Wed. Clinical Presentation

8/12/2019 Wed. Clinical Presentation

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GRAVES DISEASE

PRESENTING TEAM: ENDOCRINOLOGYUNIT.

PRESENTER: DR. NWAGBARA CT.

DATE: 6THFEBRUARY, 2013.


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OUTLINE

Introduction Epidemiology

Pathophysiology

Clinical features Differential diagnosis

Investigations

Treatment Conclusion

References


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INTRODUCTION

Graves disease, named after Robert J.Graves, MD, 1830, is an autoimmunedisease characterized by hyperthyroidism,

ophthalmopathy and dermopathy. Thyroid stimulating immunoglobulins (TSIs)

bind to and activate thyrotropin receptors,

causing the thyroid gland to grow and thethyroid follicle to increase sythesis of thyroidhormones.


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Sometimes Graves disease is associatedwith other autoimmune conditions like;

- Pernicious anemia

- Vitiligo

- Diabetic mellitus type 1

- Autoimmune adrenal insfficiency

- Systemic sclerosis

- Myasthenia gravis


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- Sjogren syndrome

- Rheumatoid arthritis

- Systemic lupus erythematosis


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Epidemiology

Prevalence of hyperthyroidism in the generalpopulation is 1.2%

0.7% subclinical hyperthyroidism

0.4% Graves Diseasemost common etiology;note there is overlap with the subclinical group

Graves Disease is more common in females

(7:1 ratio)


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The Classic Triad of Graves Disease

Hyperthyroidism (90%)

Ophthalmopathy (20-40%)

proptosis, ophthalmoplegia, conjunctival irritation

3-5% of cases require directed treatment

Dermopathy (0.5-4.3%)

localized myxedema, usually pretibial

especially common with severe ophthalmopathy

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


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PATHOGENESIS

In Graves disease,B and T lymphocyte-mediated autoimmunity are known to bedirected at 4 well-known thyroid antigens:

thyroglobulin, thyroid peroxidase, sodium-iodide sympoter, and thyrotropin receptor.

However, the thyrotropin receptor is the

primary autoantigen of Graves disease and isresponsible for the manifestation ofhyperthyroidism.


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Pathogenesis contd

Direct proof of an autoimmune disorder thatis mediated by autoantibodies is thedevelopment of hyperthyroidism in healthy

individual by transferring thyrotropin receptorantibodies in serum from patients with gravesdisease and the passive transfer of the

thyrotropin receptor antibodies to the fetus inpregnant women.


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Pathogenesis contd

The thyroid gland is under continuousstimulation by the circulating autoantibodiesagainst the thyrotropin receptor, and pituitary

thyrotropin secretion is suppressed becauseof the increased production of thyroidhormones.

The stimulating activity of thyrotropin receptorantibodies is found mostly in theimmunoglobin G1 subclass.


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Pathogenesis contd

These will lead to stimulation of iodineuptake, protein synthesis and thyroid glandgrowth.

Several autoimmune thyroid diseasesusceptibility gene have been identified:CD40, CTLA-4, thyroglobulin,TSH receptor

and PTPN22.


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Pathogenesis

An autoimmune phenomenonpresentationdetermined by ratio of antibodies

TSH

Receptor

Thyroid StimulatingAb (TSAb)

Thyroid Stimulation

Blocking Ab (TSBAb)

Thyroid

+

-

Graves Disease

AutoimmuneHypothyroidism(Hashimotos)Thyroglobulin Ab

Thyroid peroxidaseAb (anti TPO)


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Symptoms contd

Cardiovascular: palpitations, dyspnoea onexertion, chest pains, edema.

Respiratory: dyspoea

Gastrointestinal: increased bowel motility withincreased frequency of bowel movement.

Ophthalmologic: tearing, gritty,sensation in

the eye, photophobia, protruding eye,diplopia, visual.


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Symptoms contd

Renal: polyuria, polydipsia

Hematologic: easy bruising.

Metabolic: heat intolerance, weight lossdespite increase or similar appetite,worsening DM control.

Endocrine/reproductive: irregular menstrual

periods, amenorrhea, gynecomastia,impotence.

Psychiatric: restlessness, anxiety, insomnia


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Physical findings

Eyes:

- Lid lag,

- lid retraction

- proptosis

- periorbital edema

- chemosis


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Graves Ophthalmopathy

Antibodies to the TSH receptor also targetretroorbital tissues

T-cell inflammatory infiltrate -> fibroblast growth

Severe: exposure keratopathy, diplopia, com-pressive optic neuropathy

Strong link with tobacco


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Classification of eye changes

(NOSPECS)0. No s igns no symptoms

Only signs (l id-retract ion and lag), no

symptoms

Soft t issue invo lvement (sym ptom s & signs )

Prop tos is (>20mm by Hertels

exopthalometer)

Extra ocu larmusc le involvement

Corneal involvement

Sight loss (op t ic nerve invo lvement)


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Ophthalmopathy in Graves

Periorbital edema and chemosis


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Exopthalamos inGraves Disease

Lid Lag in GravesDisease


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Dermopathy

Usually occurs over the dorsum of the legs orfeet and is termed localized or pretibialmyxedema.

It is usually a late phenomenon The affected area is usually demarcated from the

normal skin by being raised and thickened andhaving a peau d orangeappearance ;it may bepruritic and hyperpigmented.

The most common presentation is non pittingoedema, but lesions maybe plaque like, nodular

or polypoid. Clubbing of the fingers and toes accompanies

and is termed thyro id acropachy


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Myxedema of Graves

Activation of fibroblasts leads to increasedhyaluronic acid and chondroitin sulfate

Asymmetric, raised,firm, pink-to-purple,brown plaques ofnonpitting edema


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Physical findings contd

Neck:

- thyroid gland enlargement

- thyroid bruits

- thyroid nodules may be palpable


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Physical findings contd

CVS:

- murmur

- hyperdynamic precordium

- S3, S4 heart sounds

- ectopic beats

- irregular heart rates and rhythm


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Differential Diagnosis

Toxic Multinodular Goiter

Toxic Adenoma

Thyroiditis

silent (Hashimotos) painless, often post partum

subacute (de Quervains) painful, post viral

drug-inducedamiodarone, lithium, interferon

Thyrotoxicosis factitia


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Differential diagnosis

Anxiety

Pheochromocytoma

Hydatidiform mole

Ectopic thyroid tissue(struma ovarii)

Pituitary macroadenomas

Pituitary microadenomas

Hyperemesis gravidarum


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Laboratory Evaluation

Suppressed TSH ( 20- Graves Disease- Toxic MN Goiter

T3:T4 < 20- Non-thyroid illness- Thyroiditis- Exogenous thyroxine


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Its Good to be Free

Thyroxin is 99% bound to thyroid bindingglobulin (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


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Laboratory Evaluation

Direct measurement of TSH receptorantibodies (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


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Diagnostic Imaging

Radioactive Iodine Uptake

Provides quantitative uptake (nl 5-25% after 24h)

Shows distribution of uptake

Technetium-99 Pertechnetate Uptake Distinguishes high-uptake from low-uptake

Faster scanonly 30 minutes

Thyroid ultrasonography Identifies nodules

Doppler can distinguish high from low-uptake


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Immediate Medical Therapy

Thionamidesinhibit central production of T3and T4; immunosuppressive effect

Methimazoleonce daily dosing

PTUadded peripheral block of T4 to T3conversion; preferred in pregnancy

Side effects: hives, itching; agranulocytosis,hepatotoxicity, vasculitis

Beta-blockadedecrease CV effects, also itinhibits the peripheral conversion of T4 to T3.

High-dose iodineWolff-Chaikoff effect


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Long-term Therapeutic Options

Continued Medical Management

Low dose (5-10mg/day of methimazole) for 12 to18 months then withdraw therapy

Lasting remission in 50-60% Radioiodine Ablation

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%


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Titration Regimen

titrate the dose of antithyroid drug, givingcarbimazole (or methimazole) 20 mg two orthree times daily, and then lowering the doseevery 3 to 4 weeks or so, based on free T4

measurements, until a maintenance dose of 5 to10 mg once daily is achieved.

Equivalent starting and maintenance doses ofpropylthiouracil are 100 to 200 mg three times

daily and 50 mg once or twice daily. Maximumremission rates occur after 18 to 24 months oftreatment.


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Block and Replace Regimen

start with the same dose of antithyroid drug butthen to add thyroxine 100 g daily after 3 to 4weeks 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 beingadjusted if necessary 4 weeks after starting toachieve normal free T4 levels.


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Treatment of Ophthalmopathy

Mild Symptoms

Eye shades, artificial tears

Progressive symptoms (injection, pain)

Oral steroidstypical dosage from 30-40mg/dayfor 4 weeks

Impending corneal ulceration, loss of vision

Oral versus IV steroids Orbital Decompression surgery


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Treatment of Dermopathy

Milder cases do not require therapy otherthan Rx of thyrotoxicosis

For severe cases, therapy with topical

steroids applied under an occlusive plasticdressing for 3 -10 weeks

Also pulse glucocorticoid therapy may be

tried


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Thyroid Storm aka Thyrotoxic crisis

A life threatening hypermetabolic state due tohyperthyroidism

Mortality rate is 10%

Usually occurs as a result of previouslyunrecognized or poorly treated hyperthyroidism

Thyroid hormone levels do not help todifferentiate between uncomplicatedhyperthyroidism and thyroid storm


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Thyroid Storm Precipitants of Thyroid Storm

Infection Trauma

DKA MI

CVA PE

Surgery, Anasthesiainduction

Withdrawal of thyroidmed

Iodine administration,RAI therapy

Vigorous Palpation ofthyroid gland

Ingestion of thyroid

hormone

Unknown etiology (20-

25%)


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Thyroid Storm

Diagnosis

Thyroid storm is a clinical diagnosis based uponsuspicion and treated empirically

Lab work is non specific and may includeLeukocytosis, hyperglycemia, elevatedtransaminase and elevated bilirubin


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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


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Thyroid Storm

Drug Treatment of Thyroid Storm(table 216-6)

Decrease de novo synthesis:

Porpythiouracil 600-1000mg PO initially, followedby 200-250 mg q 4 hrs

Methimazole 40 mg PO initial dose, then 25 mg PO q6h

Prevent relases of hormone(after synthesis blockadeintiated)

Iodine Iaponoric acid (Telepaque) 1 gm IV q8hfor the first 24 h, then 500 mg bid or Potassiumiodide (SSKI) 5 drops PO q6h or Lugol solution 8-10

drops PO q6h Lithuim 800-1200 mg PO every day


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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 minmaintenance

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


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Thyroid Storm

Treatment cont

Propranolol has the additional effects or blockingperipheral conversion of T4-T3

Avoid Salicylates because it may displace T4 fromTBG

If the patient continues to deteriorate despiteappropriate therapy circulating thyroid hormone maybe removed by dialysis, plasmapheresis

Remember you must not administer iodine until

the synthetic pathway has been blocked


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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 tomale; ratio of 7: 1.


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Conclusion contd

Pathogenesis is by immune mediated whichtargets 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.


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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 EndocrinolMetab, August 2009, 94(8):27082716

Uptodate OnlineDisorders that Cause Hyperthyroidism, Diagnosis ofHyperthyroidism, Cardiovascular Effects of Hyperthyroidism, Treatment

of Graves Ophthalmopathy


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