hypothyroidism RAI causes congenital hypothyroidism

Thyroid Storm aka Thyrotoxic crisis

A life threatening hypermetabolic state due to hyperthyroidism Mortality rate is 10% Usually occurs as a result of previously unrecognized or poorly treated hyperthyroidism Thyroid hormone levels do not help to differentiate between uncomplicated hyperthyroidism and thyroid storm

Thyroid Storm

Precipitants of Thyroid Storm

Infection Trauma

DKA

MI

CVA
Surgery, Anasthesia induction

PE
Withdrawal of thyroid med

Iodine administration, RAI therapy Ingestion of thyroid hormone

Vigorous Palpation of thyroid gland Unknown etiology (2025%)

Thyroid Storm

Clinical features

The most common signs are fever, tachycardia out of proportion to the fever, altered mental status, and diaphoresis
Neurological manifestations: severe agitation, delirium, seizure & coma. Cardiac findings: tachycardia, hTN, high CO failure and propensity to dvlp cardiac arrhythmias.

Thyroid Storm

Clinical features cont.

Common GI symptoms include nausea, vomitting , diarrhea, abdominal pain, jaundice and hyperdefecation

Thyroid Storm

Diagnosis

Thyroid storm is a clinical diagnosis based upon suspicion and treated empirically Lab work is non specific and may include Leukocytosis, hyperglycemia, elevated transaminase and elevated bilirubin

Thyroid Storm

Treatment

Initial stabilization includes airway protection, oxygenation, fluids and cardiac monitoring, hyperthermia control Treatment can then be divided into 5 areas:

General supportive care Inhibition of thyroid hormone synthesis Retardation of thyroid hormone release Blockade of peripheral thyroid hormone effects Identification and treatment of precipitating events

Thyroid Storm

Drug Treatment of Thyroid Storm (table 216-6) Decrease de novo synthesis: Porpythiouracil 600-1000mg PO initially, followed by 200-250 mg q 4 hrs Methimazole 40 mg PO initial dose, then 25 mg PO q6h Prevent relases of hormone (after synthesis blockade intiated) Iodine Iaponoric acid (Telepaque) 1 gm IV q8h for the first 24 h, then 500 mg bid or Potassium iodide (SSKI) 5 drops PO q6h or Lugol solution 8-10 drops PO q6h Lithuim 800-1200 mg PO every day

Prevent peripheral effects: B-Blocker Propanolol (IV) titrate 1-2 mg q 5min prn (may need 240-480mg PO q day) or Esmolol (IV) 500 mcg/kg IV bolus, then 50-200 mcg/kg per min maintenance Guanethidine 30-40 mg PO q 6 h Reserpine 2.5-5 mg IM q4-6h Other consideration: Corticosteroids Hydrocortisone 100 mg IV q 8 h or dexamethosone 2 mg IV q 6 hr Antipyretics Cooling blanket acteaminophen 650 mg PO q 4-6h

Thyroid Storm

Treatment cont

Propranolol has the additional effects or blocking peripheral conversion of T4-T3 Avoid Salicylates because it may displace T4 from TBG If the patient continues to deteriorate despite appropriate therapy circulating thyroid hormone may be removed by dialysis, plasmapheresis Remember you must not administer iodine until the synthetic pathway has been blocked

Conclusion

Graves disease is an autoimmune disease. It has three major manifestations: hyperthyroidism, ophthalmopathy and dermopathy. Graves disease is the commonest cause of hyperthyroidism; about 80% of cases. Graves disease is commoner in female to male; ratio of 7: 1.

Conclusion contd

Pathogenesis is by immune mediated which targets mainly TSH receptor. Some genes are implicated in the pathogenesis: CD40, PTPN22, thyroglobulin. Evaluation can be by TFT assay, radiological and radioactive iodine uptake. Treatment can be medical or surgical.

References

Alguire et al. MKSAP14 Endocrinology and Metabolism. 2006. 27-34. Andreoli et al. Cecil Essentials of Medicine. 6th Edition, 2004. 593-7. Nayak, B et al. Hyperthyroidism. Endocrinol Metab Clin N Am. 36 (2007) 617-656. In H et al. Treatment options for Graves disease: a cost-effectiveness analysis. J Am Coll Surg. 2009 Aug;209(2):170-179.e1-2. Stiebel-Kalish H et al. Treatment modalities for Graves' ophthalmopathy: systematic review and metaanalysis. J Clin Endocrinol Metab, August 2009, 94(8):27082716 Uptodate Online Disorders that Cause Hyperthyroidism, Diagnosis of Hyperthyroidism, Cardiovascular Effects of Hyperthyroidism, Treatment of Graves Ophthalmopathy

THANK YOU FOR LISTENING