Treatment of Graves’ Disease in Children and Adolescents Dr. Huen Kwai – fun

President, The Hong Kong Society of Paediatric Endocrinology & Metabolism Chief of Service & Consultant, Department of Paediatrics & Adolescent Medicine, Tseung Kwan O Hospital

Causes of Thyrotoxicosis

      Graves’ disease (60 – 80%) Acute or subacute thyroiditis Chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) Toxic nodular goitre (adenoma or multinodular goitre) Iatrogenic T4 ingestion Familial nonautoimmune hyperthyroidism and McCune - Albright’s syndrome

Diagnosis

3 criteria:

1.

Presence of C/F of thyrotoxicosis 2.

3.

Findings of hyperthyroidism on thyroid function testing Presence of either a diffuse goitre or thyroid stimulating auto-Ab or ophthalmopathy or dermopathy or other autoimmune disorders or thyroid scan diffuse uptake Other thyroid pathology e.g. thyroid nodule, Hashimoto’s thyroiditis, multinodular goitre, thyroid malignancy excluded

Laboratory Evaluation

   Dx must be confirmed biochemically by measuring TSH and free T4 Sensitive TSH is the single best screening test for hyperthyroidism because hyperthyroidism of any cause (except excess TSH production) results in a suppressed TSH If TSH is low but the fT4 is normal, serum T3 should be measured

Optional tests

 Thyroid antibody assays (TSAb)  Thyroid scan » to determine the etiology-decrease I uptake in subacute, silent thyroiditis, factitious thyroxine induced and iodine-induced hyperthyroidism

Comparison of Management of Graves’ disease in Europe and USA ( Glinoer et al., 1987; Solomon et al., 1990) Treatment Europeans(%) Americans(%) Standard case Surgery 1 1 Thioamides Duration drug treatment Age < 19 years 77 30 Radioiodine 22 69 < 6 months 5 0 > 12 months 90 90 Surgery 3 4 Thioamides 93 63 Radioiodine 4 33 Large Goitre Surgery 51 7 Thionamides 32 18 Radioiodine 17 78

Problems in management of GD

   No consensus protocol of medical treatment (investigations, choice of medication, starting dose, maintenance regimen, prognostic factors, duration of treatment) No consensus on referral for ablative treatments (surgery or radio-iodine Px). Many patients followed up for a long period of time as the chance of remission is less compared to adult population.

    

Inter-hospital Survey on Graves’ Disease in Children

Questionaires were sent to all HA hospitals with Paediatric Endocrine Service in 1997 Data collection from case records review Hospitals responding : QMH, PYNEH, QEH, KWH, CMC, YCH, PMH, TMH, 185 cases were duplications collected after adjustment of 159 cases presented from 1983 to 1996 were analyzed, those presented after 1 Jan 1997 were excluded.

    

Conclusion

159 cases presented between 1983 to 1996.

Sex ratio F:M = 7 : 1.

Median age of presentation was 11 yr..

Estimated incidence was ~ 1.5/100 000 children ( <15 yrs old) /year Associated autoimmune diseases in 6 patients: 3 myasthenia gravis, 2 alopecia totalis, 2 type 1 diabetes

      TSH receptor stimulating antibodies (TSAb) was not generally available CBZ was the chosen medication.

Starting dose of CBZ was highly variable but correlated negatively with the duration of suppressive treatment.

The overall remission was 25 % in 4.7 yr..

Sex, age of presentation, drug of choice and treatment regimen did not predict the final outcome No paediatric patients referred for I-131 Px

Natural History

    Since effective Px available, now impossible to establish natural Hx without Px Great controversy in treatment No specific cure for the illness Potential complications associated with each therapeutic option

Current Treatment



Antithyroid drugs



Surgery



Radioactive iodine

Selection of Therapy

Drug Surgery least worry sure and speedy poor result op. risks I-131 simple radiation   Surgical competency Emotional concerns about radiation

Antithyroid Drug Therapy

    Introduced in early 1940s by Astwood Mainstays: (thionamide derivatives) propylthiouracil (PTU) ;US methimazole(MMI) ;UK carbimazole (CBZ) ;Europe & Asia Largely determined by local practice Inhibit oxidation and organic binding of thyroid iodide  decrease TH synthesis

     

PTU MMI – short-half life (4-6h); 5-10mg/kg/day Q8h; starting dose 400-600 mg/day -more protein-bound, reduced passage into placental tissue and breast milk -inhibit T4



T3 conversion – 10-fold more potent on a wt basis than PTU - longer half-life (12-16h) - 0.5-1.0 mg /kg/day QD-tid - starting dose 30-40 mg/day CBZ – metabolized to MMI, less potent gm for gm Initial improvement 2-4 wks. Maximal 4-6 wks.

90% euthyroid or hypothyroid +/- B- blockers initially Thyroid storm or pre-op: Lugol’s solution (sat KI sol) Iodide blocks TH release and reduce TG vascularity

Which drug?

    No direct comparisons of CBZ/MMI and PTU available No data directly comparing long-term remission rates of one drug vs another CBZ/MMI – adv of single daily dosing, increase compliance; more literature on their use; PTU - pregnancy & lactation

At present , individual variation in choice of drug remains justified

What Initial Dose?

 Initial therapy aim to render pts euthyroid as quickly as possible   A high starting dose recommended , CBZ 30 40 mg, MMI 30-40 mg or PTU 400-600 mg

Benker et al., 1995; Page et al., 1996; Kallner et al., 1996

  Higher doses should not be used routinely , ass w/ increase incidence serious SE

Werner et al., 1989; Meyergessner et al.,1994; Arab et al.,1995

High or Low Dose Maintenance Therapy ?



Remission rates similar

(taper dose to lowest level to maintain euthyroidism) or with

‘titration’ ‘block-replace’

regimen (+ T4 to maintain high thionamide doses)

Romaini et al.,1983; Hashizume et al.,1991; Meng et al., 1991; Reinwein et al., 1993; Edwards & Tellez, 1994; Jorde et al.,1995; Mclver et al., 1996; Lucas et al., 1997 (Level 1b Evidence; Grade A Recommendation)

Does T4 Administration have an Independent Effect on Rate of Relapse ?

 Little evidence for an independent beneficial effect of T4 on relapse rates  No significant effect on level of TSAb

Hashizume et al., 1991; Tamai et al., 1995; Mclver et al., 1996; Rittmaster et al., 1996; Pfeilschifter & Zeigler, 1997; Lucas et al., 1997

Maintenance Therapy – How Long ?

   Prospective, RCTs Px > 18m confers no benefit when titration regimen used

Allanic etal., 1990; Maugendre et al., 1999

 Px > 6m confers no benefit when block – replace regimen used

Weetman et al., 1994 (Level Ib Evidence; Grade A Recommendation)



Long Term Remission Rates

Adults:

40-50% (1991); 30-40% (1994) ? due to documented increase in mean dietary iodine intake 

Children & Adolescents:

Best 50-60% Usual <30-40% Prepubertal < pubertal

 

Predictors of Outcome

No reliable markers to predict outcome after Px Large goitres (>40 ml), ophthalmopathy, young age , high titres of TSAb (>30 U/L) associated with poor remission rates (9% vs 80%)

Laurberg et al.,1986; Weetman et al.,1986; Gorton et al.,1987; Winsa et al.,1990; Vitti et al.,1997

 Persistent hyperthyroid after short term (4-6m) drug Px

Greer et al.,1977; Bouma et al.,1982

 A recent meta-analysis of 18 studies between 1975 and 1991 confirmed association between absence of TSAb at end of Px and increased long-term remisssion (P<0.00001)

Feldt-Rasmussen et al.,1994



Side – effects of Thionamide Px

Incidence of serious hematological SE (agranulocyctosis, aplastic anaemia) 0.17% to 2.8%

Romaldini et al., 1983; Tamai et al., 1989; Werner et al., 1989; Tajiri et al., 1990; Reinwein et al., 1993; Meyergessner et al., 1994; Jorde et al., 1995

 Agranulocytosis - < 3/10,000 patient-years

International agranulocytosis and aplastic anaemia study. BMJ 1988; 297: 262-5

 Most occur at high doses and within 3m of Px but reported with doses as low as 10 mg methimazole

Reinwein et al.,1993

, and as late as 12m or more after starting Px

Tamai et al., 1989



Patient must be advised to stop drug promptly and check WBC if sore throat, fever, or mouth ulcers develop

  Hepatotoxicity (acute hepatic necrosis or cholestatic hepatitis) – can continue despite discontinuation of drug Px and may be fatal, more common at higher drug doses

Werner et al., 1989; Arab et al., 1995

   Minor SE (rash, pruritus, arthralgia, gastritis) 10 – 25%, more clearly dose-related

Romaldini et al., 1983; Werner et al., 1989; Reinwein et al., 1993; Weetman et al., 1994; Meyergessner et al., 1994; Jorde et al., 1995

Complications of antithyroid drug therapy in more than 500 children (Zimmerman 1998; Vaida 1974) Complication Incidence(%) Mild increases in liver enzymes 28 Mild leucopenia 25 Skin rash * 9 Granulocytopenia # 4.5

Arthritis # 2.4

Nausea * 1.1

Agranulocytosis # 0.4

Hepatitis # 0.4

Loss of taste Rare Hypothrombinemia # Rare Thrombocytopeania # Rare Aplastic anaemia # Rare Nephrotic syndrome # Rare Death Rare *May respond favorably to other thionamide drug substitution # Necessitate discontinuation of all thionamide drugs



Risk of cancer

Patients with Graves’ disease have a higher incidence and more aggressive thyroid cancer

    

The Collaborative Thyrotoxicosis Study Group (CTSG) revealed incidence of thyroid CA and adenomas over 10-20 yr FU (not lifetime incidences) in adults – CA Adenoma Graves’ disease treated with thionamide drugs 1/332 1/76 Graves’ disease treated with iodine-131 1/1783 1/802 Graves’ disease treated surgically 1/2820 1/1692 Dobyns et al., 1974



Rather than reflecting a causative role for medical Px in pathogenesis of thyroid neoplasia, these may reflect persistence of more thyroid tissue in pts treated w/ drugs than those treated w/ radioiodine or surgery

Surgery

     A prospective randomized study comparing 3 Px modalities

(Torring et al.,1996)

– Quicker than either thionamides or radioiodine in establishing euthyroidism Lowest 2 yr failure rate (6% vs 21% for I-131 and 40% for drugs) No significant Cxs by experienced surgeons Recurrent hyperthyroidism

Subtotal thyroidectomy (5-10g) 10-15% (hypo 60%) Total thyroidectomy (<5g) <3% (hypo 100%) (increase risk and periop Cxs)

Complications of Thyroidectomy in >2000 children Ching et al.,1977; Thompson et al.,1977;Buckingham et al., 1981; Rudberg et al., 1996 Complication Incidence (%) Pain 100 Transient hypocalcemia (1-7days) 10 Keloid 2.8

Permanent hypoparathyroidism 2 Vocal cord paralysis 2 Transient hoarseness 1 Temporary tracheotomy 0.7

Hemorrhage/hematoma 0.2

Death 0.08

W/ increasing use of radioiodine, less thyroid surgery performed, fewer surgeons able to develop and maintain their skills

Radioiodine



After oral administration of I-131 to pts w/ Graves’, most radiation localized in thyroid gland



destruction of follicular cells followed by fibrosis

 

Dose (mCi) = (uCi I-131/g of thyroid x estimated thyroid wt)/ 24h radioiodine uptake

 

Individual variation in sensitivity of thyroid to I-131. Most prefer to give fixed doses of 5-15 mCi (185 – 555 MBq) on basis of thyroid size assessed by clinical or U/S (normal thyroid 0.5-1 g/yr of age; 15-20g for adults)

 Effective half-life of I-131 is 7 days.

 5 wks after Px, <1% I-131 remains in thyroid  Transient hyperthyroid 4-10 days after I-131 Px, can be controlled by B-blockers or sat KI sol, not adversely affect outcome  Consider 2 nd post-Px dose if persistent hyperthyroid >2m  Pts as young as 1 yr have been treated w/ I-131. Reported doses in children & adolescents 100 250 uCi/g (5.5-7.4 MBq/g) thyroid

Chapman 1955 Crile 1965 Starr 1968 Hayek 1970 Safa 1975 Freitas 1979 Hamburger 1985 Clark 1995 Nebesio 2002 * mean

I-131 for Children

Literature review on s eries with n

≧

30

n 30 30 73 30 87 51 191 33 40 Age yr 1-18 7-15 2.5-18 8-18 3-18 6-18 3-18 6-19 8-19 Follow up yr 1-23 3-15 10-18 9.2* 12.3* 14.6* 0-5 Activity Hypothyroid Retreated mCi % % 9.9* 27 53 40 6.6* 9.8* 27 46 42 17 24 23 14.1* 10 7.7* 15* 92 86 88 100 17 2.5

      

Long Term Cure Rates

I-131 dose: High dose (370 MBq) > low dose (185 MBq) Hyperthyroid 5-20% vs 25-40% Risk of hypothyroid 60-90% vs 40% Pre-Px hyperthyroid severity Large goitre size (>80g) High TSAb PrePx w/ ATD

Failure rate – no thionamide 9% withdrawn >7 days before 17% withdrawn 4-7 days before 29% Lloyd et al.,1997 Use of thionamides, during a period 2 wk before or after I-131 – decrease cure w/185 MBq but not 370 MBq Allahabadia et al., 2001

I-131 Px – Complications in Adults

Complication Incidence(%) ( %)

Worsening of eye disease 3-5 Transient thyroid pain 5 Nausea rare Thyroid storm rare Transient hypocalcemia rare Hyperparathyroidism rare

I-131 Px: complications (1)

 Vomiting & enuresis

4 each out of 35 TT accounts for 2 of the 4 who vomited

∴

ATD beforehand (Clark 1995)

 Thyroid storm

one case report of a 7½ yr old boy 4 days after I-131 and 13 days after stopping ATD (Kadmon 2001)



I-131 Px: complications (2)

Worsening Ophthalmopathy  Exacerbation in ¼ after I-131 vs 1/8 after surgery

(Tallstedt 1992)

 due to thyroid cell destruction → release of antigens → activation of auto immunity  need pre Px with ATD or concurrent / adjunctive steroid Px



I-131 Px: complications (3)

Hypothyroidism       

Clark 1995: 88% hypo: 80% w/i 100 days

∴

mean 3M Nebresio 2002: all hypo: a) monthly FT4 after I-131 all w/i 200 days mean 1-2 M NB: TSH response may be suppressed for months by prior TT

 

b) early T4 replacement To prevent carcinogenesis from prolonged TSH stimulation

I-131 Px: complications (4)

   Discomfort over thyroid Alopecia – pain, tenderness dysphagia – 2-3M after I-131 metabolic rather than radiation Benign thyroid nodule thyroid adenoma / Hashimoto’s

14 / 351 (4%) 0-17 yr after I-131 Clark 1995

I-131 Px: Late Effects

Stochastic uncertainty, no threshold, no repair eg, carcinogenesis, genetic damage Non-stochastic certainty, threshold, repair eg, gonadal damage, cataract, radiation fibrosis

 ↑

Thyroid Cancer Risks

risk of thyroid CA after I-131 in childhood



Thyroid cancer risk

↑

w/ exposure to low or mod external radiation. Risk much lower after high level irradiation that results in thyroid cell death



Large epidemiological surveys showed no

↑

rates of thyroid cancer nor thyroid cancer mortality in adults CTSG (36050 pts) in US (Dobyns et al.,1974) , Swedish cohort studies (Holm et al.,1991; Hall et al.,1992) Study by Ron et al., 1998



Outcomes after I-131 Px reported for about 1000 children & adolescents - no some >20 yr

↑

risk of thyroid malignancy. Duration of FU ranged from <5 yr to 15 yr, w/ only

Nonthyroid Malignancies

  No significantly increase nonthyroid cancer mortality found after I-131 Px in adults

Ron et al., 1998. JAMA. 280:347-55

 Among I-131-treated children, a comprehensive FU study of nonthyroid cancer risks has yet to be performed

 

Is developing child at higher risk for developing cancer after I-131 Px

Studies of external thyroid irradiation, nuclear disaster and atomic bomb survivors – thyroid cancer rates higher at progressively younger ages

Dolphin GW. 1968; Ron et al., 1995; Shore RE. 1992

Theoretical risk of a small increase in thyroid cancer.  Potential risk greatest in children < 5yr, progressively lower in 5-10 and 10-20 yr  Risk of increase nonthyroid cancers (salivary glands, stomach, bladder) likely very small



Health of Offspring

Radiation exposure of gonads during I-131 Px (~2.5 cGy), comparable to exposure from a Ba enema or IVU    Data on 500 offspring born to ~370 pts w/ I 131 Px during childhood and adolescence – No increase congenital anomalies

Starr et al.,1969; Hayek et al., 1970; Safa et al., 1975; Freitas et al., 1979; Hamburger JI 1985

  No increase birth defects in survivors of atomic bomb blasts exposed to higher external irradiation of gonads than ass w/ I-131 Px

Schull et al., 1981

      

QEH Experience

1995-96 n=256; age 19-97 median 50 fixed dose : +/- 50% of 70-80 Gy standard, depending on gland size re-Px rate = 24.3% large goitre + stopping ATD 3 days before I- 131  re-Px one thyroid storm – the patient stopped ATD 13 days before I-131 one year hypo T = 31%

I-131 Px – Summary (1)

 Radioiodine is a convenient and cost-effective Px for childhood GD  Efficacy dose related. 5.5-7.4 MBq/g- >90% long term cure. 85-90% only require a single dose  May be a small increase risk of thyroid CA in children Px w/ I-131. This theoretical risk probably highest in <5 yr and progressively lower at 5-10 and 10-20 yr



I-131 Px – Summary (2)

Children should receive higher doses 5.5-7.4 MBq/g to minimize residual T and decrease tumour risk.

Post I-131, T4 Px to prevent raised TSH  No evidence for increase birth defects in offspring of pts Px w/ I-131  Careful FU for all GD pts. Should include regular exam of TG. All new T nodules Bx / excised.

 Radiation-related thyroid tumours more typically appear 10-20 yr after exposure, long term FU beyond pediatric yrs essential

Advantages and Disadvantages of the 3 treatment modalities Treatment Cannot use in Advantages Disadvantages Tablets Patients with Quite rapid (4 wks) 2 yrs of tablets (thiomamides) severe reaction Predictable initial response 60% relapse after Px to these drugs Sudden swings in T4 rare 20% risk of rash, minor SE Painless 0.2% risk serious bone Safe in unfit patients marrow SE Radioiodine Pregnancy Painless Slow action (1-3 m or more) Breast Low chance of relapse High chance of hypothyroid feeding (once it works) requiring T4 tablets - permanent effect Sudden T4 swings possible May worsen eye problems ? thyroid cancer risk Surgery Pts unfit for Rapid (days) Risk of GA operation Low chance of relapse 2% parathyroid or nerve to Uncontrolled - permanent effect vocal cords damage thyrotoxicosis Discomfort / neck scar 0.08% death

Recommendations

   

Initial

Drug: esp. for mild TT, small goitre, low TSAb starting CBZ 30 mg or PTU 40 mg maintain TR x 18m or B&RR x >6m   

Failed

Surgery: higher recurrence

(compared with adults)

need more aggressive surgery  ↑ risk    I-131: preferably beyond puberty ( ≧ 15 yr old) at least 10 yr old never 5 or below

Changes

 ? I-131 Px should be considered esp for those > 15 yrs Need to overcome emotional concern of paediatricians and patients  ? Routine quantitative TSAb assay (for Dx & Pg) and delete antimicrosomal & antithyrogloublin Ab assay



Issues to be addressed (1)

Choice of drug RCT of CBZ/MMI vs PTU to monitor relapse rates at 1 year



Duration of drug Px RCT of 12 vs 18 vs 24m (titrated doses)



Role of WBC monitor Prospective multicentre (blinded) in detecting trial of 2weekly WBC for first agranulocytosis 3m of thionamide Px



Choice of Px RCT of drug Px vs I-131 + drug comparison of outcome and pt satisfaction

Issues to be addressed (2)

 Role of surgery RCT of informed pt choice ./.

Surgery and drug Px  When is pt cured? Multicentre/long-term registry of relapses after standard thionamide course  Cancer risk in children Multicentre/long-term w/ radioiodine registry of I-131 Px in children and adolescents