Long-term clinical course of IgG4-related systemic disease ...pathology.jhu.edu/hypophysitis/pdf/660_2010_Hori.pdf · ImmunoglobulIn (Ig) G4-related systemic dis-ease is a recently

Endocrine Journal Advance Publication

Endocrine Journal 2010, 57Endocrine Journal 2010, 57

ImmunoglobulIn (Ig) G4-related systemic dis-ease is a recently characterized disorder. The best-known manifestation of this disease is pancreatitis [1], but other systemic involvements have also been de-scribed, including those in salivary glands [2], lung [3], liver, bile duct, gall bladder [4, 5], kidney [6] and ret-roperitoneum [5, 7]. Significantly, they all share simi-lar features, i.e., a high serum level of IgG4 and an in-filtration of IgG4-positive plasma cells as determined using histopathological specimens of the organs in-volved. To our knowledge, only six cases of IgG4-related hypophysitis have been reported in the litera-ture (English language) thus far, and none of these reports has described the long-term clinical course as an IgG4-related systemic disease. In our current case

Long-term clinical course of IgG4-related systemic disease accompanied by hypophysitis

Michiko Hori1), Noriko Makita1), Takahiro Andoh1), Hirotoshi Takiyama1), Yuki Yajima1), Takashi Sakatani2), Seiji Fukumoto1), Taroh Iiri1) and Toshiro Fujita1)

1)Department of Endocrinology and Nephrology, The University of Tokyo School of Medicine, Tokyo 113-8655, Japan 2)Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan

Abstract. A 70-year old man with a 14 year history of Sjögren syndrome, interstitial pneumonia, and autoimmune hepatitis (AIH) was admitted to our hospital due to hyponatremia with a one month history of fatigue, thirst, and nausea. Laboratory tests on admission revealed that this patient had a central adrenal insufficiency. Pituitary magnetic resonance imaging (MRI) further showed swelling of the stalk and posterior lobe of his pituitary, suggesting infundibulo-hypophysitis. Based on his past history of autoimmune disease, his serum IgG4 levels were measured and found to be remarkably high (924 mg/dL). Previous biopsy specimens from his liver, lung, and parotid gland were immunostained for IgG4, which revealed a marked infiltration of IgG4-positive plasma cells. As a result of our tests, we made a diagnosis of IgG4-related systemic disease. Interestingly, a subsequent MRI scan at three weeks after the patient commenced glucocorticoid replacement therapy for adrenal insufficiency showed that the swelling of his pituitary stalk was reduced. This finding suggested that IgG4-related hypophysitis may improve either as a result of a supplemental dose of glucocorticoid or possibly spontaneously. Although six cases of IgG4-related hypophysitis have been reported in the scientific literature published in English, our current case is the first in which IgG4-related hypophysitis likely occurred as a result of a long-term history of IgG4-related systemic disease. We report this case herein and review the relevant literature.

Key words: IgG4, Hypophysitis, Adrenal insufficiency

study, we describe a patient who was diagnosed with hypophysitis 14 years after the onset of hepatitis, in-terstitial pneumonia, and sialadenitis, which turned out pathologically to be an IgG4-related disease.

Case Report

A 70-year-old man who had been followed up in our hospital for diabetes mellitus visited the emer-gency room and was admitted in March 2009 with se-vere hyponatremia (Na 115 mEq/L) involving a one month history of fatigue, thirst, and nausea. Fourteen years earlier, he had been diagnosed with Sjögren syn-drome, lymphoid interstitial pneumonia, and AIH, and had been treated with 30 mg per day of prednisolone. This steroid regimen had been gradually reduced nine years previously. At the time of admission, the patient showed dry mouth and dry skin, suggesting dehydra-tion. However, despite a continuous infusion of 0.9% saline, his serum sodium levels did not normalize and he was thus diagnosed with a central adrenal insuffi-

Received Dec. 9, 2009; Accepted Feb. 10, 2010 as K09E-356Released online in J-STAGE as advance publication Apr. 1, 2010Correspondence to: Noriko Makita, Department of Endocrinology and Nephrology, The University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 Japan.E-mail: [email protected]

Advance Publicationdoi: 10.1507/endocrj. K09E-356

original

2 Hori et al.

Endocrine Journal Advance Publication Endocrine Journal Advance Publication

showed thickening of the pituitary stalk, enlargement of the posterior lobe with the loss of high intensity, and a relatively atrophic anterior lobe, indicative of in-fundibulo-hypophysitis (Fig. 1A).

A hormonal provocative test, performed 10 days af-ter the glucocorticoid replacement therapy was intro-duced, revealed that the F response to CRH was low in this patient, although the basal level of ACTH was found to be high, that the GH response to GRH was normal for his age, although the IGF-1 level upon ad-mission was very low (Table 1), that the TSH and PRL responses to TRH were normal, and that the LH and FSH responses to LHRH were low and blunt, al-though the basal levels of LH and FSH were higher than those on admission (Table 4). Although the bas-al PRL level was not high, these results suggested that the lesions in this patient mainly existed at the supra-pituitary level, i.e. at the stalk, and this was compat-ible with our MRI findings. There was a discrepancy found between the ACTH level on admission (Table 1) and the basal ACTH level measured in the provocative

ciency based on his endocrinological data on admis-sion, i.e. a very low level of serum cortisol (F; 1.1 µg/dL) with normal levels of plasma ACTH (32 pg/mL) accompanied by a decrease in the levels of other pitu-itary hormones (Table 1). Immediately after perform-ing a rapid ACTH infusion test (Table 2), the patient was started on an intravenous administration of 100 mg hydrocortisone for his adrenal failure and main-tained on a glucocorticoid replacement therapy (15 mg per day of hydrocortisone). Soon after the commence-ment of this treatment, his urine volume markedly in-creased to more than 4 liters per day, suggesting that he suffered from a previously masked case of diabetes insipidus. The results of a hypertonic saline test fol-lowed by an infusion of vasopressin were compatible with the presence of complete diabetes insipidus with the exception of the basal urine osmolality level (Table 3). However, these manifestations of diabetes insipi-dus were almost fully controlled with the administra-tion of 2.5 µg of 1-desamino-8-D-arginine vasopres-sin (DDAVP) just before sleep. An MRI subsequently

WBC

Seg

Eosino

Lym

Hb

Hct

Plt

TP

Alb

AST

ALT

T.Bil

UN

Cre

Na

K

Cl

s-Osm

7800

42.0

31.0

19.0

12.5

34.7

25.1

8.8

3.1

45

14

0.9

4.8

0.65

115

3.6

84

248

/μL

%

%

%

g/dL

%

x104/μL

g/dL

g/dL

U/L

U/L

mg/dL

mg/dL

mg/dL

mEq/L

mEq/L

mEq/L

mOsm/kg

PRA

ALDS

ACTH

Cortisol

DHEA-S

ADH

PRL

TSH

FT4

FT3

FSH

LH

Testosterone

GH

IGF-1

0.3

15

32

1.1

12

0.66

11

0.18

1.00

3.0

1.1

0.2

< 0.05

0.0724.7

ng/mL/hr

pg/mL

pg/mL

μg/dL

μg/dL

pg/mL

ng/mL

μU/mL

ng/dL

pg/mL

mIU/mL

mIU/mLng/mL

ng/mLng/mL

IgA 155 mg/dL

IgG 3494 mg/dL

IgM

IgE

87

600

mg/dL

IU/mL

u-Osm

u-Na

u-Cre

228

59

48

mOsm/kg

mEq/L

mg/dL

FPG

HbA1c 6.7

mg/dL

%

81

RA

ANA

anti SS-A

anti SS-B

<5

<1.0

5.8

IU/mL

(0.0-24.0)(0.0-29.0)

40x

Table 1. Laboratory data for the current patient on admission.

Times (min) 0 30 60

ACTH (pg/mL) 44 cortisol (µg/dL) 3.6 5.0 7.0

Table 2. Response of cortisol to intravenous injection of ACTH (250 µg)

Times (min) 0 30 60 90 iv pitressin

Na (mEq/L) 139 143 144 151s-Osm (mOsm/kg) 286 289 293 306u-Osm (mOsm/kg) 376 291 268 300 356 ADH (pg/mL) 0.27 0.17 0.46 0.44

Table 3. Hypertonic saline test followed by an infusion of vasopressin

Times (min) 0 30 60 90 120

CRH testcortisol (µg/dL) 11.8 12.9 12.9 12.7 12.6ACTH (pg/mL) 143 234 232 164 149

GRH testGH (ng/mL) 0.58 3.23 2.51 1.88 1.28

TRH testTSH (mU/mL) 1.97 11.35 10.59 8.46 6.77PRL (ng/mL) 11 27 22 18 17

LHRH testLH (mIU/mL) 2.2 3.8 4.8 4.9 4.8FSH (mIU/mL) 7.5 9.3 10.7 11.9 12.8

Table 4. Response of pituitary and adrenal hormones to intravenous injections of CRH (100 µg), GRH (50 µg), TRH (500 µg), or LHRH (100 µg)


3Hypophysitis and IgG4-related disease


nephelometer (Dade Behring, Deerfield, IL). We found that the serum IgG4 level was elevated (924 mg/dL; reference range from 4.8 to 105 mg/dL) even at 14 days after the glucocorticoid replacement thera-py had been started. Previous biopsy specimens from this patient from the liver, lung, and parotid gland were then immunostained for IgG4 although they re-vealed only moderate indications of IgG4-related diseases such as fibrosis and obstructive phlebitis. However, this analysis also revealed that there was a marked infiltration of IgG4-positive plasma cells (Fig. 2) in this patient, which accounted for more than 50% of the IgG-positive cells. Thus, the symptoms in this patient previously regarded as Sjögren syndrome, lymphoid interstitial pneumonia, and AIH could in fact be attributed to Mikulicz’s disease, IgG4-related interstitial pneumonia, and IgG4-related hepatitis, re-spectively. Further imaging tests were performed to examine whether other organs were also involved. An abdominal magnetic resonance cholangio pancreatog-raphy (MRCP) showed caliber variation of the main

test (Table 4). As discussed below (see Discussion), we suspected that the inflammation of the stalk might have been partially alleviated by the glucocorticoid re-placement therapy given that the provocative test was initiated 10 days after this therapy was started.

Further laboratory and imaging tests ruled out oth-er diseases that could potentially have a similar im-pact in the hypothalamus and pituitary including ma-lignant lymphoma, germinoma, distant metastases or sarcoidosis. We ruled out malignant lymphoma as there were no specific findings of FDG-PET and we observed normal levels of serum soluble IL-2 recep-tor. We were also able to rule out germinoma and sar-coidosis as the level of β-hCG in the serum was below the limit of detection and we found that the levels of angiotensin-I-converting enzyme (ACE) in the spinal fluid were well below the lower limit of its reference range (0.2 U/L; reference range 8.3-21.4 U/L). We ruled out distant metastases as no malignant cells were evident in the spinal fluid and also because there were no suspected malignancies detected by whole body CT, FDG-PET, gastronoscopy or colonoscopy.

Based on the elevation of serum IgG (3494 mg/dL; reference range 870-1700 mg/dL) on admission and the past history of autoimmune disorders in our cur-rent case, we suspected IgG4-related hypophysitis and measured the serum IgG subclass using a Behring

Fig. 1. A gadolinium-enhanced pituitary MRI showing thickening of the pituitary stalk, enlargement of the posterior lobe and relatively atrophic anterior lobe in the sagittal section (A). Three weeks after hydrocortisone replacement therapy, both the thickness of the pituitary stalk and the enlargement of the posterior lobe were found to be reduced in the sagittal section (B).

Fig. 2. Biopsy specimen obtained from the liver (A, B), lung (C, D) and parotid gland (E, F) indicating chronic inflammation with marked lymphocytic infiltration (A, C, E; HE stain; original magnification x 400) and abundant IgG4-positive plasma cell infiltration (B, D, F; stained with IgG4 monoclonal antibody; original magnification x 400)

4 Hori et al.


quently measured during the previous 14 years (Fig. 4) with three peaks occurring, the first of which appeared concurrently with the previous history of hepatitis, sialadenitis, and interstitial pneumonia, and which showed improvement upon treatment with predniso-lone (Fig. 4, arrow (1)). One year after withdrawal of the steroids, the IgG next peak appeared (Fig. 4, arrow (2)). Subsequently, his parotid glands and submaxil-lary glands became intensely swollen, and the inter-stitial pneumonia detected on a chest X-ray appeared

pancreatic duct without any swelling of the pancreas in abdominal MRI, consistent with the prediction that the patient had previously suffered from autoimmune pancreatitis (AIP) (Fig. 3). There was no evidence of involvement of the kidney or retroperitoneum. Taken together, we made a diagnosis of a possible case of active IgG4-related hypophysitis. This was based on histological findings in the liver, lung, and parotid gland, and an assumed history of IgG4-related pancre-atitis based on MRI images.

In general, IgG4-related systemic disease has been shown to respond well to steroid treatments [8]. However, because of its rarity, there has been little re-ported on the possible effectiveness of glucocorticoid therapy in the treatment of IgG4-related hypophysitis. Interestingly, an MRI of our patient taken three weeks after he began a glucocorticoid replacement therapy revealed that both the thickness of the pituitary stalk and the enlargement of the posterior lobe were re-duced (Fig. 1B). We thus decided to refrain from ad-ministering a pharmacological dose of glucocorticoid and to use a replacement dose only.

The serum IgG levels of our patient had been fre-

Fig. 3. Abdominal MRCP showing a caliber variation of the main pancreatic duct (arrow heads)

30

0

4000

8000

0

4

8

12

‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘07 ‘08 ‘09

gluc

ocor

ticoi

d (m

g)

hydrocortisonePSL

HbA

1c (%

)Ig

G (m

g/dL

)

0

20

10

(1) (2) (3)

gliclazide 40mg20mg

glibenclamide 1.25mg

Fig. 4. Temporal profile of the current patient’s serum IgG and HbA1c levels over a 14 year period The IgG levels peaked three times during the past 14 years. The first peak coincided with his hepatitis, sialadenitis, and

interstitial pneumonia (arrow (1)) and improved after treatment with prednisolone. When the next peak appeared (arrow (2)), the parotid glands and submaxillary glands became intensely swollen, and the interstitial pneumonia detected by chest X-ray appeared worse. However, these manifestations improved without treatment. The last peak appeared concomitant with the onset of hypophysitis (arrow (3)). The drastic change in the plasma glucose levels after the second serum IgG peak supports the possibility that this patient had a past history of AIP.




was first reported in 2001 [1] at which time it was re-vealed that AIP is often accompanied by the involve-ment of systemic organs including the salivary glands, bile duct, and retroperitoneum that show histopatho-logical infiltration by IgG4-positive plasma cells [9]. However, the pituitary gland has rarely been report-ed to be involved [10]. Thus far, including our cur-rent case, seven cases of hypophysitis accompanied by IgG4-related systemic disease have been reported in the literature published in English [11-16], with only one report showing supporting histopathological data for the pituitary [14] (Table 5). Six of these seven cas-es were male, and impairment of pituitary hormones and MRI findings seemed to be patient-specific. Three of these cases showed diabetes insipidus.

In terms of treatments, IgG4-related systemic dis-ease has been generally found to respond well to ste-roids [8]. However, because of its rarity, there have been few reports on the effectiveness of glucocorti-coid therapy in treating IgG4-related hypophysitis or of the doses required. Also, in the effective treatment of lymphocytic hypophysitis, a disease caused by au-toimmune inflammation of the pituitary gland and the most frequent cause of hypophysitis, there are conflict-ing reports. In some patients glucocorticoid therapy aimed at attenuating inflammation is associated with a recovery of pituitary function and a reduction of the pituitary mass [17-21]. Conversely, however, in other patients glucocorticoid therapy failed to work [22-24]. Moreover, there have been many reports showing that lymphocytic hypophysitis remits spontaneously [25-29]. It is therefore unclear whether improvements in the clinical course of this disease can be directly at-tributed to glucocorticoid treatment or simply reflect a natural progression [30]. Because of the uncertainty regarding the efficacy of glucocorticoid treatment and its known adverse effects, the justification for this ap-proach typically requires a mass effect due to a swol-len pituitary [31]. In the case of IgG4-related hypo-physitis (Table 5), patients were treated with various doses of glucocorticoid, from a replacement dose for adrenal insufficiency to a pharmacological dose. Three of these individuals improved in terms of both secretory capacity and evidence from MRI images. Only one patient, in addition to our present case, was treated with a replacement dose of hydrocortisone, and this individual also showed improvement [15]. Our current patient showed improvement, as evidenced by MRI images taken at three weeks after commencing a

to have worsened. However, these manifestations im-proved without further treatment. At this time, the pa-tient became aware of polyuria, five times during one night, but there was no sonographical evidence of an enlarged prostate during the second IgG peak. He had not been tested for plasma glucose for two years because these levels had been well controlled after the cessation of the glucocorticoid treatment. Seven months after the patient had shown an improved trend in terms of his serum IgG levels, he was found to have a markedly elevated level of HbA1c and was started on an oral antidiabetic drug, glibenclamide, at 1.25 mg per day. As his glycemic levels were successfully brought under control, nocturnal polyuria ceased, sug-gesting that the polyuria may have been caused by hy-perglycemia but not by the diabetes insipidus that was due to IgG4-related hypophysitis. Although this antid-iabetic treatment was not required for more than three months, the HbA1c levels became elevated again in April 2006. The patient was then restarted on anoth-er oral antidiabetic drug, gliclazide, at 40 mg per day. Glycemic control has been maintained using this drug at a dose of 20 mg per day since October 2007. This drastic change in the plasma glucose after the second serum IgG peak supports the assumed history of AIP, suggesting that his diabetes may have been a second-ary consequence of AIP, as well as the glucocorticoid therapy. This may explain why glycemic control was problematic in this patient even after the cessation of glucocorticoid therapy. Before hypophysitis was di-agnosed in this patient, his IgG levels had not been checked for almost four years because he had no obvi-ous disease manifestation except for diabetes. Finally, the last peak appeared concomitant with the onset of hypophysitis, although the IgG levels in the last peak were far lower than those in previous peaks (Fig. 4, ar-row (3)). As mentioned above and below, this patient has until now been treated with a replacement dose of glucocorticoid. At the time of writing, no further im-provement in pituitary function has been found, but this patient is able to live quite comfortably with no ex-cessive morbidity and also without the side effects that high doses of glucocorticoid would likely produce.

Discussion

IgG4-related systemic disease has been proposed recently with a history that originates with AIP. An association between the serum IgG4 levels and AIP

6 Hori et al.


(ACTH 143 pg/mL, F 11.8 µg/dL; Table 4) are expli-cable, i.e. the replacement dose of glucocorticoid re-leased the congestion in the hypothalamus-infundibu-lo pathway by reducing the thickness of the pituitary stalk, thus enabling the pituitary to secrete an appro-priately high level of ACTH against a still suppressed adrenal gland in this patient (Table 4). In fact, the IgG levels decreased from 3494 to 2666 mg/dL as early as 10 days after the glucocorticoid treatment was intro-duced. The result showing that the peak F level fol-lowing CRH infusion (F 12.9 µg/dL) improved, com-pared with that resulting from the ACTH infusion (F 7.0 µg/dL), also supports this hypothesis. The finding in the provocative test that the basal levels of LH and FSH improved, compared with those on admission, is also supportive.

In the present case, the GH-IGF-1 axis showed very low levels of IGF-1 on admission (Table 1). However, one month after the start of glucocorticoid replace-ment therapy, the IGF-1 level increased to 92.1 ng/mL with an associated appetite improvement, although this level was still low. We speculate that the very low levels of IGF-1 on admission reflected malnutri-tion as well as hypopituitarism due to hypophysitis. In terms of PRL, it is possible that the anterior lobe of pituitary was also impaired because the basal lev-

daily 10 mg dose of hydrocortisone. It remained un-clear, however, whether this alleviation of the disease may have simply occurred spontaneously. We thus avoided using a high dose of glucocorticoid and de-cided to monitor our patient continually while admin-istering only a replacement dose of this hormone.

At the time of writing, the hypophysitis in our pa-tient appears to be under control. Specifically, the IgG levels significantly decreased from 3494 to 1725 mg/dL at about one month after our patient commenced the glucocorticoid replacement therapy. We specu-late that this time course may be too rapid to sus-pect that the activity remitted spontaneously. Until now, the IgG levels in this patient have been main-tained at less than 2000 mg/dL (dotted line in Fig. 4), around which the IgG levels had settled in the previ-ous two intervals. In terms of the IgG4 levels, these decreased from 949 to 744 mg/dL after four months, although this is still high. These trends from the labo-ratory data are fully compatible with those of the MRI images. Taken together, a replacement dose of glu-cocorticoids may have partially suppressed the activ-ity of IgG4-related hypophysitis. If this is the case, discrepancies between the ACTH and F levels on ad-mission (ACTH 32 pg/mL, F 1.1µg/dL; Table 1) and the basal ACTH and F levels in the provocative test

No Age Sex Impaired anterior pituitary hormones

DI findings of MRI Other involvements treatment Response Reference

1 66 F TSH - A mass lesion in the hypophysis area

Pancreas (3 years before), lung, submandibular

glands,

retroperitoneum (around the same time)

PSL 60mg

Both of the pituitary mass and secretary capacity

[11]

2 70 M Gn - Enlargement and a high intensity signal in the pituitary stalk

Submandibular gland (2 years before),

lacriminal glands (around the same time)

PSL 40mg Both of the enlarged pituitary stalk

and secretary capacity improved. [12]

3 71 M ACTH, TSH, - Swelling of pituitary gland Submandibular glands, retroperitoneum

(around the same time)

Hydrocortisone

30mg

Need for the replacement therapy with cortisol and thyroid hormone

[13]

4 77 M Gn - A pituitary tumor (1x1x0.8cm)

with suprasellar extension

Pancreas, gall bladder (4 years before)

Trans sphenoidal surgery

Need for the replacement therapy with cortisol and thyroid hormone

[14]

5 62 M ACTH, TSH + Enlargement of the pituitary stalk Pancreas, parotid glands

(around the same time)Hydrocortisone

10mg

Both of the enlarged pituitary stalk and secretary capacity improved.

[15]

6 55 M Gn, GH, ACTH + Enlargement of the proximal end of the pituitary stalk and no high intensity at the posterior lobe

Paranasal sinuses, retroperitoneum

(around the same time)

PSL 50mg

Both of the enlarged pituitary stalk

Need for the replacement therapy with DDAVP

[16]

Gn, GH, ACTH Enlargement of the pituitary stalk Liver, parotid glands, lung (14 years before)

Hydrocortisone 10mg

Still need for the replacement therapy

with cortisol and DDAVP

Our patient

Both of the enlarged pituitary stalkand secretary capacity partially improved.

7 +70 M

Gn, GH

Table 5. Seven cases of IgG4-related hypophysitis reported in the literature




organs involved at this time, apart from the fact that the lungs, salivary glands, and liver were evident in the first peak and the pancreas, lungs, parotid glands, and sub-maxillary glands were suggested by the second peak.

In summary, we herein report the seventh known case of IgG4-related systemic disease accompanied by hypophysitis. Interestingly, this case showed a long clinical course as an IgG4-related systemic dis-ease with a possible flaring up of this activity on three occasions. We thus recommend that all patients di-agnosed with an IgG4-related disorder should be fol-lowed carefully over long term and receive appropriate managed care. Some cases may recover spontaneous-ly or as a result of a replacement dose of glucocorti-coid and these patients may not need a higher pharma-cological dose of this steroid.

While we were preparing this revised version, an-other probable case was reported [32]. This case was presented as IgG4-related hypophysitis, which was proved by immunostaining for IgG4 in the biopsy specimen of the pituitary gland, without other organ involvement. This case showed normal serum IgG4 levels after a pharmacological dose of glucocorticoid therapy, although the IgG and IgG4 levels before start-ing therapy were not reported.

els of PRL were not high despite an involvement at the supra-pituitary level. Given that the PRL response to TRH was normal and that other pituitary hormones such as ACTH, LH and FSH partially improved after glucocorticoid therapy was started, the impairment of the anterior lobe of pituitary was mild, if anything. In terms of the low response of F to ACTH infusion, we suspect that it is more likely that the function of the adrenal gland was suppressed because of a long-term ACTH deficiency rather than it being involved itself in IgG4-related systemic disease. This is because there was no evidence of adrenalitis in the CT images.

In terms of the function of the posterior lobe, this patient needed only 2.5 µg DDAVP before sleep to control his polyuria, despite a diagnosis of complete diabetes insipidus. It may be due to high sensitivity to AVP at the renal collecting ducts or due to partial improvement of the function as a result of the gluco-corticoid therapy as seen in a previous case (case 5 in Table 5).

In the third IgG peak, the immunoglobulin levels were lower compared with those in the previous two peaks (Fig. 4). This suggests that IgG levels may re-flect the extent of the involved organs. The relatively low levels of IgG flaring up were compatible with the fact that the infundibula and hypophysis were the only

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Long-term clinical course of IgG4-related systemic disease ...pathology.jhu.edu/hypophysitis/pdf/660_2010_Hori.pdf · ImmunoglobulIn (Ig) G4-related systemic dis-ease is a recently