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Pituitary

DOI 10.1007/s11102-016-0773-7

Critical review of IgG4-related hypophysitis


Junpei Shikuma1 Kenshi Kan1 Rokuro Ito1 Kazuo Hara1 Hiroyuki Sakai1
Takashi Miwa1 Akira Kanazawa1 Masato Odawara1

Springer Science+Business Media New York 2016

Abstract
Purpose IgG4-related hypophysitis is a rare disease, with
only 34 cases published in English (2015). Available short
reviews may not present complete details of IgG4-related
hypophysitis. We aimed to survey case reports of IgG4related hypophysitis, including abstracts of scientific
meetings, in English and Japanese.
Methods We searched for information about IgG4-related
hypophysitis in PubMed and Igakuchuozasshi (Japan
Medical Abstracts Society). Among 104 case reports
found, we reviewed 84 fulfilling Leporatis diagnostic
criteria.
Results The mean SD age of onset was 64.2 13.9,
67.5 9.8, and 56.4 18.6 years for all subjects,
men, and women, respectively. Men:women was 2.4:1. On
magnetic resonance imaging, pituitary, stalk, and pituitarystalk mass were observed at frequencies of 14.3, 21.4, and
64.3%, respectively. Manifestations were anterior hypopituitarism in 26.2% (22 cases), central diabetes insipidus in
17.9% (15 cases), and panhypopituitarism in 52.4% (44
cases). The median level of serum IgG4 was 264.5 mg/dL
for all subjects, 405 mg/dL for men, and 226 mg/dL for
women. The mean number of IgG4-related systemic diseases was 2.7 1.5 in all subjects, 3.0 1.5 in men,
and 1.8 1.1 in women. Among the IgG4-related diseases, retroperitoneal fibrosis was the most frequent
(26.2%), followed by salivary gland diseases (25%). Glucocorticoid therapy was generally effective, except for two

& Masato Odawara


odawara@tokyo-med.ac.jp
1

Department of Diabetology, Metabolism, and Endocrinology,


Tokyo Medical University Hospital, 6-7-1 Nishishinjuku,
Shinjuku-ku, Tokyo 160-0023, Japan

cases that received replacement doses. There were significant differences between sexes in terms of age, serum
IgG4 levels, and number of IgG4-related diseases.
Conclusion IgG4-related hypophysitis may have different
clinical characteristics between genders. This survey may
lack some information because the Japanese abstracts did
not contain certain details.
Keywords IgG4-related hypophysitis  Hypopituitarism 
Diabetes insipidus  Pituitary  Glucocorticoid

Introduction
Primary hypophysitis is a rare disease; in fact, only 750
cases of primary hypophysitis were published until 2013.
Interestingly, approximately 30% of primary hypophysitis
cases were from Japan [1]. Primary hypophysitis is classified by histologic appearance as lymphocytic, granulomatous, xanthomatous, necrotizing, immunoglobulin G4
(IgG4) plasmacytic, and mixed form. Among these, IgG4related hypophysitis is a particularly rare disease and only
1.3% comprises primary hypophysitis cases.
To the best of our knowledge, only 26 reports on 34
cases of IgG4-related hypophysitis have been published in
English as of 2015 and among these, 14 reports were from
Japan. In general, IgG4-related diseases are known to
likely develop in elderly men. According to a review of 31
published English case reports, the age at onset was
66.3 9.8 years and the ratio of men to women was 9.3:1
[2]. Among all IgG4-related diseases, autoimmune pancreatitis was well-defined with respect to organ-specific
diagnostic criteria. According to a survey on 5475 Japanese
patients, autoimmune pancreatitis, which belongs to the
same disease group as IgG4-related disease, had a mean

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Pituitary

Data were statistically analyzed using IBM SPSS statistics


version22. The difference in clinical characteristics
between genders was calculated using MannWhitney
U test. The significance level of the statistical data was set
as p \ 0.05.

(1) typical organ involvement, (2) serum IgG4 level, and


(3) histopathological findings are used for diagnosis.
(1) ? (2) ? (3) indicates definite, (1) ? (2) indicates
possible, and (1) ? (3) indicates probable. These guidelines, which attach much value on histopathological findings, decrease the diagnostic yield for organs that are
difficult to biopsy. Therefore, organ-specific diagnosis
criteria are needed. Because IgG4-related hypophysitis is a
rare disease, the organ-specific diagnostic criteria are not
well defined. In 2004, van der Vliet reported the first case
of IgG4-related hypophysitis in a 66-year-old woman with
retroperitoneal fibrosis, salivary gland inflammation, and
lung tumor [5]. However, pituitary biopsy was not performed in that case. The first case of IgG4-related
hypophysitis diagnosed by pituitary biopsy was reported by
Wong in 2007 [6]. Although the most important factor for
the diagnosis of IgG4-related disease is histopathologic
findings, pituitary biopsy is a highly invasive procedure.
Furthermore, as IgG4-related disease has favorable
response to glucocorticoids, we hoped to diagnose it
without pituitary biopsy. Leporati devised new diagnostic
criteria for IgG4-related diseases [4]. Criterion 1 is pituitary histopathology, which is sufficient to establish the
diagnosis. If pituitary histopathology is not available,
magnetic resonance imaging (MRI) of the pituitary (criterion 2) and histopathology of other organs (criterion 3) are
sufficient to establish a diagnosis. If histopathology of
other organs is not available, pituitary MRI (criterion 2),
along with increased serum IgG4 level (criterion 4) and
prompt response to glucocorticoids (criterion 5) can be
used to establish the diagnosis of IgG4-related
hypophysitis. We adopted Leporatis criteria for this
survey.

Diagnostic criteria

Hormone deficiency

Guidelines for diagnosis of IgG4-related disease were


proposed by Umehara in 2011. According to the guidelines,

Anterior hypopituitarism was defined as any anterior


pituitary hormone deficiency. Panhypopituitarism was

age of onset at 66.3 11.5 years, with a 3.2:1 ratio of men


to women [3]. Comparing the two diseases, the gender
distribution had a large difference. In our opinion, these
data, which were based on English literature review, might
be insufficient to characterize IgG4-related hypophysitis
precisely. Since 2011, when Leporati devised new diagnostic criteria for the disease without the need for pituitary
biopsy [4], case reports on IgG4-related hypophysitis during scientific meetings in Japan have been increasing.
Therefore, we aimed to survey both English and Japanese
case reports, including published literature and abstracts of
scientific meetings.

Materials and methods


We searched for information about IgG4-related
hypophysitis from PubMed and Igakuchuozasshi (Japan
Medical Abstracts Society) for Japanese reports. One
hundred nineteen cases [44 abstracts (57 cases), 32 English
literatures (43 cases), and 15 Japanese literatures (19
cases)] were found. There were four duplicated reports (13
cases) found among abstracts. Among 104 case reports, we
reviewed 84 case reports that fulfilled Leporatis diagnostic
criteria (Fig. 1).
Statistical analysis

English literature

Japanese literature

Abstract
44 reports (57cases)
Duplicated reports
English literature: three reports (12 cases)
Japanese literature: one report (1 case)

32 reports (43 cases)

15 reports (19 cases)

40 reports (42cases)

87 reports (104 cases)


Fulfilled Leporatis diagnostic criteria

71 reports (84 cases)


Fig. 1 Study design of the screening for IgG4-related hypophysitis

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Pituitary

defined as anterior hypopituitarism with anti-diuretic hormone (ADH) deficiency.

Results
This review included 71 reports on 84 cases of IgG4-related hypophysitis (Table 1) [2, 46, 874]. Applying this
review to the guidelines of IgG4-related disease, 37, 14, 21,
and 12 cases were definite, probable, possible, and unknown, respectively.
Patient background
Analysis of the 84 cases showed that the mean SD age at
the time of onset was 64.2 13.9 years; women
(56.4 18.6 years)
were
younger
than
men
(67.5 9.8 years) (Table 3). The ratio of men to women
was 2.4:1.
Pituitary function
Pituitary function was normal in 1 (1.2%) case, but presented with panhypopituitarism in 44 (52.4%), anterior
hypopituitarism in 22 (26.2%), and central diabetes insipidus in 15 (17.9%); data was not available for 2 cases
(2.4%). Analysis of hormone deficiency showed that antidiuretic hormone (ADH) deficiency was the most frequent
type found in 59 cases (70.2%), followed by LH/FSH
deficiency found in 40 cases (47.6%), adrenocorticotropic
hormone deficiency found in 39 cases (46.4%), and growth
hormone and thyroid stimulating hormone deficiency found
in 34 cases (40.5%). Among anterior hypopituitarism,
although various combinations of hormone deficiencies
were observed, only one case showed isolated anterior
pituitary hormone (TSH) deficiency.
MRI of the pituitary
On pituitary MRI, there were 54 cases (64.3%) of both
pituitary gland and stalk enlargements, 18 cases (21.4%) of
stalk enlargement, and 12 cases (14.3%) of pituitary gland
enlargement.
Laboratory findings
In the 84 cases, 61 cases had serum IgG4 level available.
Data for 11 cases was lacking. Seven cases showed elevated, while five cases showed normal (no detailed data
available) serum IgG4 levels. Serum IgG4 level was elevated in 56 cases (seven cases had no detailed data available) and normal in 13 cases (four cases had no detailed
data available). Data on outcomes after steroid

administration were available in four cases, but were


lacking in 11 cases. Excluding data after administration of
steroids, the median serum IgG4 level was 264.5 mg/dL
(range 16.92620 mg/dL) (n = 58); this value was higher
in men [405 mg/dL (24.52620 mg/dL)] than in women
[226 mg/dL (16.9485 mg/dL)] (Table 3).
Other IgG4-related systemic diseases
Various IgG4-related systemic diseases have been reported to
be associated with hypophysitis. Retroperitoneal fibrosis was
most frequent found in 22 cases (26.2%) (Table 2).
Hypophysitis without other IgG4-related systemic diseases was
observed in 21 cases (25%); 13 of these cases were women. The
overall mean number of IgG4-related systemic diseases
including hypophysitis was 2.7 1.5; this was higher in men
(3.0 1.5) than in women (1.8 1.1) (Table 3).
Therapy
IgG4-related hypophysitis has been known to have a
favorable response to glucocorticoids. As with the diagnostic criteria, there are no clearly defined guidelines on
therapy for IgG4-related hypophysitis. In the analysis of 84
cases, data on the efficacy of steroid therapy were obtained
for 71 cases. Effectiveness of steroid therapy was judged
based on the decrease in pituitary size. Treatments were
effective in 69 of the 71 cases (97.2%), whereas they were
not effective in 2 cases (2.8%). The initial dose of
administered glucocorticoids varied from a pharmacologic
dose in 39 cases (46.4%) to a replacement dose in 20 cases
(23.8%); steroid pulse therapy was given in 2 cases (2.4%).
No steroid therapy was administered in two cases (2.4%)
because the manifestation was diabetes insipidus alone in
one patient and the IgG4-related disease was chronic (over
1 year). No data on steroid therapy were found in 21 cases.
The two cases that did not respond to steroid therapy
received hydrocortisone at replacement dose, which was
defined as \20 mg of hydrocortisone per day.

Discussion
IgG4-related disease is a chronic disease with hypertrophic,
massive lesion characterized by elevated serum IgG4 levels
and tissue infiltration of IgG4-positive plasma cells. It
predominantly occurs in elderly men who show a favorable
response to glucocorticoids [7]. Although IgG4-related
hypophysitis is a rare disease, reported cases are increasing
recently.
In this review, we included 84 cases of IgG4-related
hypophysitis that were reported in publications and
abstracts of scientific meetings in both English and

123

123

61

73

20

21

60

71

78

71
73

63

67

74

57

26

27

28

29
30

31

32

33

34

71

55

24

25

73

81

19

75

68

18

22

74

17

23

72

70

74
70

13
14

15

49

12

16

77

11

59

70

62

77

55

10

62

M
M

F
M

70

67

Sex

66

71

Age

No

AF

AF

AF

AF
AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF
AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

Anterior
hypopituitarism

Pituitary function

Table 1 Case report of IgG4-related hypophysitis

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

DI

Pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk

Stalk
Stalk

Stalk

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk

Stalk pituitary mass

Stalk

Stalk pituitary mass

Stalk pituitary mass

Stalk

Stalk pituitary mass

Stalk pituitary mass


Stalk

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk

Stalk

Stalk

Pituitary mass

Stalk pituitary mass

Stalk

Stalk pituitary mass

Pituitary mass

MRI

212

Normal

Normal

295

203
194

143

240

2620

127*

169

nd

nd

Elevated

1980

376

151

170

924

229

115*
nd

nd

1950

949

111

229

292

1860

720

Elevated

2220

405

485

IgG4

2
2

0
0

IgG4 related
disease

Number of other

?
?

Pituitary

Biopsy

Other
organ

Muraoka et al. [36]

Abe et al. [35]

Ochi et al. [34]

Kurihara et al. [33]

Nanba et al. [31]


Komatsu et al. [32]

Nanba et al. [31]

Nagai et al. [30]

Kotera et al. [29]

Patel and Szostek [28]

Kaneda et al. [27]

Leporati et al. [4]

Shibata et al. [26]

Okamoto et al. [25]

Yamagami et al. [24]

Yukawa et al. [23]

Haraguchi et al. [22]

Haraguchi et al. [22]

Hori et al. [21]

Tachibana et al. [20]

Osawa et al. [18]


Kinoshita et al. [19]

Fujisawa et al. [17]

Takeuchi et al. [16]

Ando et al. [15]

Taji et al. [14]

Uehara et al. [13]

Tsuboi et al. [12]

Isaka et al. [11]

Wong et al. [6]

Ralli et al. [10]

Yamamoto et al. [9]

Tanabe et al. [8]

van der Vliet et al. [5]

References

Pituitary

53

68

58

76

53

46

38

57
32

52

53

54

55

56

57

58

59
60

69

70

73

66

68

72

65

67

70

85

63

64

25

67

51

37

76

50

61

58

62

25

49

68
66

44
45

48

52

43

55

68

42

40

80

41

46

47

40

47

78

75

37

70

72

36

38

82

35

39

Age

No

Table 1 continued

F
F

M
M

Sex

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

Normal

nd
AF

AF

AF

AF

nd

AF

AF

AF

Anterior
hypopituitarism

Pituitary function

AF

AF

AF

AF

AF

AF
AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

Normal

nd

AF

nd

AF

AF

AF

AF

DI

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Pituitary mass
Stalk pituitary mass

Pituitary mass

Stalk pituitary mass

Stalk

Stalk pituitary mass

Stalk pituitary mass

Stalk

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass


Stalk pituitary mass

Stalk pituitary mass

Pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

MRI

722

226

153

106

244

300

nd

nd

Elevated
205

Normal

nd

24.5

513

405

16.9

16.9

82.5

2100

1250

Normal

413

1010

202
nd

423

226

296

317

203

143

87

181

194

IgG4

1
2

2
5

IgG4 related
disease

Number of other

?
?

Pituitary

Biopsy

?
-

?
?

Other
organ

Kaneko et al. [59]

Kaneko et al. [59]

Takahashi et al. [58]

Kikuno et al. [57]

Masaki et al. [56]

Ohkubo et al. [55]

Sosa et al. [54]

Sosa et al. [54]

Goda et al. [52]


Sakai et al. [53]

Tochiya et al. [51]

Kajimoto et al. [50]

Bando et al. [49]

Bando et al. [49]

Bando et al. [49]

Bando et al. [49]

Bando et al. [49]

Bandoet al. [49]

Iseda et al. [2]

Nakamura et al. [48]

Shiga et al. [47]

Caputo et al. [46]

Hattori et al. [45]

Takada et al. [43]


Hsing et al. [44]

Hojo et al. [42]

Hamamoto et al. [41]

Nakamura et al. [40]

Nishina et al. [39]

Shimazu et al. [38]

Shimazu et al. [38]

Shimazu et al. [38]

Shimazuet al. [38]

Fujino et al. [37]

References

Pituitary

123

123

81

72

72

73

75

84

F
M

Sex

AF

AF

AF

AF

AF
AF

AF

AF

AF

AF

AF

AF

AF

AF

Anterior
hypopituitarism

Pituitary function

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

AF

DI

Stalk pituitary mass

Stalk

Stalk

Pituitary mass

Stalk pituitary mass

Pituitary mass
Stalk

Pituitary mass

Stalk pituitary mass

Pituitary mass

Stalk

Pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Stalk pituitary mass

Pituitary mass

MRI

AF Affected function, nd not described, DI diabetes insipidus; measured after steroid therapy

55

38

81

73

43

80

82

32
72

78
79

83

87

38

76

77

62

71

71

73

69

70

74

76

69

75

Age

No

Table 1 continued

298

Elevated

95

377

79.2

nd
853

Normal*

285

Elevated

1500

Elevated

333*

nd

Elevated

Elevated

IgG4

0
1

nd

IgG4 related
disease

Number of other

?
-

Pituitary

Biopsy

Other
organ

Ohtu et al. [74]

Nagata et al. [73]

Matsuoka et al. [72]

Krystallenia et al. [71]

Ngaosuwan et al. [70]

Tauziede-Espariat et al. [68]


Harano et al. [69]

Tauziede-Espariat et al. [68]

Nakasone et al. [67]

Onoet al. [66]

Jo et al. [65]

Mogi et al. [64]

Nagata et al. [63]

Brandon et al. [62]

Yamashita et al. [61]

Ohno et al. [60]

References

Pituitary

Pituitary
Table 2 Other IgG4-related
systemic diseases

Other IgG4-related diseases

Number of cases

Frequency (%)

Retroperitoneal fibrosis
Mikuliczs disease, Kuttners tumor

22

26.2

21

25.0

Lymph node swelling

20

23.8

Lung inflammatory pseudotumor interstitial pneumonia

17

20.2

Autoimmune pancreatitis

12

14.3

Tubulointerstitial nephritis, kidney inflammatory pseudotumor

10

11.9

Hypertrophic pachymeningitis

8.3

Orbital pseudotumor iridocyclitis

8.3

Liver inflammatory pseudotumor

3.6

Nasal sinus inflammatory pseudotumor

2.4

Sclerosing cholangitis

2.4

Riedels thyroiditis

1.2

Inflammatory aneurism

1.2

Gastric wall thickness

1.2

Iliopsoas muscle
Prostatitis

1
1

1.2
1.2

Table 3 Difference in clinical


characteristics between genders

Men

Women

p value

Mean age of onset

67.5 9.8

56.4 18.6

0.018

Median serum IgG4 level

405 (24.52620)

226 (16.9485)

0.028

Mean number of IgG4-related diseases

3.0 1.5

1.8 1.1

\0.001

Japanese. More than half of the English reports were from


Japan. Although the reason for this statistics is unclear,
there are possibilities of ethnic difference, high disease
prevalence, and high utility rate of MRI in Japan. Applying
this review to the guidelines of IgG4-related disease, definite were only 44% of the cases. Because Leporatis
diagnostic criteria can diagnose IgG4-related hypophysitis
without histopathological findings if the steroid therapy is
effective, it is sensitive for detection of IgG4-related
hypophysitis. However, steroid therapy occasionally
decrease involved organ to malignant lymphoma. This
problem requires further attention.
Comparison of our data with a previous review
in 2014
Iseda et al. [2] reviewed 31 English case reports on IgG4related hypophysitis in 2014. Comparing our data with
theirs, patient background and age at the time of disease
onset were similar (this review, 64.2 13.9 years vs.
previous review, 66.3 9.8 years). The ratio of men to
women was different (this review, 2.4:1 vs. previous
review, 9.3:1). In an epidemiologic study on autoimmune
pancreatitis, which is a similar IgG4-related disease, the
average age of onset was 66.3 11.3 years and the ratio
of men to women was 3.2:1 [3]. From our data, women

were more prone to acquire IgG4-related hypophysitis


alone than men (13.6 vs. 52%). If the IgG4-related systemic diseases included the same disease group, the number of women may have been underestimated in the
previous review. As another reason for the underestimation, it was possible that the diagnosis of IgG4-related
hypophysitis alone was frequently missed. Furthermore, it
was possible that cases of IgG4-related hypophysitis
diagnosed without pituitary biopsy were often presented in
scientific meetings, rather than published in English literature because of insufficient clinical data. This bias may be
another factor for the underestimation of diagnosed women
in the previous review.
With regard to pituitary function, our review and the
previous review had similar prevalence of anterior
hypopituitarism (26.2 vs. 32%, respectively), diabetes
insipidus (17.9 vs. 20%, respectively). and panhypopituitarism (52.4 vs. 45%, respectively). A similar trend was
seen for the MRI findings: pituitary enlargement (14.3 vs.
12%, respectively), stalk enlargement (21.4 vs. 22%,
respectively), and pituitary-stalk enlargement (64.3 vs.
65%, respectively). Compared with those of the previous
review, our review had lower prevalence of other IgG4related diseases complicating hypophysitis, such as lung
lesion (20.2 vs. 39%); retroperitoneal fibrosis (26.2 vs.
32%); autoimmune pancreatitis (24.3 vs. 32%); and lymph

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Pituitary

node lesions (23.8 vs. 26%), except for salivary gland


lesions, which were more prevalent in our review than the
previous review (25 vs. 23%). Hypophysitis alone was
more prevalent in our review than in the previous review
(25 vs. 10%).
In this study, the number of women with IgG4-related
hypophysitis was high and women seemed to be predisposed to develop an associated salivary gland lesion.
Among the 25 women in this review, 14 had IgG4-related
hypophysitis alone, whereas in the remaining 11 patients
with concomitant IgG4-related diseases, 6 had lesions in
the salivary gland. From this survey, we revealed new
clinical information about IgG4-related hypophysitis,
especially in women.

4.

5.

6.

7.

8.

Limitation
In this report, we reviewed cases of IgG4-related
hypophysitis in 26 English publications, 13 Japanese publications, and 36 Japanese abstracts of scientific meetings.
This survey may lack some information because Japanese
abstracts did not contain certain details.

9.

10.
11.

Conclusion
12.

A registry of cases of IgG4-related hypophysitis might be


helpful to allow a thorough analysis of this condition. In
this survey, we revealed detailed clinical characteristics of
IgG4-related hypophysitis diagnosed by Leporatis criteria.
In addition, we described new clinical characteristics that
were different between sexes. To understand this disease
better, specialists should be responsible enough to submit
timely case reports that share important information.
Compliance with ethical standards

13.

14.

Conflict of interest None of the authors have any potential conflicts


of interest associated with this research.
15.
Informed consent For this type of study, formal consent is not
required.

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