Graves Disease• It is an autoimmune disorder; production ofthyroid-stimulating immunoglobulin (TSI) resultsin diffuse toxic goiter.• Graves disease occurs in approximately 0.02% ofchildren (1 : 5,000).• It has a peak incidence in the 11- to 15-yr old;there is a 5 : 1 female to male ratio.• Most children with Graves disease have a positivefamily history of some form of autoimmunethyroid disease.
Etiology and Pathology:• Enlargement of the thymus, splenomegaly, lymphadenopathy, infiltrationof the thyroid gland and retro-orbital tissues with lymphocytes and plasmacells, and peripheral lymphocytosis are well-established findings in Gravesdisease.• In the thyroid gland, T helper cells (CD4+) predominate in dense lymphoidaggregates; in areas of lower cell density, cytotoxic T cells (CD8+)predominate.• The percentage of activated B lymphocytes infiltrating the thyroid is higherthan in peripheral blood.• A postulated failureof T suppressor cells allows expression of T helpercells, sensitized to the TSH antigen, which interact with B cells.• These cells differentiate into plasma cells, which produce thyrotropinreceptor–stimulating antibody (TRSAb).• TRSAb binds to the receptor for TSH and stimulates cyclic adenosinemonophosphate, resulting in thyroid hyperplasia and unregulatedoverproduction of thyroid hormone.• In addition to TRSAb, thyrotropin receptor-blocking antibody (TRBAb) mayalso be produced, and the clinical course of the disease usually correlateswith the ratio between the two antibodies.
• In whites, Graves disease is associated withHLA-B8 and HLA-DR3.• Graves disease is also associated with otherHLA-D3–related disorders such as Addisondisease, type 1 diabetes mellitus, myastheniagravis, and celiac disease.• In family clusters, the conditions associatedmost commonly with Graves disease areautoimmune lymphocytic thyroiditis andhypothyroidism.
CLINICAL MANIFESTATIONS:• The earliest signs in children may be emotionaldisturbances accompanied by motor hyperactivity.• The children become irritable and excitable, and theycry easily because of emotional lability.• They are restless sleepers and tend to kick their coversoff.• Their schoolwork suffers as a result of a short attentionspan and poor sleep.• Tremor of the fingers can be noticed if the arm isextended.• There may be a voracious appetite combined with lossof or no increase in weight.• Recent height measurements might show anacceleration in growth velocity.
Symptoms:• Hyperactivity, irritability, altered mood, insomnia,anxiety• Heat intolerance, increased sweating• Palpitations• Fatigue, weakness• Dyspnea• Weight loss with increased appetite (weight gainin 10% of patients)• Pruritus• Increased stool frequency• Thirst and polyuria• Oligomenorrhea or amenorrhea
Signs:• Sinus tachycardia, atrial fibrillation (rare in children),supraventricular• tachycardia• Fine tremor, hyperkinesis, hyperreflexia• Warm, moist skin• Palmar erythema, onycholysis• Hair loss• Osteoporosis• Muscle weakness and wasting• High-output heart failure• Chorea• Periodic (hypokalemic) paralysis (primarily in Asianmen)• Psychosis (rare
MANIFESTATIONS OF GRAVES DISEASE• Diffuse goiter• Ophthalmopathy Upper eyelid retraction (the most common sign of Graves ophthalmopathy) Infrequent or incomplete blinking (Stellwag sign) Lid lag upon infraduction (Von Graefesign) or globe lag on supraduction (Kocher sign) Widened palpebral fissure during fixation (Dalrymple sign) Incapacity to close eyelids completely (lagophthalmos) Prominent stare (Binswanger sign) Inability to keep the eyeballs converged (Mobius sign) Limited extraocular gaze (especially upward) Blurred vision due to inadequate convergence and accommodation Swollen orbital contents and puffy lids Chemosis Globe pain Exophthalmos Enlarged lacrimal glands (visible on inspection and palpable) Dysfunctional lacrimal glands with decreased quantity and abnormal composition of tears Corneal injection, ulceration, punctate epithelial erosions, or superior limbic keratoconjunctivi(rare) Decreased visual acuity due to papilledema, retinal edema, retinal hemorrhages, or optic nervdamage (rare)• Localized dermopathy (rare in children)• Lymphoid hyperplasia• Thyroid acropachy (rare in children)
• Many scoring systems have been used to gauge the extent andactivity of the orbital changes in Graves disease.• The "NO SPECS" scheme is an acronym derived from thefollowing eye changes:0 = No signs or symptoms1 = Only signs (lid retraction or lag), no symptoms2 = Soft tissue involvement (periorbital edema)3 = Proptosis (>22 mm)4 = Extraocular muscle involvement (diplopia)5 = Corneal involvement6 = Sight loss
• Thyroid crisis, or thyroid storm, is a form ofhyperthyroidism manifested by an acute onset,hyperthermia, severe tachycardia, heart failure,and restlessness.• There may be rapid progression to delirium,coma, and death. Precipitating events includetrauma infection, radioactive iodine treatment, orsurgery.• Apathetic, or masked, hyperthyroidism isanother variety of hyperthyroidismcharacterized by extreme listlessness, apathy, andcachexia.• A combination of both forms can occur.• These symptom complexes are rare in children.
LABORATORY FINDINGS• Serum levels of thyroxine (T4), triiodothyronine (T3), freeT4, and free T3 are elevated.• In some patients, levels of T3 may be more elevated thanthose of T4.• Levels of TSH are suppressed to below the lower range ofnormal.• Antithyroid antibodies, including thyroid peroxidaseantibodies, are often present.• Most patients with newly diagnosed Graves disease havemeasurable TRSAb;• Measurement of TSI or TBII is useful in confirming thediagnosis of Graves disease.• Radioiodine is rapidly anddiffusely concentrated in thethyroid, but this study is rarely necessary.• Children who experience an acceleration of growth mightalso have advanced skeletal maturation.• Bone density may be reduced at diagnosis but returns tonormal with treatment.
TREATMENT:1. Antithyroid drugs2. Radioactive iodine (131I)3. Surgery
1. Antithyroid drugs1. Propylthiouracil (PTU) and2. Methimazole (Tapazole).• Both compounds inhibit incorporation of trapped inorganiciodide into organic compounds, and they might alsosuppress TRSAb levels by directly affecting intrathyroidalautoimmunity.• Methimazole is at least 10 times more potent than PTU,longer serum half-life (6-8 hr vs 0.5 hr); PTU generally isadministered 3 times daily, but methimazole can be givenonce daily.• Unlike methimazole, PTU is heavily protein bound and has alesser ability to cross the placenta and to pass into breastmilk; theoretically, PTU is the preferred drug duringpregnancy and for nursing mothers.• Due to reports of severe liver disease in patients treatedwith PTU, with some patients requiring liver transplant orpotentially suffering a fatal outcome, the consensus is to useonly methimazole to treat children with Graves disease.
• The initial dosage of methimazole is 0.25-1.0mg/kg/24 hr given once or twice daily.• Smaller initial dosages should be used in earlychildhood.• Rising serum levels of TSH to greater thannormal indicates overtreatment and leads toincreased size of the goiter.• Clinical response becomes apparent in 3-6 wk,and adequate control is evident in 3-4 mo.• The dose is decreased to the minimal levelrequired to maintain a euthyroid state.
• Transient granulocytopenia (<2,000/mm3) iscommon; it is asymptomatic .• Transient urticarial rashes are common.• They may be managed by a short period offtherapy, and then restarting the antithyroiddrug.• The most severe reactions are hypersensitiveand include agranulocytosis (0.1-0.5%),hepatitis (0.2-1%), a lupus-like polyarthritissyndrome, glomerulonephritis, and an ANCA-positive vasculitis involving the skin and otherorgans.
• Radioiodine treatment or surgery isindicated:- when adequate cooperation for medicalmanagement is not possible,- when adequate trial of medical managementhas failed to result in permanent remission, or- when severe side effects preclude further useof antithyroid drugs.
2. Radioiodine• It is an effective, relatively safe first or alternative therapyfor Graves disease in children >10 yr of age.• Pretreatment with antithyroid drugs is unnecessary; if apatient is taking them, they should be stopped a weekbefore radioiodine administration.• Many pediatric endocrinologists prefer to select a dose ofradioiodine to ensure complete ablation of thyroid tissue.• A dose of 300 μCi/g of thyroid tissue, or a total dose ofapproximately 15 mCi, will achieve this goal.• Essentially all patients treated at this dose will becomehypothyroid; the time course to hypothyroidism averages11 wk, with a range of 9-28 wk.• Because the full effects of treatment may not be completefor 1-6 mo, adjunctive therapy with a β-adrenergicantagonist and lower doses ofantithyroid drugs arerecommended.
3. Surgery• Subtotal thyroidectomy, a safe procedure when performedby an experienced team, is done only after the patient hasbeen brought to a euthyroid state.• This may be accomplished with methimazole over 2-3 mo.• After a euthyroid state has been attained, a saturatedsolution of potassium iodide, 5 drops/24 hr, are added tothe regimen for 2 wk before surgery to decrease thevascularity of the gland.• Complications of surgical treatment are rare and includehypoparathyroidism (transient or permanent) and paralysisof the vocal cords.• The incidence of residual or recurrent hyperthyroidism orhypothyroidism depends on the extent of the surgery.• Most recommend near-total thyroidectomy.• The incidence of recurrence is low, and most patientsbecomehypothyroid.
• A β-adrenergic blocking agent such as propranolol(0.5- 2.0 mg/kg/24 hr orally, divided 3 times daily)or atenolol (1-2 mg/ kg orally given once daily) is auseful supplement to antithyroid drugs in themanagement of severely toxic patients.