Eur J Nucl Med (1988) 14:180-183 European ~ ] 1 I~l,"~'~r Journal of ! IIIUI~./II~;t~I./

Medicine © Springer-Verlag 1988

Early prediction of hypothyroidism following 131i treatment for Graves' disease Rhoda Wilson a, James H. McKillop a, Elizabeth Black z, Carol Jenkins 1, and John A. Thomson 1 1 University Departments of Medicine, Royal Infirmary, Glasgow, UK 2 Queen Elizabeth Hospital, Birmingham, UK

Abstract. The aim of this study was twofold. Firstly to assess the post treatment predictive value of various bio- chemical and immunological tests for early hypothyroidism after t3~I therapy for Graves' disease, and secondly to de- termine whether or not pretreatment with Carbimazole pro- tects against post treatment hypothyroidism. The early changes observed in serum Ta, T4, TSH, thyroid microsom- al and thyroglobulin antibody levels were found to be of no predictive value. A sharp rise, around 2 months, in TRAb levels following z31I therapy indicated that hypoth- yroidism was likely to occur. This rise was thought to reflect a greater degree of thyroid damage. Lower levels of thyrog- lobulin in patients who had become hypothyroid by 12 months after treatment would support this view. Five weeks Carbimazole pretreatment in this relatively small group of patients did not appear to protect against hypoth- yroidism.

Key words: Thyrotropin receptor antibodies - Thyroglobu- lin - Hypothyroidism

Graves' disease is known to affect 1.0%-2.7% of the female population and 0.1%-0.2% of the male population (Tun- bridge et al. 1977). In many centres therapeutic radioiodine (~31I) is now the treatment of choice, particularly for pa- tients over the age of 40 years. In most centres within the UK the aim of such treatment is to render the patient euthy- roid, with hypothyroidism being seen as a disadvantage. Despite attempting this, the rate of hypothyroidism result- ing from a3~I therapy is high. In keeping with this is a report from the Mayo Clinic stating that of 1005 women treated with 13q between 1946-1969, 54% had become hy- pothyroid by 1984 (Hoffman 1984).

Some previous reports have stated that pretreatment with antithyroid drugs reduced the incidence of post 13aI hypothyroidism (Crooks etal. 1960; Viherkoski etal. 1970). Others however, have not found this to be the case (Goolden and Fraser 1969).

While it would be advantageous if patients likely to become hypothyroid following 131I therapy could be pre- dicted as early as possible after therapy, this has not yet been possible. A previous study (Lee et al. 1986) investi- gated the use of thyroid iodine content as a diagnostic pre- dictor of hypothyroidism following 13 ~i therapy. While they

Offprint requests to." R. Wilson, Department of Medicine, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK

found that an iodine content > 2 mg at 3 months post lalI had a 14% risk of hypothyroidism, which increased to 82% if the iodine content was < 2 rag, this was clearly of only limited use.

The aim of this study therefore was twofold. Firstly, to examine the predictive value of various biochemical and immunological changes following 131I therapy for Graves' disease, and secondly to assess whether pretreatment with Carbimazole had any radioprotective effect.

Materials and methods

Patients. The study comprised 30 patients (2 male, 28 fe- male) in whom the diagnosis of Graves' disease was made on the basis of clinical, biochemical and scintigraphic find- ings. The patients were followed at 2 monthly intervals dur- ing the first 12 months following 131I therapy. Sixteen of the 30 patients became hypothyroid within the 1 st year after 3 ~I treatment (Group 1), with 14 patients remaining euthy-

roid (Group 2). Ten of the 30 patients studied were pre- treated with Carbimazole for a mean period of 5 weeks prior to ~3~I therapy. The selection for Carbimazole pre- treatment was at the discretion of the referring clinician and was not made as part of the study. At the time of presentation there was no significant difference in the size of goitre, assessed clinically, between the two groups.

Biochemical tests. Serum total T3 and T4 levels were mea- sured using conventional radioimmunoassays. Reference ranges were T3 0.9-2.8 nmol/1; T4 55-144 nmol/1. Serum TSH levels were measured using a 2 site immuno-radiomet- tic assay where the reference range was 0.5-5 g/1. Thyroid microsomal and thyroglobulin antibody levels were mea- sured using commercial haemagglutination tests. Thyrotro- pin receptor antibody (TRAb) levels were measured accord- ing to the method of Shewring and Smith (1982) where the normal range was <25 (Wilson et al. 1985). Thyroglo- bulin levels were measured by radioimmunoassay (Black et al. 1981, 1983) the normal range being < 1 30 gg/1.

Patients were diagnosed to be hypothyroid mainly on the basis of biochemical findings although this merely con- firmed the clinical diagnosis on some occasions.

Results

The mean dose of 131I given did not differ significantly between groups 1 and 2 (320_+ 131 MBq vs 342_+95 MBq) nor between Carbimazole and non Carbimazole pretreated

181

TRAb levels post 1311 therapy in patients who became hypothyroid.

100-

60

4o

Normal ange

T i m e - m o n t h s

mean 35 52 50 48 51 36 30

Fig. 1. TRAb levels post 13xI therapy in patients who became hy- pothyroid

TRAb levels post 1311 therapy in patients who remained euthyroid

tO0

8 0

60 g

40-

20-

O-

Table 1. Mean thyroid hormone levels at zero and two months post 131I therapy

Hypothyroid (Group 1) Euthyroid (Group 2)

Pre Post Pre Post

T4 159 +56 92 -t-26 a 147 +38 84.1+31 a (nmol/1)

T3 3.8_+ 2.9 1.9_+ 1.2 b 3.6+ 1.5 1.9_+ 0.7" (nmol/1)

a P < 0 . 0 1 ; b P < 0 . 0 5

Table 2. Serum thyroxine and TSH levels in Group 1 at the time hypothyroidism was diagnosed

Patient T4 Ta TSH (nmol/1 (nmol/1) (mg/1)

1 35 0.9 11.0 2 17 0.6 15.0 3 12 1.0 25.0 4 44 1.4 17.0 5 < 10 0.7 35.0 6 < t0 0.5 65.0 7 12 0.5 67.0 8 < 10 0.8 65.0 9 33 1.4 10.0

10 < 10 0.6 74.0 11 96 1.4 1.0 12 39 1.5 11.0

57 2.0 29.O 18 1.3 10.0

< 10 0.5 78.0 < 10 0.9 97.0

13 - - 1 4

15 16

did not change significantly during the initial 2 months after 0 2 4 6 8 10 12 therapy (34 compared to 38 at 2 months post t31I). By

Time - months

mean 34 38 32 32 30 30 33

Fig. 2. TRAb levels post 131I therapy in patients who became euthyroid

patients (368 + 46 MBq vs 329 ___ 26 MBq). The mean per iod of time taken for pat ients in G r o u p I to become hypothyr- oid was 5 months. There was no correlat ion between the dose of 13~I given and the time taken to become hypothyr- oid.

Eight of 10 patients pre t reated with Carbimazole be- came hypothyro id compared to only 8/20 patients who were not pretreated. At the time of 13tI therapy, T R A b levels did not differ significantly between groups 1 and 2 (35+17.3 compared to 34+20.2) . In those patients who became hypothyro id (Group 1), T R A b levels were elevated in 11/16 at the time of 131I therapy (Fig. 1). F o u r of 11 pa- tients had been pret reated with Carbimazole. Mean T R A b levels rose significantly ( P < 0.01) f rom 35 to 52 during the initial 2 months after t reatment and subsequently fell except in 2 pat ients whose peak values were at 4 months. By 12 months after therapy, T R A b levels were still elevated in 10/16 patients. In those patients who remained euthyroid following 131I therapy (Group 2), T R A b levels were initial- ly elevated in 11/14 patients (Fig. 2). Mean T R A b levels

12 months after therapy mean T R A b levels did not differ significantly from those at presentation. At this t ime T R A b levels were elevated in 9/14 patients.

Thyro id hormone levels at 0 and 2 months post 131I therapy are presented in Table 1. By 2 months after therapy T3 and T , levels had fallen significantly in all patients. T3 and T4 levels did not differ significantly between Groups 1 and 2 either at the time of t reatment or 2 months later. TSH levels did not change significantly during the initial two months after therapy, being undetectable in all but one patient. Serum T , and TSH levels at the time hy- pothyroid ism was diagnosed are given in Table 2. In one pat ient who commenced thyroxine treatment, the biochemi- cal results were discordant with this.

Thyroid microsomal antibodies were initially found to be present in 15/30 patients. All patients with microsomal antibodies pr ior to t reatment showed a rise in titre two months after treatment, but no addi t ional patients became positive for the ant ibody at this time. Thyroglobul in anti- bodies were only found initially in 3/30 patients studied. These an t ibody titres rose in all three patients during the two months after treatment. There was no significant differ- ence in the ant ibody response between Groups 1 and 2.

In order to assess thyroid damage retrospectively, thyr- oglobulin levels were measured I year after therapy in all

182

Thyroglobulin levels 12 months post 1311 therapy

Tg jg/ I) 100.

80'

60"

40.

0 0

8 e m . . . . . . . . . . . 6 . . . . . . . . . . . . . . . . . . . . . . m . . . .

• 1 2 0 " • normal

| : rang,

' 1 mm •

Group 1. Group 2. mean 231Jg/I 590Jg/I

Fig. 3. Thyroglobulin levels in patients at 12 months after 1311 ther- apy

patients in Group 1 and 10/15 patients in Group 2. The results (Fig. 3) showed thyroglobulin levels to be signifi- cantly higher in those patients who remained euthyroid compared to those who became hypothyroid.

Discussion

Of the 30 patients studied, 16 (53%) became hypothyroid within the 1st year after treatment, most doing so within the first 5 months. Why therefore should some patients de- velop hypothyroidism following 131I therapy while others do not?

Pretreatment with antithyroid drugs has previously been suggested to have a radioprotective effect, but our results obtained using carbimazole would not support this view. In the present study only 10 patients were pretreated with carbimazole prior to 131I and of those 8 (80%) became hypothyroid compared to only 8/20 (40%) who were not pretreated. One possible explanation for these conflicting findings is that patients in this study were pretreated for a mean period of only five weeks prior to 131I therapy and this may not have been long enough to give the putative radioprotective effect. Goolden and Fraser (1969), also found carbimazole to have no significant effect on the sub- sequent response to 131I therapy for patients pretreated for two-four months in contrast to Crooks et al. (1960) who pretreated with Methylthiouracil for between three months and one year. While it is possible that the withdraw- al of carbimazole produced a rebound increase in thyroidal 131I uptake, this is unlikely to be due to an action on iodide trapping. In addition, the time between the discontinuation of carbimazole and 1131 therapy (seven days) was too short to allow a marked exacerbation in the severity of thyrotoxi- cosis.

In the two months after therapy, serum T3 and T4 levels fell significantly while TSH levels remained undetectable in both groups due to continued suppression of the pituitary and hypothalamus. This failure of serum TSH levels to

indicate impending hypothyroidism has been noted pre- viously (Toft et al. 1973).

At the time of 131I treatment, thyroid microsomal anti- bodies were present in 15/30 patients and thyroglobulin antibodies in 3/30. Following therapy the titre of both anti- bodies rose in all patients with antibodies. No patient who was antibody negative at the time of treatment developed antibodies post therapy. While a rise in thyroid antibody titre post 131I therapy is well documented, the relationship between this rise and thyroid function is less well known. Burke and Silvester (1969) found antibodies to be present in high titre in those patients who later became hypothyr- oid. The present study found no such correlation.

In the initial months after therapy TRAb levels rose significantly in those patients who became hypothyroid. This initial rise was not observed in those patients who became euthyroid. Previous studies have reported variable changes in TRAb levels following 131I therapy (Atkinson et al. 1982; Bech and Madsen 1980). The majority of pre- vious studies have not considered the changes in TRAb levels following 1311 therapy in relation to the patients clini- cal course. More recently however, Kennedy et al. (1986) reported in abstract form the finding of a sharp rise in TRAb levels between zero and three-four months after therapy in those patients who became hypothyroid. They too found little change in TRAb levels post treatment in those patients who became euthyroid.

Thyroglobulin levels were measured 1 year after ra- dioiodine therapy to give a retrospective estimate of thyroid damage. Lower levels of thyroglobulin were found in pa- tients who became hypothyroid suggesting that greater thy- roid damage had occurred in these patients. Patients with thyroid cancer receiving T4 who have suppressed TSH levels are known to have reduced levels of thyroglobulin (Black et al. 1981). While patients in Group 1 were receiving T4, all were clinically and biochemically euthyroid at the time thyroglobulin measurements were made. By 12months after 131I therapy there was no significant difference in mean TSH levels between groups 1 and 2 (2.23+2.0 vs 1.004-0.47 P > 0.01). This would suggest that the reduced levels of thyroglobulin seen in this study are likely to be due to the damage caused by 131I treatment. The degree of thyroid damage may have been responsible for the initial rise in TRAb levels in those patients who became hypothyr- oid. In those patients who remained euthyroid the damage caused by 1311 irradiation was less severe resulting in less TRAb being released. As more functioning tissue remained the gland was still capable of thyroglobulin production. While an explanation for the observed rise in TRAb levels in patients who became hypothyroid can be postulated, the reason why TRAb levels should remain elevated in some patients, regardless of their clinical state, for as long as two years or more after therapy is less clear. A number of possible explanations exist. Firstly, following 131I thera- py, radioresistant T helper cells may remain to stimulate TRAb production. Secondly, suppressor T lymphocytes within the thyroid may be more susceptible to radiation and this may be the cause of the rise in TRAb levels. Thirdly, the released antigen brought about by 1311 therapy may stimulate extrathyroidal lymphoid tissue to produce TRAb 0Neetman and McGregor 1984).

In conclusion, it would appear that pretreatment with carbimazole for a mean period of five weeks prior to 13tI therapy had no radioprotective effect. A sharp rise in TRAb

183

levels during the two months following 1311 treatment would suggest that subsequent hypothyroidism is likely. None of the other biochemical parameters tested were of any early predictive value. The sharp rise in T R A b levels was thought to be due to greater thyroid damage and this was supported by the subsequent decreased thyroglobulin levels in these patients.

References

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Bech K, Madsen SN (1980) Influence of treatment with radioiodine and propylthiouracil on thyroid stimulating immunoglobnlins in Graves' disease. Clin Endocrinol 13:417-429

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Received August 11, 1987 / December 18, 1987