J Endocrinol Metab

Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access

Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc

Journal website http://www.jofem.org

Original Article

Volume 6, Number 2, April 2016, pages 46-51

Clinical, Endocrinological and Immunological Characteristics of Japanese Patients With Autoimmune Polyglandular Syndrome Type 3a

**Table 1.** Clinical, Endocrinological and Immunological Characteristics of Our Previously Reported Japanese Patients With Autoimmune Polyglandular Type 3a
Cases [Reference]	Age (years)/sex	Type of diabetes	Anti-GAD antibody	Urinary C-peptide (μg/day)	Positivity for anti-TPO or anti-TG antibody	Thyroid function	Other complication
F: female; GAD: glutamic acid decarboxylase; MRHE: mineralocorticoid-responsive hyponatremia with the elderly; RA: rheumatoid arthritis; ref: reference; RF: rheumatoid factor; SPIDDM: slowly progressive insulin-dependent diabetes mellitus; TG: thyroglobulin; TPO: thyroid peroxidase. Normal ranges of anti-GAD antibody and urinary C-peptide are < 1.5 U/mL and 29.2 - 167.0 μg/day, respectively.
Case 1 [4]	53/F	SPIDDM	10,000	70	(+)	Euthyroid	Symptomatic Sjogren’s syndrome with anti-SSA/Ro ab (+) and anti-SSB/La ab (+); asymptomatic RA with RF (+)
Case 2 [7]	83/F	SPIDDM	3.2	9.1	(+)	Treated by levothyroxine (25 μg/day)	MRHE
Case 3 [8]	68/F	SPIDDM	34	52.9	(+)	Euthyroid	None
Case 4 [9]	84/F	SPIDDM	65.2	< 0.3	(-)	Treated by levothyroxine (50 μg/day)	Sarcoidosis, candidiasis, and liver cirrhosis due to autoimmune hepatitis

Table 1. Clinical, Endocrinological and Immunological Characteristics of Our Previously Reported Japanese Patients With Autoimmune Polyglandular Type 3a

Cases [Reference]

Age (years)/sex

Type of diabetes

Anti-GAD antibody

Urinary C-peptide (μg/day)

Positivity for anti-TPO or anti-TG antibody

Thyroid function

Other complication

F: female; GAD: glutamic acid decarboxylase; MRHE: mineralocorticoid-responsive hyponatremia with the elderly; RA: rheumatoid arthritis; ref: reference; RF: rheumatoid factor; SPIDDM: slowly progressive insulin-dependent diabetes mellitus; TG: thyroglobulin; TPO: thyroid peroxidase. Normal ranges of anti-GAD antibody and urinary C-peptide are < 1.5 U/mL and 29.2 - 167.0 μg/day, respectively.

Case 1 [4]

53/F

SPIDDM

10,000

(+)

Euthyroid

Symptomatic Sjogren’s syndrome with anti-SSA/Ro ab (+) and anti-SSB/La ab (+); asymptomatic RA with RF (+)

Case 2 [7]

83/F

SPIDDM

3.2

9.1

(+)

Treated by levothyroxine (25 μg/day)

MRHE

Case 3 [8]

68/F

SPIDDM

52.9

(+)

Euthyroid

None

Case 4 [9]

84/F

SPIDDM

65.2

< 0.3

(-)

Treated by levothyroxine (50 μg/day)

Sarcoidosis, candidiasis, and liver cirrhosis due to autoimmune hepatitis

**Table 2.** Clinical, Endocrinological and Immunological Data of Our 26 Patients With Autoimmune Polyglandular Type 3a
Cases	Age (years)/sex	Type of diabetes	Anti-GAD antibody (U/mL)	Anti-IA2 antibody (U/mL)	HbA1c (%)	Serum CPR (ng/mL)	Urinary CPR (μg/day)	Treatment for diabetes	Anti-TPO antibody (IU/mL)	Anti-TG antibody (IU/mL)	Anti-TR antibody (IU/L)	Thyroid function, findings of thyroid ultrasonography and treatment
No swelling indicates the absence of thyroid swelling determined by thyroid ultrasonography. AOT1D: acute onset type 1 diabetes; CPR: C-peptide immunoreactivity; F: female; GAD: glutamic acid decarboxylase; GLP-1: glucagon-like peptide-1; IA2: islet antigen 2; M: male; MMI: methylmercapto-imidazole; NGT: normal glucose tolerance; OAD: oral anti-diabetic drug; SPIDDM: slowly progressive insulin-dependent diabetes mellitus; TG: thyroglobulin; TPO: thyroid peroxidase; TR: thyroid stimulating hormone receptor; UD: undetermined. Normal ranges of anti-GAD antibody, anti-IA2 antibody, serum CPR, urinary CPR, anti-TPO antibody, anti-TG antibody and anti-TR antibody are < 1.5 U/mL, < 0.4 U/mL, 0.61 - 2.09 ng/mL, 29.2 - 167.0 μg/day, < 16 IU/mL, < 28 IU/mL and < 2.0 IU/L, respectively.
1	80/F	UD	13	0.9	12.1	< 0.03	< 0.5	Insulin	11	207	0.4	Euthyroidism, no treatment
2 [4]	53/F	SPIDDM	10,000	11	10.2	0.26	70	Insulin	> 600	298	0.7	Euthyroidism, no treatment
3	49/M	SPIDDM	4,140	11	5.8	1.86	UD	Insulin + OAD	454	546	11.3	Euthyroidism, no treatment
4	81/F	UD	49,000	2.9	9.8	< 0.03	1.2	Insulin	< 5	82	0.4	Euthyroidism, no swelling, and no treatment
5	72/F	AOT1D	970	8.4	10	< 0.03	1.7	Insulin	109	21	25.2	Hyperthyroidism, treated by MMI
6 [8]	68/F	SPIDDM	34	< 0.4	8.3	4.77	52.9	Insulin + OAD + GLP-1 analog	71	497	0.5	Euthyroidism, no swelling, and no treatment
7	62/F	SPIDDM	1,300	< 0.4	8.7	< 0.03	UD	Insulin	195	23	0.4	Euthyroidism, no treatment
8	71/F	SPIDDM	6.3	< 0.4	11.9	6.04	36.4	Insulin	26	17	< 1	Euthyroidism, no swelling, and no treatment
9	50/M	SPIDDM	2.4	> 0.4	8.5	4.75	UD	OAD	> 600	411	0.4	Euthyroidism, no treatment
10	80/F	SPIDDM	53	< 0.4	6.8	2.64	UD	OAD	62	11	0.6	Euthyroidism, no treatment
11	69/M	SPIDDM	36	< 0.4	6.5	3.84	UD	OAD	502	480	0.7	Euthyroidism, no treatment
12 [9]	84/F	SPIDDM	65.2	UD	5.9	< 0.03	< 0.3	Insulin	< 5	< 10	UD	Hypothyroidism, treated by levothyloxine
13 [7]	83/F	SPIDDM	3.2	< 0.4	6.3	0.84	9.1	Diet + exercise	8	< 10	UD	Hypothyroidism, treated by levothyloxine
14	47/M	NGT	2.9	< 0.4	5.6	3.0	UD	No treatment	73	488	0.4	Hypothyroidism, treated by levothyloxine
15	42/M	AOT1D	39	< 0.4	10.5	0.05	4.9	Insulin	163	23	10.2	Hyperthyroidism, treated by MMI
16	43/M	AOT1D	155	< 0.4	8.6	0.18	UD	Insulin	251	946	1	Hypothyroidism, treated by levothyloxine
17	76/F	SPIDDM	57	< 0.4	7.2	1.87	UD	OAD	> 600	12	0.4	Subclinical hypothyroidism, no treatment
18	67/M	SPIDDM	2.2	< 0.4	6.9	1.65	UD	OAD	9	182	0.4	Euthyroidism, no swelling, and no treatment
19	60/F	SPIDDM	550	< 0.4	6.6	3.41	30.9	OAD	16	76	2.6	Hyperthyroidism, treated by iodine isotope treatment
20	83/F	SPIDDM	> 2,000	< 0.4	9.6	< 0.03	< 0.9	Insulin + OAD	417	121	< 0.3	Euthyroidism, no swelling, and no treatment
21	67/F	UD	< 0.3	1	7.5	< 0.03	9.8	Insulin	20	818	< 0.3	Euthyroidism, no treatment
22	42/F	AOT1D	0.7	3.9	8.7	< 0.03	UD	Insulin	8	12	164	Hyperthyroidism, treated by MMI
23	53/F	SPIDDM	< 0.3	0.5	6.6	2.64	153	Diet + exercise	8	14	4.5	Hyperthyroidism, treated by MMI
24	53/F	UD	1.1	< 0.4	9.7	0.08	UD	Insulin	392	151	0.5	Subclinical hypothyroidism, no treatment
25	52/F	AOT1D	< 0.3	< 0.4	8.0	< 0.03	< 0.9	Insulin	188	577	0.7	Euthyroidism, no treatment
26	51/M	AOT1D	< 0.3	< 0.4	12.7	0.43	UD	Insulin	27	12	< 0.3	Euthyroidism, no treatment

Table 2. Clinical, Endocrinological and Immunological Data of Our 26 Patients With Autoimmune Polyglandular Type 3a

Cases

Age (years)/sex

Type of diabetes

Anti-GAD antibody (U/mL)

Anti-IA2 antibody (U/mL)

HbA1c (%)

Serum CPR (ng/mL)

Urinary CPR (μg/day)

Treatment for diabetes

Anti-TPO antibody (IU/mL)

Anti-TG antibody (IU/mL)

Anti-TR antibody (IU/L)

Thyroid function, findings of thyroid ultrasonography and treatment

No swelling indicates the absence of thyroid swelling determined by thyroid ultrasonography. AOT1D: acute onset type 1 diabetes; CPR: C-peptide immunoreactivity; F: female; GAD: glutamic acid decarboxylase; GLP-1: glucagon-like peptide-1; IA2: islet antigen 2; M: male; MMI: methylmercapto-imidazole; NGT: normal glucose tolerance; OAD: oral anti-diabetic drug; SPIDDM: slowly progressive insulin-dependent diabetes mellitus; TG: thyroglobulin; TPO: thyroid peroxidase; TR: thyroid stimulating hormone receptor; UD: undetermined. Normal ranges of anti-GAD antibody, anti-IA2 antibody, serum CPR, urinary CPR, anti-TPO antibody, anti-TG antibody and anti-TR antibody are < 1.5 U/mL, < 0.4 U/mL, 0.61 - 2.09 ng/mL, 29.2 - 167.0 μg/day, < 16 IU/mL, < 28 IU/mL and < 2.0 IU/L, respectively.

80/F

0.9

12.1

< 0.03

< 0.5

Insulin

207

0.4

Euthyroidism, no treatment

2 [4]

53/F

SPIDDM

10,000

10.2

0.26

Insulin

> 600

298

0.7

Euthyroidism, no treatment

49/M

SPIDDM

4,140

5.8

1.86

Insulin + OAD

454

546

11.3

Euthyroidism, no treatment

81/F

49,000

2.9

9.8

< 0.03

1.2

Insulin

< 5

0.4

Euthyroidism, no swelling, and no treatment

72/F

AOT1D

970

8.4

< 0.03

1.7

Insulin

109

25.2

Hyperthyroidism, treated by MMI

6 [8]

68/F

SPIDDM

< 0.4

8.3

4.77

52.9

Insulin + OAD + GLP-1 analog

497

0.5

Euthyroidism, no swelling, and no treatment

62/F

SPIDDM

1,300

< 0.4

8.7

< 0.03

Insulin

195

0.4

Euthyroidism, no treatment

71/F

SPIDDM

6.3

< 0.4

11.9

6.04

36.4

Insulin

< 1

Euthyroidism, no swelling, and no treatment

50/M

SPIDDM

2.4

> 0.4

8.5

4.75

OAD

> 600

411

0.4

Euthyroidism, no treatment

80/F

SPIDDM

< 0.4

6.8

2.64

OAD

0.6

Euthyroidism, no treatment

69/M

SPIDDM

< 0.4

6.5

3.84

OAD

502

480

0.7

Euthyroidism, no treatment

12 [9]

84/F

SPIDDM

65.2

5.9

< 0.03

< 0.3

Insulin

< 5

< 10

Hypothyroidism, treated by levothyloxine

13 [7]

83/F

SPIDDM

3.2

< 0.4

6.3

0.84

9.1

Diet + exercise

< 10

Hypothyroidism, treated by levothyloxine

47/M

NGT

2.9

< 0.4

5.6

3.0

No treatment

488

0.4

Hypothyroidism, treated by levothyloxine

42/M

AOT1D

< 0.4

10.5

0.05

4.9

Insulin

163

10.2

Hyperthyroidism, treated by MMI

43/M

AOT1D

155

< 0.4

8.6

0.18

Insulin

251

946

Hypothyroidism, treated by levothyloxine

76/F

SPIDDM

< 0.4

7.2

1.87

OAD

> 600

0.4

Subclinical hypothyroidism, no treatment

67/M

SPIDDM

2.2

< 0.4

6.9

1.65

OAD

182

0.4

Euthyroidism, no swelling, and no treatment

60/F

SPIDDM

550

< 0.4

6.6

3.41

30.9

OAD

2.6

Hyperthyroidism, treated by iodine isotope treatment

83/F

SPIDDM

> 2,000

< 0.4

9.6

< 0.03

< 0.9

Insulin + OAD

417

121

< 0.3

Euthyroidism, no swelling, and no treatment

67/F

< 0.3

7.5

< 0.03

9.8

Insulin

818

< 0.3

Euthyroidism, no treatment

42/F

AOT1D

0.7

3.9

8.7

< 0.03

Insulin

164

Hyperthyroidism, treated by MMI

53/F

SPIDDM

< 0.3

0.5

6.6

2.64

153

Diet + exercise

4.5

Hyperthyroidism, treated by MMI

53/F

1.1

< 0.4

9.7

0.08

Insulin

392

151

0.5

Subclinical hypothyroidism, no treatment

52/F

AOT1D

< 0.3

< 0.4

8.0

< 0.03

< 0.9

Insulin

188

577

0.7

Euthyroidism, no treatment

51/M

AOT1D

< 0.3

< 0.4

12.7

0.43

Insulin

< 0.3

Euthyroidism, no treatment

**Table 3.** Sex, Type of Diabetes or Glucose Intolerance, the Positivity for Diabetes-Associated Autoantibodies, Treatment for Diabetes, Kinds and Thyroid Function of Autoimmune Thyroid Diseases and the Positivity for Thyroid-Associated Autoantibodies in Patients With Autoimmune Polyglandular Type 3a in Japan
GAD: glutamic acid decarboxylase; GLP-1: glucagon-like peptide-1; IA2: islet antigen 2; OAD: oral anti-diabetic drug; SPIDDM: slowly progressive insulin-dependent diabetes mellitus; TG: thyroglobulin; TPO: thyroid peroxidase; TR: thyroid stimulating hormone receptor.
Sex (male/female)	8/18
Autoimmune diabetes
SPIDDM	15/26 (57.7%)
Acute onset type 1 diabetes	6/26 (23.1%)
Normal glucose tolerance	1/26 (3.8%)
Anti-GAD antibody (+)	20/26 (76.9%)
Anti-IA2 antibody (+)	8/26 (30.8%)
Treatment for diabetes
Insulin	14/26 (53.8%)
Insulin + OAD	2/26 (7.7%)
Insulin + OAD + GLP-1 analog	1/26 (3.8%)
OAD	6/26 (23.1%)
Diet + exercise	2/26 (7.7%)
No treatment	1/26 (3.8%)
Autoimmune thyroid diseases
Possible Hashimoto thyroiditis	21/26 (80.8%)
Overt Hashimoto thyroiditis	4/26 (15.4%)
Subclinical hypothyroidism due to Hashimoto thyroiditis	2/26 (7.7%)
Immunological Hashimoto thyroiditis	15/26 (57.7%)
Anti-TPO antibody (+)	19/26 (73.1%)
Anti-TG antibody (+)	15/26 (57.7%)
Possible Graves’s disease	6/26 (23.1%)
Overt Grave’s disease	5/26 (19.2%)
Immunological Grave’s disease	1/26 (3.8%)
Anti-TR antibody (+)	6/26 (23.1%)

Table 3. Sex, Type of Diabetes or Glucose Intolerance, the Positivity for Diabetes-Associated Autoantibodies, Treatment for Diabetes, Kinds and Thyroid Function of Autoimmune Thyroid Diseases and the Positivity for Thyroid-Associated Autoantibodies in Patients With Autoimmune Polyglandular Type 3a in Japan

GAD: glutamic acid decarboxylase; GLP-1: glucagon-like peptide-1; IA2: islet antigen 2; OAD: oral anti-diabetic drug; SPIDDM: slowly progressive insulin-dependent diabetes mellitus; TG: thyroglobulin; TPO: thyroid peroxidase; TR: thyroid stimulating hormone receptor.

Sex (male/female)

8/18

Autoimmune diabetes

SPIDDM

15/26 (57.7%)

Acute onset type 1 diabetes

6/26 (23.1%)

Normal glucose tolerance

1/26 (3.8%)

Anti-GAD antibody (+)

20/26 (76.9%)

Anti-IA2 antibody (+)

8/26 (30.8%)

Treatment for diabetes

Insulin

14/26 (53.8%)

Insulin + OAD

2/26 (7.7%)

Insulin + OAD + GLP-1 analog

1/26 (3.8%)

OAD

6/26 (23.1%)

Diet + exercise

2/26 (7.7%)

No treatment

1/26 (3.8%)

Autoimmune thyroid diseases

Possible Hashimoto thyroiditis

21/26 (80.8%)

Overt Hashimoto thyroiditis

4/26 (15.4%)

Subclinical hypothyroidism due to Hashimoto thyroiditis

2/26 (7.7%)

Immunological Hashimoto thyroiditis

15/26 (57.7%)

Anti-TPO antibody (+)

19/26 (73.1%)

Anti-TG antibody (+)

15/26 (57.7%)

Possible Graves’s disease

6/26 (23.1%)

Overt Grave’s disease

5/26 (19.2%)

Immunological Grave’s disease

1/26 (3.8%)

Anti-TR antibody (+)

6/26 (23.1%)

**Table 4.** Mean ± SD and Range of Age, HbA1c, and Levels of Anti-GAD Antibody, Anti-IA2 Antibody, Serum Fasting CPR, Urinary CPR, Anti-TPO Antibody, Anti-TG Antibody and Anti-TR Antibody in Patients With Autoimmune Polyglandular Type 3a in Japan
	Mean ± SD	Range
When we determined mean ± SD of each variable including variables under the lower limit and above the upper limit, we used variables of upper and lower limit. CPR: C-peptide immunoreactivity; GAD: glutamic acid decarboxylase; fT4: free thyroxine; fT3: free triiodothyronine; IA2: islet antigen 2; TG: thyroglobulin; TPO: thyroid peroxidase; TR: thyroid stimulating hormone receptor; TSH: thyroid stimulating hormone. Normal ranges of anti-GAD antibody, anti-IA2 antibody, serum CPR, urinary CPR, anti-TPO antibody, anti-TG antibody, anti-TR antibody, TSH, fT3 and fT4 are < 1.5 U/mL, < 0.4 U/mL, 0.61 - 2.09 ng/mL, 29.2 - 167.0 μg/day, < 16 IU/mL, < 28 IU/mL, < 2.0 IU/L, 0.54 - 4.26 μIU/mL, 2.39 - 4.06 pg/mL and 0.71 - 1.52 ng/dL, respectively.
Age	63.0 ± 14.2	42 - 86
HbA1c	8.4 ± 2.0	5.6 - 12.7
Anti-GAD antibody (U/mL)	2,632.0 ± 9,685.0	< 0.3 - 49,000
Anti-IA2 antibody (U/mL)	1.86 ± 3.26	< 0.4 - 11.0
Serum CPR (ng/mL)	1.48 ± 1.84	< 0.03 - 3.84
Urinary CPR (μg/day)	29.9 ± 55.2	< 0.5 - 153
Anti-TPO antibody (IU/mL)	185.4 ± 215.7	< 5.0 - > 600
Anti-TG antibody (IU/mL)	232.5 ± 275.1	< 10.0 - 946
Anti-TR antibody (IU/L)	9.47 ± 33.4	< 0.3 - 25.2
TSH	3.54 ± 6.09	< 0.03 - 29.91
fT3	3.65 ± 2.03	2.09 - 5.92
fT4	1.15 ± 0.75	0.67 - 1.74

Table 4. Mean ± SD and Range of Age, HbA1c, and Levels of Anti-GAD Antibody, Anti-IA2 Antibody, Serum Fasting CPR, Urinary CPR, Anti-TPO Antibody, Anti-TG Antibody and Anti-TR Antibody in Patients With Autoimmune Polyglandular Type 3a in Japan

Mean ± SD

Range

When we determined mean ± SD of each variable including variables under the lower limit and above the upper limit, we used variables of upper and lower limit. CPR: C-peptide immunoreactivity; GAD: glutamic acid decarboxylase; fT4: free thyroxine; fT3: free triiodothyronine; IA2: islet antigen 2; TG: thyroglobulin; TPO: thyroid peroxidase; TR: thyroid stimulating hormone receptor; TSH: thyroid stimulating hormone. Normal ranges of anti-GAD antibody, anti-IA2 antibody, serum CPR, urinary CPR, anti-TPO antibody, anti-TG antibody, anti-TR antibody, TSH, fT3 and fT4 are < 1.5 U/mL, < 0.4 U/mL, 0.61 - 2.09 ng/mL, 29.2 - 167.0 μg/day, < 16 IU/mL, < 28 IU/mL, < 2.0 IU/L, 0.54 - 4.26 μIU/mL, 2.39 - 4.06 pg/mL and 0.71 - 1.52 ng/dL, respectively.

Age

63.0 ± 14.2

42 - 86

HbA1c

8.4 ± 2.0

5.6 - 12.7

Anti-GAD antibody (U/mL)

2,632.0 ± 9,685.0

< 0.3 - 49,000

Anti-IA2 antibody (U/mL)

1.86 ± 3.26

< 0.4 - 11.0

Serum CPR (ng/mL)

1.48 ± 1.84

< 0.03 - 3.84

Urinary CPR (μg/day)

29.9 ± 55.2

< 0.5 - 153

Anti-TPO antibody (IU/mL)

185.4 ± 215.7

< 5.0 - > 600

Anti-TG antibody (IU/mL)

232.5 ± 275.1

< 10.0 - 946

Anti-TR antibody (IU/L)

9.47 ± 33.4

< 0.3 - 25.2

TSH

3.54 ± 6.09

< 0.03 - 29.91

fT3

3.65 ± 2.03

2.09 - 5.92

fT4

1.15 ± 0.75

0.67 - 1.74