Transcript Management of Graves’ Disease in Children and Adolescents

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. Findings of hyperthyroidism on thyroid function
testing
3. Presence of either a diffuse goitre or thyroidstimulating 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
Standard case
Europeans(%)
Americans(%)
Surgery
Thioamides
Radioiodine
1
77
22
1
30
69
< 6 months
> 12 months
5
90
0
90
Surgery
Thioamides
Radioiodine
3
93
4
4
63
33
51
32
17
7
18
78
Duration drug treatment
Age < 19 years
Large Goitre
Surgery
Thionamides
Radioiodine
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 collected after adjustment of
duplications
 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
least
worry
poor
result
Surgery
sure and
speedy
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 – 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
 MMI – 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 3040 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 with ‘titration’
(taper dose to lowest level to maintain
euthyroidism) or ‘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 –
 Graves’ disease treated with thionamide drugs
 Graves’ disease treated with iodine-131
 Graves’ disease treated surgically

CA
Adenoma
1/332
1/76
1/1783
1/802
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)
Total thyroidectomy (<5g)
(increase risk and periop Cxs)
10-15% (hypo 60%)
<3% (hypo 100%)
Complications of Thyroidectomy in >2000 children
Ching et al.,1977; Thompson et al.,1977;Buckingham et al., 1981; Rudberg et al., 1996
Complication
Pain
Transient hypocalcemia (1-7days)
Keloid
Permanent hypoparathyroidism
Vocal cord paralysis
Transient hoarseness
Temporary tracheotomy
Hemorrhage/hematoma
Death
Incidence (%)
100
10
2.8
2
2
1
0.7
0.2
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 2nd dose if persistent hyperthyroid >2m
post-Px
 Pts as young as 1 yr have been treated w/ I-131.
Reported doses in children & adolescents 100250 uCi/g (5.5-7.4 MBq/g) thyroid
I-131 for Children
Literature review on series with n≧30
Chapman 1955
Crile 1965
Starr 1968
Hayek 1970
Safa 1975
Freitas 1979
Hamburger 1985
Clark 1995
Nebesio 2002
* mean
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 Activity Hypothyroid Retreated
yr
mCi
%
%
1-23
27
3-15
9.9*
53
40
10-18
42
9.2*
6.6*
27
17
12.3*
9.8*
46
24
14.6*
14.1*
92
23
10
86
0-5
7.7*
88
17
15*
100
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
( %)
Worsening of eye disease
Transient thyroid pain
Nausea
Thyroid storm
Transient hypocalcemia
Hyperparathyroidism
Incidence(%)
3-5
5
rare
rare
rare
rare
I-131 Px: complications (1)
 Vomiting & enuresis
4 each out of 35
(Clark 1995)
TT accounts for 2 of the 4 who vomited
∴ ATD beforehand
 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:


Nebresio 2002:
all hypo:



80% w/i 100 days
mean 3M
all w/i 200 days
mean 1-2 M
∴ a) monthly FT4 after I-131
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 – pain, tenderness
dysphagia
 Alopecia – 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 ↑ risk of thyroid malignancy.
Duration of FU ranged from <5 yr to 15 yr, w/ only
some >20 yr
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/ I131 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
Tablets
Patients with
(thiomamides) severe reaction
to these drugs
Radioiodine
Surgery
Advantages
Quite rapid (4 wks)
Predictable initial response
Sudden swings in T4 rare
Painless
Safe in unfit patients
Disadvantages
2 yrs of tablets
60% relapse after Px
20% risk of rash, minor SE
0.2% risk serious bone
marrow SE
Pregnancy
Breast
feeding
Painless
Low chance of relapse
(once it works)
- permanent effect
Slow action (1-3 m or more)
High chance of hypothyroid
requiring T4 tablets
Sudden T4 swings possible
May worsen eye problems
? thyroid cancer risk
Pts unfit for
operation
Uncontrolled
thyrotoxicosis
Rapid (days)
Low chance of relapse
- permanent effect
Risk of GA
2% parathyroid or nerve to
vocal cords damage
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
in detecting
agranulocytosis
 Choice of Px
Prospective multicentre (blinded)
trial of 2weekly WBC for first
3m of thionamide 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
w/ radioiodine
Multicentre/long-term
registry of I-131 Px in
children and adolescents