Yonago Acta medica 1996;39:177–182

A Patient with Graves’ Hyperthyroidism Associated with Non-Insulin
Dependent Diabetes Mellitus Who Showed T4-Toxicosis
Sachiko Teshima, Koushi Narasaki, Yasushi Tanaka, Akio Yoshida and Chiaki
Shigemasa
First Department of Internal Medicine, Faculty of Medicine, Tottori University, Yonago 683,
Japan
A 41-year-old man was admitted to Tottori University Hospital because of a very poor
control state of diabetes mellitus (DM). At admission, he showed T4-toxicosis [T4 13.4
µg/dL, free T4 (FT4) 3.0 ng/dL, T3 105 ng/dL, and free T3 (FT3) 2.7 pg/mL] with ahigh reverse T3 (rT3; 189 ng/dL) and a high thyroid 99mTcO4¯-uptake (8.0%), and did
not show apparent physical findings suggestive of hyperthyroidism except for a diffusegoiter. After the initiation of diet and insulin therapy for DM, his serum FT3 level was
gradually increased despite a slight decrease in his serum FT4 level, and reached asupra-normal level (5.4 pg/mL) on the 35th day after admission. In this interval, hebecame to show apparent physical findings suggestive of hyperthyroidism, such as
tachycardia, moist skin, finger tremor and a decrease in diastolic blood pressure. Bothserum FT4 and FT3 levels were in normal ranges 3 weeks after the initiation of methimazole therapy. Thus, the patient with Graves’ hyperthyroidism associated with avery poor control state of DM may show T4-toxicosis, which is induced by the inhibitionof extrathyroidal conversion of T4 to T3. Such a patient may not show apparent physicalfindings suggestive of hyperthyroidism owing to normal FT3 level and probably owing
to the diminished T3-binding to the T3 receptor and/or post-T3 receptor responses.
Key words: diabetes mellitus; Graves’ hyperthyroidism; T4-toxicosis

well understood. It has been reported that rat
hepatic (Surcs et al., 1978) and pituitary (St.
Germain and Galton, 1985) nuclear T3-receptor
numbers are reduced by NTI and starving.
Furthermore, a divergence in post-receptor T3
responses occur in fasted rats (Oppenheimer
and Schwartz, 1980), and T3 administration
does not appear to alter the rate of weight loss inrats (Schwartz et al., 1980).
We reported herein a patient with Graves’
hyperthyroidism associated with NIDDM whodeveloped T4-toxicosis and did not show apparent physical findings suggestive of hyperthyroidism except for a diffuse goiter.

Some hyperthyroid patients associated withsevere non-thyroidal illness (NTI) may show
T4-toxicosis (Joasso, 1975; Engler et al., 1978;
Caplan et al., 1980; Shigemasa et al., 1982) because the illness inhibits extrathyroidal conversion of T4 to T3. In diabetic patients, who are
not in diabetic coma, inhibition of extrathyroidal T4 to T3 conversion has also been reported(Pittman et al., 1979; Kabadi, 1984). To ourknowledge, however, there have been no reportsof hyperthyroid patients associated with noninsulin dependent diabetes mellitus (NIDDM)
who showed T4-toxicosis. On the other hand,
the metabolic impact and adaptive significanceof the low T3 state in patients with NTI is lessAbbreviations: DM, diabetes mellitus; FBS, fast blood sugar; FT3, free T3; FT4, free FT4; MMI, methimazole; NIDDM, non-insulin dependent diabetes mellitus; NTI, non-thyroidal illness; rT3, reverse T3; TBG,
T4-binding globulin; TSH, thyroid-stimulating hormone

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S. Teshima et al.

Patient report
A 41-year-old man was admitted to Tottori
University Hospital because of general fatigue,thirst, and polydipsia for one month. He hadlost progressively 13 kg over the previous one
and a half months. He had noted already theexcretion of urine sugar 4 years before. Thereafter, however, he did not visit any physician.
He also had not ingested an excessive amountof seaweed and had not received treatment withiodide.
At admission, he was emaciated weighing
42.4 kg (at 170 cm). His blood pressure was
108/74 mmHg, pulse rate 66 beats/min andbody temperature 36.2˚C. Moist skin andfinger tremors were not found. The thyroid was
diffusely enlarged (transverse width, 4.3 cm)
with a smooth surface and soft consistency.
Results of chest and abdomen examinations
were unremarkable. Abnormal neurologicalfindings, such as hyperactive deep tendon reflexes with a brisk relaxation phase and sensory
disturbance, and abnormal findings of ocularfundi were not noted.
Laboratory values were as follows: fastingblood sugar, (FBS) 445 mg/dL; HbA1c, 12.5%;
serum sodium, 136 mEq/L; potassium, 4.9
mEq/L; chloride, 95 mEq/L; blood urea nitrogen, 20 mg/dL; and creatinine, 0.6 mg/dL; total

serum calcium, 9.6 mg/dL with albumin, 4.3 g/dL; alkaline phosphatase, 253 IU/L (normal,
111–295); total bilirubin, 0.5 mg/dL; glutamic
oxaloacetic transaminase, 27 IU/L (normal, < 40);
glutamic pyrubic transaminase, 27 IU/L (normal, < 47); lactic dehydrogenase, 159 IU/L (normal, 100–225) and total cholesterol, 186 mg/
dL; hematocrit, 44.3% and Hb, 14.8 g/dL; Creactive protein, < 0.06 mg/dL; arterial bloodbicarbonate, 24 mmol/L (normal, 21–26); urine
sugar, > 1.0 g/dL; ketonuria, (+); albuminuria,(–); and a daily excretion of urine sugar, 126.9
g; finally, urinary excretion of C-peptide was at
14.6 µg/day (normal, 43–146).

Methods
Serum T4, T3, rT3 and TBG concentrations
were measured by RIA kits (Amerlex M-T4;
Amersham International Ltd., Amersham,United Kingdom, T3-RIA·Beads and rT3 kit;
Dainapot Radioisotope Laboratories, Tokyo,
Japan, and Riagnost TBG; Hoechst Japan,
Tokyo, respectively). The T3-uptake value wasdetermined using macroaggregated albumin as
inert binding material (Amersham International). The serum thyroid-stimulating hormone(TSH) level was measured using immunoradiometric assay (Riagnost hTSH, Hoechst Japan).
Serum free T4 (FT4) and free T3 (FT3) concentrations were measured using Amerlex MAB

Table 1. Results of thyroid function tests at admission
Parameter(unit)

Datum

Normal range

T4(µg/dL)
13.4
4.5 – 12.0
T3
(ng/dL)105
80 – 190
rT3(ng/dL)189
19.0 – 37.5
T3-uptake(%)
43.3
24 – 35FT4(ng/dL)
3.0
0.95 – 1.84
FT3
(pg/mL)
2.7
2.2 – 4.6
TBG(µg/mL)
17.6
12 – 30
TSH(mU/L)< 0.03
0.1 – 3.0
Anti-thyroglobulin antibody< 80 ×< 80 ×Anti-microsomal antibody
8100 ×< 100 ×
TSH-binding inhibitory immunoglobulin(%)
14.6< 14.8Thyroid-stimulating antibody*
(%)
113
< 145
99m
Tc4 –-uptake(%)
8.0
0.7 – 3.0
FT3, free T3; FT4, free T4; rT3, reverse T3; TBG, TS-binding globulin; TSH, thyroid-stimulating hormone.
*Measured using cultured porcine thyroid cells.

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Grave’s hyperthyroidism and NIDDM

Insulin

unit
20
10
0
mg

MMI

40
20
0

HbA1c
8.8%

mg/dL HbA1c
500

12.5%
C

C

FBS

FBS

400
300
200

C

CC

C

100

C

C

0

pg/dL

ng/dL

5

E
E
J

J
J

4

J

E
J

3

E
2

J

E

3

E

1

2

G
B

kg
48

G
G
B
G G
B G
B B
G B

BW

47
46
45
44
43
42

FT4

FT3

6

4

FT3
FT4

E
J

G
B
0

BW
PR

beats/min
100

G
B

G G

80

B

B

B
10

20

30

90

G

G
B
40

50

Fig. 1. The sequencial changes inclinical findings after the initiationof therapy for diabetes mellitus.
BW, body weight; FBS, fastingblood sugar; FT3, free triiodothyronine; FT4, free thyroxine;
MMI, methimazole; PR, pulse rate.

PR

7

70

60

Admission day

kits (Amersham International). Urinary excretion of C-peptide was measured by a RIA kit(C-Peptide Kit “Daiichi” III, Daiichi Radioisotope Laboratories, Ltd., Japan). Serum insulin concentration was measured by a RIA kit(Ab bead insulin “Eiken”, Tokyo). HbA1c wasmeasured by HPLC (Hi-AUTO A1c HA-8131,
Kyoto-Daiichi Kagaku, Kyoto, Japan).

Serum T4-binding globulin (TBG) concentration was normal (17.6 µg/mL).

Clinical course

Thyroid function at admission

We evaluated the sequential changes in clinicalfindings including serum FT4 and FT3 concentrations after the initiation of therapy for diabetes mellitus (DM). The sequential changes inserum FT4 and FT3 concentrations were evaluated in the same assay series.
Immediately after admission, diet (1920–
2080 kcal/day) and insulin (Humalin N-40; 14–
10 U/day) therapies were initiated. As shown in
Fig. 1, according to the improvement of thecontrol state of BS and the increase of bodyweight, the serum FT3 concentration gradually

Results for the thyroid function tests at the initial examination were shown in Table 1. T4toxicosis (T4 13.4 µg/dL, T3 105 ng/dL, T3uptake 43.3%, FT4 3.0 ng/dL FT3 2.7 pg/mL)with high reverse T3 (rT3; 189 ng/dL) and highthyroid 99m TcO4¯-uptake (8.0%) was observed.
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S. Teshima et al.

increased in spite of a slight decrease in serum
FT4 which reached a supra-normal level (5.4
pg/mL) on the 35th day after admission. At thattime, serum T3, rT3, T4 and FT4 concentrations
and the T3-uptake value were 198 ng/dL, 52 ng/
dL, 12.8 µg/dL, 2.51 ng/dL and 39.1%, respectively. In this interval, the pulse rate at rest
gradually increased and reached 90 beats/min
on the 35th day after admission. Physical examination revealed finger tremor, moist skin, adecrease in diastolic blood pressure (bloodpressure, 120–46 mmHg) and hyperactive deep
tendon reflexes with a brisk relaxation phase.
Therefore, methimazole (MMI: a 30 mg dailydose) therapy was initiated on the 35th day after
admission. Thereafter, body weight that was
gained decreased again. Thereafter, the pulse
rate at rest gradually decreased and body weightgradually increased with the normalization ofserum FT4 and FT3. The HbA1c level was 8.8%
44 days after admission.

Discussion
It has been generally known that the NTIs thatvary widely from trauma, sepsis, malignancy,and metabolic disorders to febrile illness andundernutrition may show a low T3 state because the illness inhibits extrathyroidal tissue
conversion of T4 to T3 (Nikoloff and LoPresti,
1991). Therefore, some hyperthyroid patients
who are admitted due to Graves’ disease or a
toxic nodule and who concomitantly havesevere NTIs may show T4-toxicosis (Joasso,
1975; Engler et al., 1978; Caplan et al., 1980;
Shigemasa et al., 1982). The present case also
shows T4-toxicosis before treatment for DM. It
has been reported that T4-toxicosis may befound in patients with iodide induced thyrotoxicosis (Sobliho et al., 1977) and in elderly
hyperthyroid patients (Caplan et al., 1978).
Furthermore, the pattern of T4-toxicosis as anormal biochemical finding has been observedin elderly women (Britton et al., 1975) or inpatients with acute or chronic NTIs (Braverman
and Veganakis, 1979; Gavin et al., 1979). Ourpatient, however, had not ingested an excessive
amount of seaweed nor received any treatment

with iodide, and showed a high 99mTcO4¯-uptake
with very low serum TSH level. Furthermore, thepatient showed a marked elevation of serumrT3 level despite a normal serum T3 level at theinitial examination. Usually in patients with
NTI, serum rT3 levels have been generally
known to increase reciprocally as serum T3
falls, because impaired rT3 clearance is ascribed secondary to a decrease in 5'-deiodinationand not because of an increase in rT3 production (Fabel et al., 1981; LoPresti et al., 1991).
Accordingly, T4-toxicosis in our case is strongly suggested to be induced by the increased
inhibition of peripheral tissue 5'-deiodination
owing to the association of a very poor control
state of DM with Graves’ hyperthyroidism. Indeed, the patient showed the common pattern ofthe elevations of both T4 and T3 with a reduction of rT3 after the initiation of diet and insulin
therapy.
The changes in serum FT3 concentration inpatients with T4-toxicosis due to hyperthyroidism associated with severe NTI have been lesswell understood. It has been reported that freeT3 concentration is predicted to vary from anormal to supra-normal level. Indeed, serum
FT3 in our case showed a normal value.
It has been suggested that inhibitors of thyroid hormone binding to T4-binding protein
exist in the serum of patients with NTI (Chopra
et al., 1979; Woeber and Maddux, 1981). A T4binding inhibitor in the serum of NTI patientshas been suspected to be a free fatty acid
(Chopra et al., 1986; Haynes et al., 1989). It has
been generally known that free fatty acids increase in the serum of DM patients with a very
poor control state. Therefore, the serum FT4level slightly decreased after the initiation of
DM therapy. Nevertheless, the serum FT3 level
was elevated gradually after the initiation of
DM therapy. This might be due to recovery
from the inhibition of T4 to T3 conversion in
the extra-thyroidal tissues.
The metabolic impact and adaptive significance of the low T3 state associated with NTI is
less well understood. In the present case, any
apparent physical findings suggestive of hyperthyroidism were not observed at admission.
This might be due to the normal FT3 level.

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Grave’s hyperthyroidism and NIDDM

However, if the patient was not associated withhyperthyroidism, serum T3 and FT3 levels
should be further decreased. It has been reported that the rat hepatic nuclear T3 receptor
number is reduced by NTI and fasting (Surcs etal., 1978). Furthermore, there is evidence thatT3 receptor capacity is decreased in DM (Dasand Ganguly, 1981; Wartofsky et al., 1981). On
the other hand, a divergence in post T3 receptor
responses occur in fasted rats (Oppenheimer
and Schwartz, 1980), and T3 administration
does not appear to alter the rate of weight loss inrats (Schwartz et al., 1980). In the present case,the pulse rate at rest abruptly increased despite
little increase in the serum FT3 level at 2 weeks
after the initiation of DM therapy. This might
be reflected in the diminished T3-binding to theT3 receptor or the post receptor response
probably due to intra-cellular glucose deficiency.
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(Received August 22, Accepted October 1, 1996)

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