Graves disease in children and adolscent

GRAVES DISEASE

Dr.YASSIN M ALSALEH

• 15 year old girl known case of graves disese diagnosed at age of 9 yaers.

• At that time started on carbimazole , dose weaned gradually recently she is off of medication.

Case scenario

Introduction

• in 1835, Graves Give the classic description of the disease.

• Also called Basedow-Graves disease.

• Pediatric Graves' disease accounts for 10-15% of thyroid disorders in patients less than 18 yr of age.

• Graves disease is the most common cause of hyperthyroidism in pediatric patients.

• It May result in significant morbidity, and even rarely death.

Introduction

Graves triad

Dermopathy

Hyperthyroidism

Ophthalmopath

y

• Graves' disease is most common cause of hyperthyroidism in children. (96 % of cases).

• Overall, the prevalence in children is approximately 0.02 % of children (1 in 5000) .

• The incidence increases with age and peaks during adolescence.

• mostly in the 11- to 15-year age group.

epidemiology

Pik-shun Cheng , Treatment Choices of Childhood Graves' Disease. Medical Bulletin

VOL.13 NO.4 APRIL 2008

• 38 % of cases are prepubertal at diagnosis.

• Girls are affected more • F:M is 5:1 .• The ratio is considerably lower among

younger children.

epidemiology

• The cause of GD remains unclear.• it is believed to result from a complex

interaction between genetic background (heredity), environmental factors and the immune system.

epidemiology

• there is a high prevalence of GD or other autoimmune disese in first-degree relatives .

• Incidence of Graves disease in identical twins is 30-50%.

• Graves disease has been reported to be associated with the HLA gene on chromosome 6p, the CTL4 gene on chromosome 2q33 and the PTPN22 (lymphoid tyrosine phosphatase) gene on chromosome 1p13.

GENETIC role

• Graves disease results from the production of thyroid-stimulating immunoglobulins (TSI) by stimulated B lymphocytes.

• These immunoglobulins bind to the thyroid-stimulating hormone (TSH) receptor to mimic the action of TSH ,resulting in follicular cell growth, an increase in vascularity and the excessive synthesis and secretion of thyroid hormone.

etiologyPathophysiology

• An imbalance between pathogenic and regulatory T cells is thought to be involved in both the development of Graves disesas and its severity .leading to production of autoantibodies.

Pathophysiology

• Patient with GD may have an increased frequency of other autoimmune endocrine diseases (eg, diabetes mellitus, celiac disease and primary adrenal insufficiency) and nonendocrine autoimmune disorders (eg, vitiligo, SLE, rheumatoid arthritis, myasthenia gravis .ITP,

Pathophysiology

Brea Prindaville, Incidence of vitiligo in children with Graves’disease and Hashimoto’s thyroiditis. International Journal of

Pediatric Endocrinology 2011, 2011:18

• Children with trisomy 21 have an increased risk for Graves' disease .

• And tended to be diagnosed at an earlier age .

• Graves' disease has been reported in association with moyamoya disease.

• Patients with Turner syndrome may also be at increased risk for hyperthyroidism.

Pathophysiology

• Graves' ophthalmopathy may result from antibodies against a TSH receptor-like protein in retroorbital connective tissue .

• in children with Graves' disease, positive association between elevated levels of thyroid stimulating immunoglobulin (TSI) and the development of ophthalmopathy was reported.

Pathophysiology ophthalmopathy

• The onset of the disease is often insidious, and the changes may be present for months or years before the diagnosis is made.

• Interestingly, manifestation of GO begins to resemble the adult findings more closely when adolescence approaches.

Clinical presentation

Gogakos Al, Pediatric aspects in Graves' orbitopathy. Pediatr Endocrinol Rev. 2010 Mar;7 Suppl

2:234-44

Clinical presentationSIGN SYMPTOM

Goiter hyperactivity

Tachycardia palpitation

Weight loss Sleep disturbance

Heat intolerance Fatigue

Tremor Poor school performance

Systolic hypertensuion Emotional lability

Increased pulse pressure Neck fullness or lump

Hair loss Irritabilityand nervousness

Enuresis Increased stool frequency

Advanced bone age Increased appitite

opthalmopathy

G E Krassas. Treatment of juvenile Graves’ disease and its ophthalmic complication: the ‘European way’.

European Journal of Endocrinology (2004) 150 407–414

• Most children with Graves' have a diffuse goiter .

• The surface tends to be smooth, fleshy in consistency, without palpable nodules.

• A large goiter may cause dysphagia and tracheal compression with complaints of dyspnea.

• A bruit can often be auscultated over the gland in hyperthyroid patients.

Clinical presentationGoiter

• Ophthalmic abnormalities are less severe in children than in adults.

• less severe eye findings in prepubertal as compared with postpubertal children .

Clinical presentationEYE

Clinical presentationEYE

• The stare and wide palpebral fissures are the commonest.

• It is presumed that these eye findings are the direct consequence of excessive thyroid hormone action, and that they are not immunologically mediated.

• These findings remit when the thyrotoxicosis is controlled

G E Krassas. Treatment of juvenile Graves’ disease and its ophthalmic complication: the ‘European way’.

European Journal of Endocrinology (2004) 150 407–414


• restricted eye muscle motility, severe strabismus and optic neuropathy are practically absent

• Ophthalmopathy is caused by inflammation of the extraocular muscles and orbital fat and connective tissue, which results in proptosis (exophthalmos), impairment of eye muscle function, and periorbital edema.


Gogakos Al, Pediatric aspects in Graves' orbitopathy. Pediatr Endocrinol Rev. 2010 Mar;7 Suppl

2:234-44

• Patients with gravs have an increase in cardiac output, caused by both increased peripheral oxygen needs and increased cardiac contractility.

• pulse pressure is widened, and peripheral vascular resistance is decreased .

• Mitral valve prolapse is two to three times more prevalent in hyperthyroid patients

• Atrial fibrillation, is rare in children.

Clinical presentationCardiovascular

• Acceleration of growth is accompanied by advancement of epiphyseal maturation.

• The acceleration is usually subtle. • And related to the duration of

hyperthyroidism

Clinical presentationGrowth

• The age of onset of puberty does not appear to be altered by hyperthyroidism.

• Girls may develop oligomenorrhea or secondary amenorrhea

• anovulatory cycles are common .

Clinical presentationPuberty

• Failure to gain weight or weight loss, despite an increase in appetite.

• Weight loss is caused by increased calorigenesis, increased gut motility and malabsorption.

• Mild elevation of liver enzymes.


Magdalena .Graves’ disease, celiac disease and liver function abnormalitiesin a patient — clinical

manifestation and diagnostic difficulties. The Journal of the Polish Biochemical Society Vol. 61, No

2/2014. 281-284

GIT

• easy fatigability.• Proximal myopathy.• decreased muscle mass .• Hypokalemic periodic paralysis

(thyrotoxic periodic paralysis).

Clinical presentationMusculoskeletal

• Thyroid hormone stimulates bone resorption,

• Serum alkaline phosphatase and osteocalcin concentrations are high,

• The increase in bone resorption may lead to an increase in serum calcium concentrations, thereby inhibiting parathyroid hormone secretion

• The net effect is osteoporosis and an increased fracture risk.


• tremor are common.• Deep tendon reflexes are

hyperactive. • Ataxia and chorea have been

reported .• Benign intracranial hypertension,

has been reported.• Speech and language delay .

Clinical presentationNeuropsychologic

• Children with hyperthyroidism tend to have greater mood swings and disturbances of behavior

• Their attention span decreases, they are usually hyperactive, they sleep poorly, and their school performance deteriorates.

• Among very young children (<4 years), it may cause neurodevelopmental delay

Clinical presentationNeuropsychologic

• The skin is warm in hyperthyroidism because of increased blood flow; it is also smooth because of a decrease in the keratin layer .

• Sweating is increased .• Onycholysis (loosening of the nails

from the nail bed, Plummer's nails) .

Clinical presentationSKIN

• Patients with hyperthyroidism tend to have low serum total and high-density lipoprotein (HDL) cholesterol concentrations.


LIPID

clinical • history and physical examination.

lab • Thyroid function test.• antibodies.

imaging • Iodine uptake.• Thyroid US.

Diagnosis

• Serum TSH is suppressed. ( < 0.3 mU/l)

• Most children with hyperthyroidism have very high serum FT4 and FT3 concen.

• Rarely, some children will have typical physical features of Graves’ disease, but thyroid function tests will be normal, so-called “euthyroid Graves’ disease”.

Diagnosis LABTFT

• some patients may have normal FT4 concentrations and high FT3 concentrations – a condition termed T3 toxicosis, which may be observed at diagnosis or at times of relapse during the course of the disease.

Diagnosis LABTFT

• (TSHR-Ab) to confirm Graves' disease as the etiology.

• TRAbs are specific to GD.• They are detected in most patients.

(60-94%)• The most accurate TSHR-Ab test is a

measurement of thyroid stimulating immunoglobulin (TSI).

Diagnosis LABTRAbs

• There is a positive correlation between serum TRAb and FT4 levels.

• Serum TRAb levels are significantly higher in young patients and in patients with a severe initial clinical presentation.

DiagnosisTRAbs

LAB

• An alternative TSHR-Ab test is thyrotropin binding inhibitor immunoglobulin (TBII).

• (up to 100%).• TBII may be helpful if TSI is negative.

Diagnosis LAB

• thyrotropin-releasing hormone (TRH) tests may be carried out.

• antibodies against thyroperoxidase and, thyroglobulin

LABDiagnosisOTHER

• If the TSI level is not elevated, the next step is to perform radioactive iodine (RAI) uptake.

• 123-I is the radionucleotide of choice for thyroid uptake and scans, as it has a shorter half-life (13.2 hours) .

• And delivers a much smaller radiation dose to the thyroid gland as compared with 131-I.

DiagnosisIMAGINGRAI

uptake

• The RAI uptake is elevated in Graves' disease.

• scan typically will show diffuse uptake throughout the gland.

• a thyroid scan should be added to work up in the presence of thyroid nodularity.

DiagnosisIMAGINGRAI

uptake

• The thyroid gland is diffusely enlarged, and often homogeneous.

• parenchymal hypervascularity is observed.

• Goiter size is variable,

Florentia K, Graves’ Disease in Childhood: Advances in Management with Antithyroid Drug

Therapy. Horm Res 2009;71:310–317

DiagnosisIMAGING

US

• The optimal treatment of GD in childhood remains a matter of debate

• Treatment is directed at alleviating symptoms and reducing thyroid hormone production.

• The choice of therapy is determined by individual consideration of the risks and benefits of the three treatment modalities

Treatment

Treatment

ANTITHYROID DRUG

RDI

SURGERY

• Most pediatric endocrinologists recommend antithyroid drug therapy as initial treatment .

• There is, however, a growing acceptance of radioactive iodine therapy for children older than 10 years and adolescents as a second, and in some cases initial treatment.

• Surgical near-total thyroidectomy is an equally effective and safe treatment too.

Treatment

• Antithyroid drugs are the best-established treatment in this age group, and provide a chance of permanent remission with euthyroidism.

• Improvement is gradual.• the course of treatment is long.• and patients must be monitored for

potential side effects.

TreatmentAntithyroid drugs

• Most children and adolescents with Graves' respond well to an antithyroid drug, with 87 to 100% becoming euthyroid within a few weeks to a few months .

• More prolonged use of ATD (at least 2–4 years) in children may be required to achieve remission.

• carbimazole and its active metabolite, methimazole are the drug of choice.


• Propylthiouracil is also effective.• PTU may not be suitable for initial

use in children and adolescents with GD, even with the risk of major adverse reactions such as liver failure excluded.


Sato H, Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves'

disease: efficacy and adverse reactions during initial treatment and long-term

outcome. J Pediatr Endocrinol Metab. 2011;24(5-6):257-63.

• may be reserved for:• children who experience a minor

side effect with MMI that is not a contraindication to continued antithyroid drug use, and for whom radioactive iodine or surgery are not treatment option.


• Mechnisim of action:• They inhibit thyroid hormone

synthesis by inhibiting the oxidation of iodide and block the coupling of iodotyrosyl residues in thyroglobulin.

• PTU can also block the peripheral conversion of T4 to T3.


• The initial starting dose is based on clinical severity, size of goiter, and biochemical severity.

• PTU:• 5–10 mg/kg/day, with a maximum of

300 mg/ day in three equal doses.• carbimazole or MMI• 0.5–1 mg/kg/day, with a maximal

dose of 30 mg per day.



• beta-blockers :• during the first 2 weeks of

management may help to reduce the patient’s symptoms.

• stopped when the patient becomes euthyroid.

• Atenolol is preferred over propranolol.

Treatment OTHER MED.

• L –thyroxine:• Giving levothyroxine in combination

with ATDs to enhance remission rates is no more recommended.

Treatment OTHER MED.

Scott A. Rivkees .Pediatric Graves’ Disease:Controversies in Management .Horm Res Paediatr

2010;74:305–311

• Dose adjustment:• Moniter serum free T4 and total T3

every four to six weeks initially.

• If these values are elevated, then increase the dose of methimazole by approximately 0.25 mg/kg increments until thyroid function is normal.


• Stopping therapy : • When only a low dose is needed to

maintain a euthyroid state drug can be stopped with close follow up.


• Remission : • The rate of remission of Graves'

hyperthyroidism in children and adolescents varied from 25 to 65 % .

• 25 % of children went into a remission every 2 years.


• prepubertal children may take longer to enter remission than pubertal children .

• and are also less likely to enter remission even after prolonged treatment.

Gemli J [Graves's disease in children and adolescent: study of seven cases.Tunis

Med. 2008 Aug;86(8):728-34.


• Predictors of remission:• lower thyroid hormone

concentrations at presentation.• older age.• euthyroid status after three months

of antithyroid drug therapy .• smaller goiter size.• high body mass index (BMI).


• Relapse : • is defined as the presence of

suppressed levels of TSH (< 0.05 mIU/l) combined with FT4 > 21 pmol/l or FT3 >11 pmol/l.

• the relapse rate in children varied from 3 to 47 % .




• About 75% of patients relapse within 6 months of the end of drug treatment.

• only 10% relapse after 18 months.


• Relapse risk factors: • non-Caucasians.• patients with higher initial free T4.• the risk decreases with increasing

age and with longer duration of antithyroid drug therapy.

• history of previous relapse• Relapse pridictor: • measurement of (TSHR-Ab) is the

most useful predictor of subsequent outcome


• Side effects :

TreatmentAntithyroid drugsMAJOR MINOR

agranulocytosis papular or urticarial skin rashes

vasculitis (lupus-like syndrome)

arthralgias

polyarthritis nausea

Hepatitis pruritis

cholestatic jaundice Hair loss

liver failure abnormal taste sensation.

thrombocytopenia

Stevens-Johnson syndrome *

Andrew J. Bauer.Approach to the Pediatric Patient with Graves’ Disease: When Is Definitive Therapy

Warranted?.J Clin Endocrinol Metab 96: 580 –588, 2011

• In case of minor side effects:• discontinue the drug for a few days

until the symptom subsides, and then resume.

• In case of major side effects: • Patient should be treated with

radioactive iodine or surgery instead of antithyroid medication

Treatment

• agranulocytosis :.• Agranulocytosis occurs in 0.1 to

0.5 %

• If a patient develops a febrile illness or pharyngitis, antithyroid drug treatment should be stopped immediately and WBC measured.


• If the granulocyte count is normal, antithyroid drug treatment may be restarted.

• If the granulocyte count is low but not meeting criteria for agranulocytosis ( <500/mm3) neutrophil counts usually recover spontaneously within one to two weeks.

• Agranulocytosis (<500/mm3) is a contraindication to future antithyroid drug treatment .


• Severe hepatitis develops in up to 1:1000 of children treated with PTU.

• liver failure occurring in 1:2000 to 1:4000 .

• Prior to initiating antithyroid drug therapy, patients should have, as a baseline, complete blood cell count and a liver profile .

Antithyroid drugs

Treatment

• Pregnancy risks: . • MMI is associated with an

embryopathy characterized by cutis aplasia and omphalocele,osephegal and choanal atresia.

• PTU with malformations of the face and neck.

• both assosiated urinary tract malformations.

Antithyroid drugs

Treatment

• RAI of graves was introduced for more than 60 years more than one million individual have been treated.

• (RAI) is an effective alternative treatment for children and adolescents with Graves.

• some pediatric endocrinologists consider it the initial treatment of choice in children >10 years of age and adolescents.

Treatment

Radioactive iodine

• Its recommend it for :• patients who have recurrent

hyperthyroidism who request definitive treatment.

• those who have a major side effect while receiving an antithyroid drug.

Treatment

Radioactive iodine

• its recommend that if radioactive iodine is used in children between 5 and 10 years of age the total dose should be limited to <10 milliCi.

• it should not be used at all in children <5 years of age.

Treatment

Radioactive iodine


2010;74:305–311

• Mechanisim of action: • It is the beta radiation which destroys

the follicular cells.• There would be epithelial swelling,

necrosis, oedema and leukocyte infiltration of the thyroid gland.

• At the end, the thyroid gland becomes fibrotic.

Treatment

Radioactive iodine

destruction→swelling →necrosis →edema →infiltration →fibrosis

• Dose:• The dose of iodine-131 is usually from

50 to 200 microCi per gram of thyroid tissue calculated according to the formula :

• Dose (mCi)=50-200microCi of I-131/gm of thyroid X estimated thyroid weight.

• Usually, a dose of 150 microCi/g of thyroid tissue yields radiation doses of 12,000 cGy to the thyroid.

Treatment

Radioactive iodine

• children with GD having free T4 estimates >5 ng/dL (60 pmol/L) should be be pretreated with methimazole and beta-adrenergic blockade until total T4 and/or free T4 estimates normalize

• Symptoms of hyperthyroidism may appear 4-10 days after iodine-131 administration.

• It can be controlled by beta-blockers or Lugol's solution.

Treatment

Radioactive iodine

• if radioactive iodine is to be used, it is better to use a higher dose such that most children become hypothyroid.

• To achieve hypothyroidism, doses of radioactive iodine approximating 200 to 300 microCi/gram of thyroid tissue are recommended.

Treatment

Radioactive iodine

Scott A. Rivkees. An Optimal Treatment for Pediatric Graves’ Disease Is Radioiodine. J Clin Endocrinol

Metab 92: 797– 800, 2007

• Cure rate:• Hyperthyroidism persists in 25-40% if a

dose of 50-100 microCi/g thyroid tissue is given.

• It would be only 5-20% if 150-200 microCi/g thyroid tissue is administered.

• The success rate is inversely related to the size of the thyroid gland and the circulating levels of TSAb

Treatment

Radioactive iodine



• factors that may predict a poor response to RAI treatment in children.

• Graves’ eye disease .• An interval of greater than 12 months

from diagnosis to RAI treatment .• large thyroid glands ( > 80 g).

Treatment

Radioactive iodine


2010;74:305–311

• Pretreatment with ATD did not appear to alter the efficacy or outcome after RAI therapy.

• there was no relationship between ATD use and an increased need for a second dose of radioiodine.

Adriano N Cury. clinical experience with radioactiveiodine in the treatment of childhood and adolescent

Graves’Disease. Endocrine Connections.32-37 (2013)

Treatment

Radioactive iodine

• When hyperthyroidism due to GD persists after 6 months following 131-I therapy.

• if there is minimal response 3 months after therapy, retreatment with 131-I is suggested.

Treatment

Radioactive iodine

• Monitoring: • We measure serum free T4 and TSH

six weeks after radioactive iodine treatment, and then at three-month intervals then six months.

Treatment

Radioactive iodine

• Side effects:• transient thyroid pain in about 5%.• Nausea.• transient hypocalcaemia • thyroid storm.

Treatment

Radioactive iodine

• There is no evidence that radioactive iodine causes or worsens Graves' ophthalmopathy in children or adolescents.

Treatment

Radioactive iodine

Scott A. Rivkees. An Optimal Treatment for Pediatric Graves’ Disease Is Radioiodine. J Clin Endocrinol

Metab 92: 797– 800, 2007

• four cases of thyroid malignancy in children treated with iodine-131 were reported.

• They were all treated with low to moderate doses of iodine-131.

• Recent studies have not revealed an increased risk of thyroid cancer, leukemia, or other cancers .

Treatment

Radioactive iodine



• The incidence of congenital anomalies reported among the offspring of patients treated with RAI does not differ from the incidence in the general population.

TreatmentRadioactive iodine


2010;74:305–311

• The association between the development of parathyroid hyperplasia and hyperparathyroidism after radioactive iodine therapy is another point of controversy.

TreatmentRadioactive iodine

Christopher Breuer1 ,Pediatric Thyroid Disease: When is Surgery Necessary, and Who Should be Operating

on Our Children? J Clin Res Pediatr En docrinol 2013;5(Suppl 1):79-85 DO I: 10.4274/Jcrpe.817

• the risks and outcomes for surgery have been known since Kocher’s first successful series of thyroidectomies in 1883.

• Surgery provides the most rapid resolution of hyperthyroidism.

• avoids the theoretical risk of radiation.• most of the patient is rendered

hypothyroid, and requires lifelong thyroid hormone replacement therapy.

Treatment Surgery

• indications for thyroidectomy include :• Suspicious nodules or known cancer.• pregnancy.• large glands> (80 g).• requirement for immediate control .• obstructive or compressive symptoms.• age younger than 5 yr.

Treatment Surgery

James A. Lee,CONTROVERSY IN CLINICAL ENDOCRINOLOGY The Optimal Treatment for

Pediatric Graves’ Disease Is Surgery. The Journal of Clinical Endocrinology & Metabolism 92(3):801–

803

• The operation of choice is total or near-total thyroidectomies to reduce the risk of high recurrence rate associated with subtotal thyroidectomy.

• The complications of surgery in children are similar to those in adults, and mortality is very rare.

Christopher K Breuer,Effect of patient Age on surgical outcomes for Graves’ disease: a case–control study of

100 consecutive patients at a high volume thyroid surgical center. International Journal of Pediatric

Endocrinology 2013, 2013:1

Treatment Surgery

• Methimazole is typically given for one to two months in preparation for thyroidectomy.

• The vascularity of the gland is decreased by adding iodine to ATD (5–10 drops of Lugol’s solution) for 1 week before surgery.



Treatment Surgery

• Complications: • Transient hypocalcemia 10%. • keloid formation 2.8%.• permanent hypoparathyroidism 2%.• recurrent laryngeal nerve injure 2%.• postoperative hemorrhage in 0.7 %.

Treatment Surgery

• when the thyroid remnant is less than 4 g, the likelihood of recurrent thyrotoxicosis is small.

• Surgical management of GD is technically more challenging in children as evidenced by longer operative times.

Christopher K Breuer,Effect of patient Age on surgical outcomes for Graves’ disease: a case–control study of

100 consecutive patients at a high volume thyroid surgical center. International Journal of Pediatric

Endocrinology 2013, 2013:1

Treatment Surgery

• Surgery should be performed by a high-volume thyroid surgeon .

• temporary hypocalcemia occurs more commonly in children than adults.

Treatment Surgery

• In children most physicians prefer a 'wait-and-see' policy.

• Lubricants ,Head elevation at night• Stop smoking (Adolescence)• steroid therapy.• orbital decompression.• Recent studies have shown successful

therapy with the long-acting somatostatin analogs (SM-a), octreotide and lanreotide.

Ophthalmopathy treatment

Gogakos Al, Pediatric aspects in Graves' orbitopathy. Pediatr Endocrinol Rev. 2010

Mar;7 Suppl 2:234-44

• No matter how children and adolescents are treated, lifelong monitoring of thyroid function is indicated.

• serum free T4 and TSH shoulde be monitored every six months.

MONITORING

• problems with schooling. • chronic loss of bone mineralization.• thyroid storm.

complications

• Graves’ disease (GD) is the most common cause of thyrotoxicosis in children and adolescents.

• Caused by immunologic stimulation of the thyroid-stimulating hormone receptor.

• lasting remission occurs in only a minority of pediatric patients treated with antithyroid drugs (ATDs) for many years.

conclusion

• Thus the majority of pediatric patients with GD will need thyroidectomy or treatment with radioactive iodine.

• When ATDs are used in children, only methimazole should be used.

• Propylthiouracil is associated with an unacceptable risk of severe liver injury in children and should never be used as first-line therapy.

conclusion

• If remission is not achieved after 2 years of ATD therapy, 131- I or surgery may be considered.

• When 131 I is used, administered doses should be>150 Ci/g of thyroid tissue.

• When surgery is performed, near total or total thyroidectomy is recommended.

conclusion

• Choosing a treatment approach for childhood GD is often a difficult and highly personal decision.

• Discussion of the advantages and risks of each therapeutic option by the physician is essential to help the patient and family select a treatment option.

conclusion

REFERENCES

Health & Medicine

Graves disease in children and adolscent