Clinical Endocrinology ( 1 990), 33, 687-698

GRAVES’ DISEASE FOLLOWING HYPOTHYROIDISM DUE

T O HASHIMOTO’S DISEASE: STUDIES OF EIGHT CASES

N . T A K A S U , T . Y A M A D A , A. S A T O , M . N A K A G A W A , I. K O M I Y A ,
Y . N A G A S A W A A N D T. ASAWA

Department 01Gerontology, Endocrinoiogy. and Metabofism. Shinshu Uniuersity,

School of Medicine, Matsumoto, Japan

(Received 2 May 1990: rerurnedjor revision 18 M a y 1990:finally revised 6 June 1990;

accepted 22 June 1990)

SUMMARY

Hashimoto’s and Graves’ diseases represent the main two types of autoimmune
thyroid disease. The combination of these two is well known. However,
occurrence of Graves’ disease after primary hypothyroidism is rare. We report
seven patients with hypothyroidism due to Hashimoto’s disease, who developed
Graves’ disease with hyperthyroidism. We also report one patient with
hypothyroidism due to Hashimoto’s disease, who continued to be hypothyroid
even in the presence of TSAb (thyroid stimulating antibody). These patients
were divided into three groups according to the changes in thyroid function and
clinical course: ( I ) transient hyperthyroidism due to Graves’ disease following
hypothyroidism; (2) persistent hyperthyroidism due to Graves’ disease follow-
ing hypothyroidism; and (3) persistent hypothyroidism with positive TSAb.
Such changes in thyroid function and clinical course seem to be decided by three
factors: ( I ) TSAb and (2) TSBAb (thyroid stimulation blocking antibody)
activities in the blood and (3) the responsiveness of the thyroid glahd to TSAb.
Seven patients had hyperthyroidism, when they had TSAb, which stimulated
the thyroid gland; one of these seven patients had TSBAb during the
hypothyroid state and TSAb during the hyperthyroid state, indicating that the
alterations in the thyroid state related to the balance between the activities of
TSAb and TSBAb. Another patient continued to be hypothyroid despite the
presence of TSAb; his thyroid gland was not palpable and could not respond to
TSAb.

Hashimoto’s and Graves’ diseases represent the main two types of autoimmune thyroid
disease. The combination of these two is well known. Some of the patients with Graves’
disease develop hypothyroidism due to Hashimoto’s disease spontaneously. An unusual
sequence of events is Graves’ disease with hyperthyroidism following hypothyroidism due
Correspondence: Dr Nobuyuki Takasu. Department of Gerontology. Endocrinology, and Metabolism,
Shinshu University, School of Medicine. Asahi 3-1 - I , Matsumoto, Nagano-ken 390. Japan

687
 N . Takasu ei a1
to Hashimoto’s disease. These unusual cases have occasionally been reported (Bell et a/.,
1985; Kasagi et af., 1986; Takeda et al., 1988; Cho el al., 1989). However, long-term
follow-up studies of these patients have not been done and their final outcome is not
known. We have encountered seven patients who developed Graves’ disease with
hyperthyroidism following hypothyroidism due to Hashimoto’s disease. In addition, we
saw one patient who continued to be hypothyroid due to Hashimoto’s disease even in the
presence of thyroid stimulating antibody (TSAb) in the blood. We studied these eight
patients and divided them into three groups according to the changes in thyroid function
and clinical course. We will also discuss the possible mechanisms for these changes.

PATIENTS
Eight patients (seven females and one male) with hypothyroidism due to Hashimoto’s
disease were studied. The clinical diagnosis of hypothyroidism due to Hashimoto’s
disease was made on the basis of history, clinical findings, endocrine data (T4, T3, and
TSH), and positive antithyroid microsomal antibodies (MHA) and antithyroglobulin
antibodies (TA). Exophthalmos was diagnosed when proptosis was 17 mm or more by
exophthalmometry. Initially all these eight patients had been hypothyroid. They were
treated with thyroxine. During the thyroxine therapy, seven patients (Cases 1-7) had
hyperthyroidism but another patient (Case 8) continued to be hypothyroid even in the
presence of TSAb in the blood. None of the patients had been taking any drugs or
excessive iodine-rich foods, such as seaweed. None of them had past or family history of
autoimmune or thyroid diseases, unless otherwise stated. The study plan was reviewed
and approved by our institutional review committee and consent was obtained from the
patients. Blood samples were collected at regular intervals.

METHODS
Serum triiodothyronine (T3), thyroxine (T4), and TSH were determined by radioimmu-
noassay (RIA) using commercially available kits (Takasu et al., 1987). The normal ranges
of T4 and T3 are 77-155 nmol/l and 1.2-2.8 nmo!/l, respectively. The normal range of
TSH is below 5 mU/I. Antithyroid microsomal antibodies (MHA) and antithyroglobulin
antibodies (TA) were measured using commercial kits (Fuji Zoki, Tokyo, Japan). The
antibodies were considered to be present when positive reactions were obtained with
serum dilutions of 1 :40 or greater. TSH-binding inhibitory immunoglobulin (TBII) was
measured by radioreceptor assay using a commercial kit (R.S.R. Limited, Cardiff, UK)
(Smith & Hall, 1981), as reported previously (Takasu et al., 1987) (normal< ISo/0).
Thyroid stimulating antibody (TSAb) was determined as described previously by Kasagi
et af. (1 982). Porcine thyroid cells were isolated and cultured as before (Takasu et a[.,
1978, 1984). The cells were incubated with 3 mg IgG in 0.3 ml Hank’s solution without
NaCI, pH 7.5, containing 1.5% bovine serum albumin, 20 mM Hepes and 0.5 mM
3-isobutyl- I -methylxanthine. After 2 h incubation at 37”C, cAMP was measured by
radioimmunoassay (RIA) using a commercial kit (Yamasa, Chiba, Japan). The activities
were expressed as percentage cAMP production compared with the mean values for 20
normal subjects (normal < 150%). For determination of thyroid stimulation blocking
antibody (TSBAb), IgG ( 3 g/0.3 I) was incubated with porcine thyroid cells in the presence
of 100 pU/ml bovine TSH for 2 h. TSBAb activity was expressed as percentage inhibition
of cAMP production as follows:
 Graves ’ disease fo110 wing hypo thy r o idism 689

cAMP generated in the presence cAMP generated in the

-
of test IgG and TSH presence of test IgG

cAMP generated in the presence cAMP generated in the

of normal IgG and TSH - presence of normal IgG
The normal values were obtained from 32 normal subjects and < 30%. IgG was prepared
by Protein-A affinity chromatography (Ochi et al., 1976). Normal IgG was obtained from
normal pooled serum. The 24-h thyroidal I3’I uptake was measured by the standard
procedure with normal values from 10 to 40%. TSH was obtained from Armour
Parmaceutical Co. (Phoenix, AZ). All other chemicals were of the highest purity available
commercially.

RESULTS
The eight patients with hypothyroidism due to Hashimoto’s disease were divided into
three groups according to the changes in thyroid function and clinical course: ( I ) transient
hyperthyroidism due to Graves’ disease following hypothyroidism (Cases 1-5); (2)
persistent hyperthyroidism due to Graves’ disease following hypothyroidism (Cases 6 and
7); and (3) persistent hypothyroidism with positive TSAb (Case 8). The main features of
Cases 1-8 are summarized in Table 1.

Group I . Transient hyperthyroidism due to Graves’ disease following hypotlzyroidism due to

Hashimoto’s thyroiditis
Case I . A 23-year-old female presented with a 3-month history of tiredness, cold
intolerance, and hoarseness, in October 1985. She had dry skin, facial puffiness,
bradycardia, and hoarseness. The thyroid gland was palpable and its weight was
estimated to be 42 g. The diagnosis of primary hypothyroidism due to Hashimoto’s
disease was made on the basis of low serum T4 (25 nmol/l) and T3 (0.13 nmol/l), high TSH
(1 88 mU/l), and positive M H A ( 1 : 3202) and TA (1 :go2). Thyroxine was started.
With the thyroxine therapy, the symptoms regressed and the T3, T4, and TSH levels
became normal. During the thyroxine therapy, in November 1986, she presented with
symptoms of hyperthyroidism such as irritability, perspiration, palpitation, diarrhoea,
and body weight loss. She had a tachycardia of 120/min at rest, moist, warm skin, and a
marked finger tremor. She did not have exophthalmos, but the goitre size increased
(estimated weight, 56 g). Serum T 4 and T3 levels were high. The thyroxine therapy was
discontinued. Two weeks later, she was still thyrotoxic with elevated serum T 4 (260 nmol/
1) and T3 (5.6 nmol/l). TSAb, TBII, MHA, and TA titres were increased to 1900Y0,75”/0,
1 :6402, and 1 : 3202, respectively. The thyroidal I3lI uptake was 47%. She was observed
without drugs. Her symptoms of hyperthyroidism had disappeared spontaneously.
Serum T4, T3, and TSH levels became normal. TSAb, TBII, MHA, and T A titres were
decreased to loo%, I % , 1 :802, and negative, respectively. The goitre size decreased
(estimated weight, 48 9). She remained euthyroid thereafter. TSBAb has been negative so
far.
Case 2. A 53-year-old female presented with tiredness and cold intolerance in October
1984. She had rheumatoid arthritis since 1968. She had dry skin, facial puffiness,
bradycardia, and hoarseness. The thyroid gland was palpable and its weight was
690 N . Takasu et al.

Table I . Summary of Cases 1-8 with Graves’ disease following hypothyroidism due to Hashimoto’s thyroiditis

Case no. Age’ During During

Antibodies Sex (years) hypothyroidism hyperthyroidism Recently Treatment

Group I . Transient hyperthyroidism due to Graves’ disease following hypothyroidism

Case 1. F 23 Euthyroid No
TSAB - + -
TBII -
-
+
-
-
-
TSBAb
MHA + + +
TA + + +
Case 2. F 53 Euthyroid No
TSAB - + -
TBII -
-
+
-
-
-
TSBAb
MHA + + +
TA f + +
Case 3. F 28 Euthyroid No
TSAB - + -
TBII
TSBAb
-
-
+
-
-
-
MHA + + +
TA + + -
Case 4. F 24 Euthyroid Thyroxine
TSAB - + -
TBII -
-
+
-
-
-
TSBAb
MHA +
-
+
- -
+
TA
Case 5. F 38 Euthyroid No
TSAB - + -
TBII + + -
TSBAb + - -
MHA +
-
+
- -
+
TA
Group 2. Persistent hyperthyroidism due to Graves’ disease following hypothyroidism
Case 6. F 42 Euthyroid MMI
TSAB - + - (methyl-
TBII - + - mercapto-
TSBAb - - - imidazole)
MHA + + +
TA + + +
Case 7. F 38 Euthyroid MMI
TSAB - + -
TBII
TSBAb
-
-
+
-
-
-
MHA + + +
TA + + +
Group 3. Persistent hypothyroidism with positive TSAb
Case 8. M 65 (continued to be hypothyroid) Euthyroid Thyroxine
TSAB + -
TBII + -
TSBAb - -
MHA + +
TA + +
*The age when the patient was found to be hypothyroid
 Graves ' disease following hypothyroidism 69 1
estimated to be 40 g. The diagnosis of primary hypothyroidism due to Hashimoto's
disease was confirmed by low serum T4 (38 nmol/l) and T3 (0.25 nmol/l), high TSH (36
mU,/l), and positive MHA (1 : 640') and TA (1 : 3202). Thyroxine was started.
With the thyroxine therapy, the symptoms regressed and serum T4, T3, and TSH values
became normal. During the thyroxine therapy, she presented with symptoms of
hyperthyroidism such as irritability, perspiration, palpitation, and body weight loss, in
September 1985. She had a tachycardia of 108/min at rest, moist, warm skin, and a finger
tremor. She did not have exophthalmos, but the goitre size increased (estimated weight, 50
8). Serum T4 and T3 levels were increased. TSAb and TBII became positive. The
thyroxine therapy was discontinued. Two weeks later, she was still thyrotoxic with
elevated serum T4 (270 nmol/l) and T3 (5.4 nmol/l). TSAb, TBII, MHA, and TA titres
were increased to 780%, 49%, 1 : 6402, and 1 : 3202, respectively. The thyroidal I3'I uptake
was 48%. She was observed without any thyroid drugs. However, within 2 months, her
symptoms of hyperthyroidism had disappeared. The serum T4, T3, and TSH levels
became normal. TSAb, TBII, MHA, and TA titres were decreased to 96%, 1 %, 1 : 1602,
and 1 :80', respectively. The goitre size decreased (estimated weight, 42 g). She remained
euthyroid.
However, in February 1987 she again presented with such symptoms of hyperthyr-
oidism as irritability, perspiration, palpitation, and body weight loss. She had hyperthyr-
oidism. She did not have exophthalmos, but the goitre size increased (estimated weight, 49
8). Serum T4 (320 nmol/l) and T3 (6.5 nmol/l) were high. The thyroidal I3'I uptake was
52%. The TSAb, TBII, MHA, and TA titres were increased to 1050%, 65%, 1 :640', and
1 :320', respectively. She was observed without drugs. However, within 2 months her
symptoms of hyperthyroidism had disappeared. The serum T4, T3, and TSH levels
became normal. TSAb, TBII, MHA, and TA titres were decreased to loo%, 0, I : 160',
and 1 :80', respectively. The goitre size decreased (estimated weight, 42 g). She remained
euthyroid thereafter. TSBAb has been negative so far.
Case 3. (Fig. I ) . A 28-year-old female presented with lack of energy and tiredness, in
October 1985. She had increased in weight and had become sensitive to cold. She was
mildly hypothyroid with dry, coarse skin and bradycardia. A diffusely enlarged goitre was
palpable and its weight was estimated to be 58 g. She had no exophthalmos with no
pretibial oedema or acropachy. The diagnosis of primary hypothyroidism due to
Hashimoto's disease was confirmed by low serum T4 and T3 values, high TSH value and
positive MHA and TA. Thyroxine was started.
With the thyroxine therapy, the symptoms regressed and serum T4, T3, and TSH values
became normal. The goitre size decreased (estimated weight, 48 g). During the thyroxine
therapy, in May 1987, she presented with symptoms of hyperthyroidism such as
irritability, perspiration, palpitation, and body weight loss. She had a tachycardia of
100/min a t rest, moist, warm skin, and a finger tremor. She did not have exophthalmos,
but the goitre size increased (estimated weight, 60 g). Serum T4 and T 3 levels were
elevated. The thyroxine therapy was discontinued. Two weeks later, she was still
thyrotoxic with elevated serum T4 and T3 levels. M H A and TA titres were increased to
1 :640' and 1 : 160' positive, respectively. TSAb and TBII titres were increased. The
thyroidal uptake was 52%. One month later, therapy with 20 mg methylmercaptoimi-
dazole (MMI) daily was started, and thyroid function was quickly normalized and then
depressed; she became hypothyroid. The dose of M M I was decreased and she became
euthyroid. The goitre size decreased (estimated weight, 52 g). Meanwhile. she was found
692 N . Takasu et al.

40
6-

4-
I
v)
m 20 I-
I-

2-

0- 0
0
1
1000 - 1
I

c
O I
6002

- 4002
4
I-

500 -
n
4 4
v) 50 I
I- P
I-
2002

Q- 0 0
Month
Year I 1986 I 1987 I 1988 I 1989

Fig. I . Case 3 . Clinical and laboratory findings. 0 , Thyroxine therapy; 9. pregnant; H,

methylmercaptoimidazole (MMI); she was treated with 20.5 and then 2.5 mg of MMI daily. a, 0 ,
T4; 0, T3; 0,TSH. b, 0 , TBII; 0, TSAb; 0 , MHA; H, TA.

to be pregnant and MMI was discontinued. She remained euthyroid during the
pregnancy, until she delivered a full-term male in October 1988.
Immediately after delivery, she began to have symptoms of hyperthyroidism such as
tachycardia at rest, moist, warm skin, and a finger tremor. The goitre size increased
(estimated weight, 65 8). Serum T4 and T3 levels were increased. The thyroidal I3lI uptake
was 48%. However, within 1 month, her hyperthyroidism improved spontaneously. She
was observed without drugs and became euthyroid within 1 month. The serum T4,T3,
and TSH levels became normal. TSAb, TBII, MHA, and TA titres were decreased. The
goitre size decreased (estimated weight, 42 g). She is now euthyroid without drugs.
TSBAb has been negative so far.
Case 4 . (Fig. 2). A 24-year-old female presented with a 2-month history of a goitre, in
May 1985. On examination, she had mild hypothyroidism; her skin was not moist and her
face was puffy. The thyroid gland was palpable and its weight was estimated to be 60 g.
The diagnosis of primary hypothyroidism due to Hashimoto’s disease was confirmed by
low serum T4 value, elevated TSH value, and positive MHA. She was observed without
drugs. The thyroid function became normal spontaneously. From October 1985 to July
 Graves' diseuse following hypothyroidism 693

8
6oo t 100

-- --
\
> 3
-
E

-s
0
4 I
c)
50 fl
t

0
C

I00
3000 5 00'

- - a
5 ag 4002 +-

n
a
m
200c
--
m
50
a
I
I
I- t

I000 200'

0 0 0
Month

Year 1985 I986 1987 1988 1989

Fig. 2. Case4. Clinical and laboratory findings. 0 , Thyroxine therapy. a, 0 , T4; 0 . T3; 0 ,TSH. b,
0 , TBII; 0, TSAb; 0 , MHA; H,TA.

1986, she did not come to us. In July 1986 she presented with a goitre (estimated weight, 65
g). The diagnosis of primary hypothyroidism was again confirmed by low serum T 4 and
T 3 values, high T S H value, and positive M H A . This time she was treated with thyroxine.
With the thyroxine therapy, the goitre size decreased (estimated weight, 5 5 9). During
the therapy, in December 1987, she presented with symptoms of hyperthyroidism such as
irritability, perspiration, palpitation, and body weight loss. She had a tachycardia of 120/
min a t rest, moist, warm skin, and a marked finger tremor. She did not have
exophthalmos, but the goitre size increased (estimated weight, 65 9). Serum T4 and T 3
levels were high. The thyroxine therapy was discontinued. Two weeks later, she was still
thyrotoxic with elevated serum T 4 and T 3 levels. Thyroidal I3'I uptake was 53%. She was
observed without drugs. However, her symptoms of hyperthyroidism had disappeared
spontaneously. She continued to be euthyroid over 18 months without drugs and then
694 N . Takasu et al.
developed hypothyroidism; serum T4 and T 3 levels became low and TSH high. Thyroxine
was started in May 1989. She is now taking thyroxine and euthyroid. TSBAb has been
negative so far.
Case 5. A 38-year-old female presented with a 3-month history of tiredness and cold
intolerance, in October 1987. She had increased in weight by 3 kg. She had mild
hypothyroidism; her skin was not moist and her face was puffy. The thyroid gland was not
palpable. The diagnosis of primary hypothyroidism due to Hashimoto’s disease was
confirmed by low serum T4 (25 nmol/l) and T3 (0.13 nmol/l), elevated TSH (108 mU/l)
and positive MHA (1 :802). TSBAb was positive (96%) but TSAb was negative (92%).
Thyroidal I3’I uptake was 2%. She was treated with thyroxine.
During the thyroxine therapy, in December 1988, she presented with symptoms of
hyperthyroidism such as irritability, perspiration, palpitation, and body weight loss. She
had a tachycardia of 120/min at rest, moist, warm skin, and a marked finger tremor. She
did not have exophthalmos. The thyroid gland was palpable and its weight was estimated
to be 42 g. Serum T4 and T3 levels were high. TSBAb became negative (2%) and TSAb
positive (1490%). The thyroxine therapy was discontinued. One month later, she was still
thyrotoxic with elevated serum T4 (295 nmolil) and T3 (6.3 nmol/l). Thyroidal I3’I uptake
was 53%. However, her symptoms of hyperthyroidism had disappeared. TSAb activities
decreased and became negative. She was observed without drugs. TSAb and TSBAb have
been negative and she has been euthyroid thereafter.

Group 2. Persistent hyperthyroidism dire to Graves’ diseasefollowing hypothyroidism due to

Hashimoto’s thyroiditis
Case 6 (Fig. 3). A 42-year-old female presented with a 2-month history of tiredness and
cold intolerance, in November 1986. She had dry skin, facial puffiness, bradycardia, and
hoarseness. The thyroid gland was palpable and its weight was estimated to be 35 g. The
diagnosis of primary hypothyroidism due to Hashimoto’s disease was confirmed by low
serum T4 and T3 values, high TSH value, and positive M H A and TA. Thyroxine was
started.
With the thyroxine therapy, the symptoms regressed and serum T4, T3, and TSH values
became normal. During the thyroxine therapy, in February 1988, she presented with
symptoms of hyperthyroidism such as irritability, perspiration, palpitation, and body
weight loss. She had a tachycardia of 116/min at rest, moist, warm skin, and a finger
tremor. She did not have exophthalmos, but the goitre size increased (estimated weight, 52
g). Serum T4 and T3 levels were high. The thyroxine therapy was discontinued. Two
weeks later, she was still thyrotoxic with elevated serum T4 and T3 levels and TSAb was
positive. MHA and TA titres were increased to 1 : 6402 and 1 : 160’ positive, respectively.
The thyroidal I3’I uptake was 56%. Therapy with 20 mg M M I daily was started. She
became quickly euthyroid and then hypothyroid. The dose of MMI was decreased and
she has been euthyroid with MMI. TSBAb has been negative so far.
Case 7. A 38-year-old female presented with tiredness and cold intolerance, in April
1986. She had dry skin, facial puffiness, bradycardia, and hoarseness. The thyroid gland
was palpable and its weight was estimated to be 55 g. The diagnosis of primary
hypothyroidism due to Hashimoto’s disease was confirmed by low serum T 4 (30 nmol/l)
and T3 (1.1 nmol/l), high TSH ( 1 62 mU/l), and positive M H A (1 :640’) and TA (1 :6402).
Thyroxine was started.
 Gruves ' disease f0110 wing hypo t hyro idisni 695

6-

4-

2-

0-

600'

a
c
4002 $
I

2002

., ..
Fig. 3. Case 6 . Clinical and laboratory findings. 0 ,Thyroxine therapy; methylmercaptoimida-
zole (MMI); she was treated with 20,2.5 and then 5 mg of MMI. a. 0 , T4; 0 , T3: 0. TSH. b, 0 ,
TBII; 0, TSAb; 0, MHA; TA.

With the thyroxine therapy, the symptoms regressed and serum T4, T3, and TSH values
became normal. During the thyroxine therapy, in October 1987, she presented with mild
symptoms of hyperthyroidism such as irritability, perspiration, and palpitation. She had
a tachycardia of 100/min at rest and moist, warm skin. She did not have exophthalmos,
but the goitre size increased (estimated weight, 65 g). Serum T4 (238 nmol/l) and T3 (3.4
nmol/l) were high. The thyroxine therapy was discontinued. MH A and TA titres were
both 1 : 12802positive. The thyroidal I3'I uptake was 47%. In March 1988, therapy with 10
mg MMI daily was started. She became quickly euthyroid and then hypothyroid. The
dose of MMI was decreased and since then she has been euthyroid with MMI. TSBAb has
been negative so far.
696 N . Takasu et al.
Group 3. Persistent hyporhyroidism with positive TSAb
Case 8. A 65-year-old male presented with exophthalmos and diplopia, in December
1986. He had dry skin, facial puffiness, bradycardia, hoarseness, and slow-relaxing
reflexes. The thyroid gland was not palpable. He had exophthalmos (1 7 mm right eye; 18
mm left eye) with no pretibial myxoedema o r acropachy. A computed tomographic (CT)
scan revealed that the eye muscles were hypertrophic. The diagnosis of primary
hypothyroidism due to Hashimoto’s disease was confirmed by low serum T4 (25 nmol/l)
and T3 (0.56 nmol/l), high TSH (75 mU/l), and positive M H A (1 :6402)and TA (1 :6402).
TSAb (3200%) and TBII (60%) were positive but TSBAb was negative. Thyroxine was
started.
With the thyroxine therapy, the symptoms regressed and serum T4, T3, and TSH values
became normal. In contrast to the other seven patients, he did not present with symptoms
of hyperthyroidism during the thyroxine therapy. He is now taking thyroxine and has
been euthyroid. The TSAb titres were very high but gradually decreased; TSAb continued
to be positive until December 1988 and then became negative. Recently, TSAb and TBII
have both been negative. His thyroid gland has never been palpable. TSBAb has been
negative so far.

DISCUSSION
The occurrence of Graves’ disease after primary hypothyroidism is rare. We have
described seven patients with hypothyroidism due to Hashimoto’s disease, who
developed Graves’ disease with hyperthyroidism. We have also described one patient with
hypothyroidism due to Hashimoto’s disease, who continued to be hypothyroid even in
the presence of strongly positive TSAb. These patients can be divided into three groups
according to the changes in thyroid function and clinical course: ( I ) transient
hyperthyroidism due to Graves’ disease following hypothyroidism (Cases 1-5); (2)
persistent hyperthyroidism due to Graves’ disease following hypothyroidism (Cases 6 and
7); and (3) persistent hypothyroidism with positive TSAb (Case 8). The changes in thyroid
function and clinical course may be decided by three factors; (1) TSAb and (2) TSBAb
activities in the blood and (3) the responsiveness of the thyroid gland to TSAb. Cases 1-7
had hyperthyroidism, when they had positive TSAb. Case 5 had TSBAb during the
hypothyroid state and TSAb during the hyperthyroid state; thus the alterations in the
thyroid state related to the balance between the activities ofTSAb and TSBAb. Case 8 had
been hypothyroid despite the presence of TSAb. H e continued to be hypothyroid. His
thyroid gland was not palpable and could not respond to TSAb.
The clinical findings and laboratory data in Cases 1-7 confirmed the diagnosis of
Hashimoto’s disease with hypothyroidism preceding Graves’ disease with hyperthyr-
oidism. The history exclude the possibility of subacute o r silent thyroiditis and drug or
iodine-induced hyper or hypo-thyroidism. In Cases 1-7, the hyperthyroidism was found
to be due to Graves’ disease, being clearly differentiated from destructive thyroiditis,
because of positive TSAb and high I3’Iuptake. The sequential changes in TSAb activities
were studied during the whole observation periods of both hypothyroid and hyperthyroid
phases. The changes in thyroid function were associated with those in TSAb activities,
indicating that Graves’ disease with hyperthyroidism is due to TSAb (Adams & Purves,
1956). The hyperthyroidism following hypothyroidism in Cases 1-7 is attributed to the
changes in TSAb activity; in Cases 1-5, their episodes of hyperthyroidism were transient
 Graves ’ disease .following hypothyroidism 697
and were associated with the transient appearance ofTSAb in the blood; in Cases 6 and 7,
TSAb activities continued to be high over 1 year after occurrence of Graves’ disease and
they have been taking MMI. It should be noted that Case 5 had TSBAb during the
hypothyroid state and TSAb during the hyperthyroid state; thus the alterations in the
thyroid state related to the balance between the activities of TSAb and TSBAb, as
reported by others (Takeda et al., 1988; Cho et al., 1989).
It is interesting to note that Case 8 continued to be hypothyroid despite the presence of
potent TSAb. The TSAb activities changed from extremely high to low but he continued
to be hypothyroid. His thyroid gland had not been palpable during the whole course. It is
speculated that the thyroid gland was atrophic and unable t o respond to TSAb. Cases 1-7
had goitre, when they had hyperthyroidism.
The results indicated that the changes in thyroid function and clinical course might be
decided by three factors; (1) TSAb and ( 2 ) TSBAb activities in the blood and (3) the
responsiveness of the thyroid gland to TSAb. During the hyperthyroid state, Cases 1-7
had TSAb, which stimulated the thyroid gland; thus they had hyperthyroidism. In the
patients of group 1, transient hyperthyroidism due to Graves’ disease, TSAb appeared
transiently in the blood and the thyroid gland responded to this TSAb; thus they had
transient hyperthyroidism. In the patients of group 2, persistent hyperthyroidism due to
Graves’ disease, TSAb continued to be present in the blood as observed in most patients
with Graves’ disease and their thyroid glands responded to TSAb; thus they had
persistent hyperthyroidism. Case 8, the patient of group 3, with persistent hypothyroid-
ism with positive TSAb, continued to be hypothyroid. We presume that his thyroid gland
was atrophic and unable to respond to TSAb.
Case 3 developed hyperthyroidism after delivery. In this case, the hyperthyroidism was
due to Graves’ disease. This case also showed postpartum recurrence of Graves’
hyperthyroidism, which was reported by Amino (1983). Kasagi et a/. (1986) reported a
similar case with Hashimoto’s disease, who developed hyperthyroidism due to Graves’
disease after delivery.
It should be also noted that Cases 3, 6, and 7 developed hypothyroidism soon after
starting MMI, indicating that these patients were very sensitive to MMI and easily
developed hypothyroidism.
Hashimoto’s and Graves’ diseases are the main two types of autoimmune thyroid
diseases. They have much in common. Evidence for common features includes the
observation that both conditions may aggregate in the same families (Doniach, 1975) or
may even coexist within the same thyroid gland (Doniach, 1975; Fatourechi et al., 1971).
In some cases, Graves’ disease may spontaneously culminate in hypothyroidism due to
Hashimoto’s disease (Wood & Ingbar, 1979). Conversely, Hashimoto’s disease with
hypothyroidism may change into Graves’ disease with hyperthyroidism (Bell et al., 1985;
Kasagi et a/., 1986; Takeda et al., 1988; Cho et a/., 1989). The latter cases are not so often
seen. This is the first report to describe the follow-up studies of these cases. Some patients
hypothyroid due to Hashimoto’s disease may spontaneously develop hyper or eu-
thyroidism. These data may provide further insight into the pathogenesis and natural
course of some cases of Graves’ and Hashimoto’s diseases.

REFERENCES
ADAMS,D.D. & PURVES. H.D. (1956) Abnormal responses in the assay of thyrotropin. Proceerlirigs qfL’nirersitv
of Olago Medical School. 34, 1 I - I 2
698 N . Takasu et al.
AMINO,N. (1983) Postpartum autoimmune endocrine syndrome. In Autoimmune Endocrine Disease (eds T.F.
Davies). pp. 242-247, John Wiley & Sons, New York.
BELL,P.M., SINNAMON, D.G., SMYTH,P.P.A., DREXHAGE, H.A., HAIRE,M., BOTTAZZO, G.F. & ATKINSON, A.B.
(1 985) Hyperthyroidism following primary hypothyroidism in association with polyendocrine autoimmu-
nity. Acra Endocrinologica, 108, 491-497.
CHO,B.Y., SHONG,Y .K., LEE,H.K., KOH,C.S. & MIN,H.K. (1989) Graves’ hyperthyroidism following primary
hypothyroidism: sequential changes in various activities of thyrotropin receptor antibodies. Aria
Endocrinologica, 120, 447450.
DONIACH,D. (1975) Humoral and genetic aspects of thyroid autoimmunity. Clinical Endocrinology and
Metabolism, 4, 267-285.
FATOURECHI, V., MCCONAHEY, W.M. & WOOLNER,L.B. (1971) Hyperthyroidism associated with histological
Hashimoto’s thyroiditis. Mayo Clinic Proceedings, 46, 682-686.
KASAGI, K., KONISHI,J., IIDA,Y., IKEKUBO, K., MORI,T., KUMA,K. & TORIZUKA, K. (1982) A new in-vitro assay
for human thyroid stimulator using cultured thyroid cells: effects of sodium chloride on adenosine 3’5‘-
monophosphate increase. Journal of Clinical Endocrinology and metabolism, 54, 108-1 14.
KASAGI, K., KONISHI,J., IIDA, Y., MORI,T. & TORIZUKA, K. (1986) Changes in thyroid stimulating and TSH-
binding inhibitory activities in a patient who developed hyperthyroidism due to Graves’ disease following
primary hypothyroidism. Clinical Endocrinology, 25, 5 19-525.
OCHI, Y., YOSHIMURA, M., HACHIYA,T. & MIYAZAKI,T. (1976) Immunological studies on LATS-
immunoglobulin by the reaction with staphylococcal protein A. Endocrinologia Japonica, 23, 183-186.
SMITH,B.R. & HALL,R. (1981) Measurement of thyrotropin receptor antibodies. Methods in Enzymology, 74,
405-420.
TAKASU, N., CHARRIER, B., MAUCHAMP, J. & LISSITZKY,S. (1978) Modulation of adenylate cyclase/cyclic AMP
response by thyrotropin and prostaglandin Ez in cultured thyroid cells. European Journal of Biochemistry,
90, 131-146.
TAKASU,N., HANDA,Y., SHIMIZU,Y. & YAMADA, T. (1984) Electrophysiological and morphological cell
polarity and iodine metabolism in cultured porcine and human (normal and Graves’) thyroid cells. Journal
of Endocrinology, 101, 189-196.
TAKASU, N., YAMADA, T., KATAKURA, M., YAMAUCHI, K., SHIMIZU, Y. & ISHIZUKI,Y. (1987) Evidence for
thyrotropin (TSH)-blocking activity in goitrous Hashimoto’s thyroiditis with assays measuring inhibition
of TSH receptor binding and TSH-stimulated thyroid adenosine 3’,5‘-monophosphate responses/cell
growth by immunoglobulins. Journal of Clinical Endocrinology and Metabolism, 65,239-245.
TAKEDA, K., TAKAMATSU, J., KASAGI,K., SAKANE, S., IKEGAMI, Y . , ISOTANI,H., MAJIMA,T., MAJIMA,M.,
KITAOKA, H., IIDA,Y., IKEKUBO,K., KONISHI,J. & MOZAI,T. (1988) Development of hyperthyroidism
following primary hypothyroidism: a case report with changes in thyroid-related antibodies. Clinical
Endocrinology, 28, 34 1-344.
WOOD, L.C. & INGBAR,S.H. (1979) Hypothyroidism as a late sequela in patients with Graves’ treated with
antithyroid agents. Journal of Clinical Investigarion, 64,1429- 1432.