Endocrine Journal 2008, 55 (4), 723–728

A Case of IgG4-Related Multifocal Fibrosclerosis Complicated by Central Diabetes Insipidus

YOSHIHIRO ISAKA, KATSUNOBU YOSHIOKA, MINAKO NISHIO, KEIKO YAMAGAMI, YOSHIO KONISHI,

TAKESHI INOUE*, AYAKO HIRANO**, MASAYUKI HOSOI AND MASAHITO IMANISHI

Department of Internal Medicine, Osaka City General Hospital, Osaka

*Department of Pathology, Osaka City General Hospital, Osaka

**Department of Otolaryngology, Osaka City General Hospital, Osaka

Abstract. A 55-years-old man was admitted to our hospital with a 6-month history of general fatigue, purulent nasal

discharge, polyuria, and polydipsia. Endocrinological findings revealed central diabetes insipidus (CDI) with mild

anterior pituitary dysfunction. Imaging studies revealed thickening of the proximal end of the pituitary stalk just below the

third ventricle, a mass in the paranasal sinus, and a mass encompassing the abdominal aorta. Histopathology of the mass

in the paranasal sinus revealed abundant IgG4-positive plasma cells, and the IgG4 serum level was markedly elevated.

Thus, he was diagnosed with IgG4-related multifocal fibrosclerosis. Therapy with prednisolone resulted in complete

resolution of clinical symptoms and reduction in size of the masses in the affected organs. However, CDI remained

unchanged. This is the first case in which the cause of CDI was IgG4-related multifocal fibrosclerosis. IgG4-related

sclerosing disease should be included in the differential diagnosis of thickening of the pituitary stalk with CDI, and a

search for extra-pituitary involvement is essential.

Key words: Central diabetes insipidus, Periaortitis, Paranasal sinusitis, IgG4-related sclerosing disease

(Endocrine Journal 55: 723–728, 2008)

CENTRAL diabetes insipidus (CDI) is a disorder of

urinary concentration ability due to a deficiency of

arginine vasopressin (AVP). This condition usually

occurs secondary to surgical trauma, craniopharingioma,

head injury, granulomatous disease, infectious disease,

or autoimmune processes.

IgG4-related sclerosing disease was first proposed

by Kamisawa et al., in the process of studying autoim-

mune pancreatitis [1]. It is characterized by elevation

of serum IgG4 levels [2], dense infiltration of IgG4-

positive plasma cells and T lymphocytes with fibrosis

[3–4], and a favorable response to steroid therapy.

Multifocal fibrosclerosis (MFS) is used to describe a

combination of similar fibrous proliferation occurring

at different anatomical sites, including autoimmune

pancreatitis, periaortitis, retroperitoneal fibrosis, medi-

astinal fibrosis, sclerosing cholangitis, and Riedel’s

thyroiditis. Recently, a close relationship between

MFS and autoimmune pancreatitis has been suggested,

based on the similarity of pathological findings [3].

Although a few cases of adenohypophysitis associ-

ated with IgG4-related sclerosing disease have been

reported [5–7], CDI has never been reported to be as-

sociated with this condition. Here, we report the first

case in which IgG4-related sclerosing disease was

causally related to CDI.

Case report

A 55-year-old man was admitted to our hospital on

August 13, 2007, with a 6-month history of general

fatigue, purulent nasal discharge, polyuria, and poly-

Received: January 28, 2008

Accepted: March 25, 2008

Correspondence to: Dr. Yoshihiro ISAKA, Department of

Internal Medicine, Osaka City General Hospital, 2-13-22,

Miyakojima-Hondori, Miyakojimaku, Osaka city, Osaka, 534-

0021, Japan

ISAKA et al.724

dipsia. Before his visit to our hospital, he consulted an

otolaryngologist; he was diagnosed with paranasal

sinusitis and treated with antibiotics, which had no

noticeable effect. There was a past history of otitis

media and surgery for this disorder 20 years previously.

At the time of admission, he was 176 cm in height

and weighed 66 kg. His temperature was 36.7°C,

pulse rate was 88/min, and blood pressure was 170/

108 mmHg. No goiter or enlargement of the lymph

nodes was noted. The reminder of the physical exami-

nation was unremarkable.

Laboratory results revealed the following: serum

sodium 145 mEq/l, potassium 3.8 mEq/l, chloride

104 mEq/l, calcium 9.3 mg/dl, phosphate 3.4 mg/dl,

fasting plasma glucose 126 mg/dl, and glycohemoglobin

A1c 5.0% (Table 1). Serologic revealed a mild

increase in γ-globulin fragment. However, specific

antibodies such as antinuclear antibody were normal.

Endocrinological data revealed a mild decrease in free

thyroxine levels with normal TSH levels. Plasma os-

molality was 301 mOsm/kgH2O, with a urinary osmo-

lality of 163 mOsm/kgH2O, and arginine vasopressin

(AVP) level was 0.79 pg/ml. Urinary output was 4 to

5 liters per day with no glucosuria.

His clinical course and laboratory finding led us to

suspect CDI with anterior pituitary dysfunction. A hy-

pertonic saline test failed to concentrate the urine and

to increment of the AVP despite an appropriately

increased plasma osmolality (Table 2). Hormonal

provocative tests revealed that TSH response to TRH

was normal, GH response to GRH was low, and FSH

and LH responses to LHRH were low and blunted. Al-

though ACTH response to CRH was low to normal,

cortisol response to CRH was low and blunted. Basal

prolactin level was high. These endocrinological find-

ings indicated that affected lesion existed above the

pituitary level (Table 3).

Magnetic resonance imaging (MRI) revealed thick-

ening of the proximal end of the pituitary stalk just

below the third ventricle and disappearance of high

intensity at the posterior lobe, compatible with a

diagnosis of CDI (Fig. 1A, B). Paranasal computed

tomography (CT) revealed a mass in the maxillary,

sphenoidal, and frontal sinus (Fig. 2A). Because we

suspected the likelihood of sarcoidosis or Wegener’s

granulomatosis, biopsy from the paranasal sinus was

performed, which showed non-specific chronic in-

flammation with lymphocytes, plasma cells, and

eosinophils (Fig. 3A).

Table 1. Laboratory Data on Admission

Blood cell count

White blood cell 6.96 × 103/mm3

neutrophils 40.8%

lymphocytes 34.1%

monocytes 5.9%

eosinophils 17.8%

basophils 1.4%

Red blood cell 3.98 × 104/mm3

Hemoglobin 11.7 g/dl

Platelet 29.9 × 104 μl

Blood chemistry

Total protein 8.3 g/dl

albumin 55.5%

α1 2.1%

α2 6.7%

β 7.2%

γ 28.5%

AST 28 IU/L

ALT 13 IU/L

ALP 269 IU/L

LDH 189 IU/L

Urea nitrogen 14.0 mg/dl

Creatinine 1.12 mg/dl

Uric acid 8.1 mg/dl

Sodium 145 mEq/L

Potassium 3.8 mEq/L

Chloride 104 mEq/L

Calcium 9.3 mg/dl

Phosphate 3.4 mg/dl

Glucose 126 mg/dl

HbA1c 5.0%

ACE 12.5 IU/l

Lysozyme 6.2 μg/ml

CRP 0.06 mg/dl

IgG 2701 mg/dl

IgA 159 mg/dl

IgM 46 mg/dl

Osmolality 301 mOsm/kgH2O

Immunity test

ANA <40

ss-A (–)

ss-B (–)

proteinase 3 ANCA <3.5 U/ml

myeloperoxidase ANCA <1.3 U/ml

Endocrinological findings

Free T3 2.3 pg/ml

Free T4 0.6 ng/dl

TSH 2.030 μIU/ml

ACTH 23 pg/ml

Cortisol 5.1 μg/dl

AVP 0.79 pg/ml

GH 0.30 ng/ml

Prolactin 54.43 ng/ml

LH <0.10 mIU/ml

FSH 0.61 mIU/ml

Urinalysis

Osmolality 163 mOsm/kgH2O

AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH:lactate dehydrogenase, ALP: alkaline phosphatase, CRP: C-reactiveprotein, ANA: anti-nuclear antibody, ANCA: antineutrophil cytoplasmicantibody, ACE: angiotensin converting enzyme, T3: triiodothyronine,T4: thyroxine, TSH: thyrotropin, ACTH: adenocorticotropin, AVP:antidiuretic hormone, GH: growth hormone, LH: luteinizing hormone,FSH: follicle stimulating hormone, ss-A: anti-ss-A/Ro antibody, ss-B:anti-ss-B/La antibody

IgG4-RELATED CENTRAL DIABETES INSPIDUS 725

During further examination, an abdominal CT

revealed a mass encompassing the abdominal aorta,

suggesting retroperitoneal fibrosis (Fig. 4A). This led

us to suspect the likelihood of IgG4-related sclerosing

disease, and we reexamined the pathological specimen

to aid our diagnosis. Histopathology of the mass in the

paranasal sinus revealed abundant IgG4-positive plas-

ma cells. Furthermore, serum levels of IgG4 ware

markedly elevated (1860 mg/dl; 60% of total IgG).

Thus, he was diagnosed with IgG4-related sclerosing

disease. Fuluorodeoxyglucose positron emission to-

mography (FDG-PET) showed uptake in the pituitary

stalk, paranasal sinus, and abdominal mass.

He was treated with 50 mg of prednisolone and his

general condition improved immediately after treat-

ment. CT and MRI showed a reduction in size of the

mass in pituitary stalk, the paranasal sinus, and en-

compassing the abdominal aorta (Fig. 1, 2, 4). Free

thyroxine levels recovered to within normal limits;

however CDI remained unchanged and was treated

with 1-desamino-8-D-arginine vasopressin. The dose

of prednisolone was gradually tapered and he is now

being treated as an outpatient without recurrence of the

disease.

Discussion

In the present case, the cause of CDI was considered

IgG4-related MFS based on the elevation of serum

IgG4, dense infiltration of IgG4-positive plasma cells

and lymphocytes in the paranasal sinus, and existence

of chronic periaortitis. The excellent response to ste-

roid treatment supported our diagnosis. Although we

could not obtain pathological informations on the

thickened stalk or periaortic tissue, we believe that

Table 2. Hypertonic saline test

Times (min) 0 30 60 90 120

Plasma Osmolality (mOsm/kgH2O) 293 298 303 306 313

Urinary Osmolality (mOsm/kgH2O) 188 196 209

AVP(pg/ml) 0.54 0.18 0.39 0.75 0.58

Table 3. Responses of pituitary and adrenal hormones to intra-

venous injection of CRH (100 µg), GRH (100 µg),

TRH (200 µg), GHRH (100 µg)

Times (min) 0 30 60 90 120

CRH test

Cortisol (ug/ml) 19.2 13.4 14.4 14.4 12.1

ACTH (pg/ml) 34 71 53 47 40

GRH test

GH (ng/ml) 0.15 1.18 2.18 1.67 0.91

TRH test

TSH (µU/ml) 2.350 15.910 12.310 9.920 7.320

PRL (ng/ml) 45.59 67.18 57.80 51.15 49.11

GHRH test

LH (mIU/ml) 0.10 0.28 0.33 0.33 0.30

FSH (mIU/ml) 1.10 2.26 3.00 3.26 3.63

Fig. 1. Gadoliunium-enhanced brain MRI showed thickening

of the proximal end of the pituitary stalk just below the

third ventricle and disappearance of high intensity at the

posterior lobe on admission, in the sagittal section (A)

and the coronal section (B). After treatment, thickening

of the pituitary stalk showed a reduction in size of the

mass in (C) and (D).

Fig. 2. Paranasal computed tomography (CT) revealed a mass

in the maxillary and sphenoidal sinus. (A). After

treatment, the mass disappeared (B).

ISAKA et al.726

these are identical to that of the paranasal sinus be-

cause all affected organs responded similarly to steroid

therapy.

Differential diagnosis of inflammatory thickening of

the pituitary stalk causing CDI includes lymphocytic

infundibuloneurohypophysitis (LIN), Langerhans his-

tiocytosis, sarcoidosis, and Wegener’s granulomatosis.

LIN has become a distinct entity since the proposal of

Imura et al. in 1993 [8], which proved that CDI can be

caused by autoimmune processes. LIN is character-

ized radiologically by thickening of the pituitary stalk

and enlargement of the neurohypophysis and histolog-

ically by infiltration of lymphocytes and plasma cells.

Because our patient presented with CDI, and MRI re-

vealed thickening of the pituitary stalk, he might have

been diagnosed with LIN if chronic periaortitis or

paranasal sinusitis had not been identified. Etiology of

the autoimmune process of LIN is not well understood

and may be diverse. Because histological similarities

exist between LIN and the present case, we speculate

that some of the reported cases of LIN may be other

manifestations of IgG4-related sclerosing disease.

Langerhans histiocytosis, sarcoidosis, and Wegener’s

granulomatosis were ruled out by the pathological

findings.

Intra- or para-sellar involvement of IgG4-related

MFS is rare and only three cases of lymphocytic ade-

nohypophysitis (LAH) with anterior pituitary dysfunc-

tion have been reported [5–7]. On the other hand,

involvement of IgG4-related MFS to neurohypophysis

with CDI has not been reported so far. In 1989,

Kojima et al. reported the first case of LIN, which was

complicated by chronic pancreatitis [9]. Although

staining for IgG4 was not performed, this case might

have been IgG4-related sclerosing disease. Further-

more, two reported cases of MFS associated with CDI

[10–11] could possibly have been IgG4-related MFS

because the clinical presentations were similar to the

present case. With the widespread awareness of

IgG4-related sclerosing disease, the etiology of LAH

and LIN may become clarified.

We diagnosed the present case as IgG4-related scle-

rosing disease based on the histological findings of the

paranasal sinus. To our knowledge, IgG4-related para-

nasal sinusitis has not been reported. Amagasa et al.

reported that without medical treatment, LIN became

Fig. 3. Biopsy specimen obtained from the paranasal sinus indicated chronic inflammation with lymphocytes, plasma cells, and

eosinophils (A; HE stain × 100) and abundant IgG4-positive plasma cells (B; stained with IgG4 monoclonal antibody × 200)

Fig. 4. Abdominal enhanced CT revealed a mass encompassing the abdominal aorta, consistent with retroperitoneal fibrosis (A). CT

showed a reduction of the mass after treatment.

IgG4-RELATED CENTRAL DIABETES INSPIDUS 727

chronic and leaked to the sphenoid sinus, suggesting

that protection between the paranasal sinus and sellar

turnica is fragile [12]. Furthermore, some cases of

MFS with intra- or para-sellar involvement are accom-

panied by paranasal sinusitis [10, 11, 13]. Although it

is not clear whether involvement of the paranasal sinus

is one of the presentations of systemic disease or direct

invasion from the sellar lesion, it is important to search

for the complication of paranasal sinusitis in a suspect-

ed case with inflammatory pituitary disorder.

Chronic periaortitis includes idiopathic retroperito-

neal fibrosis, which is characterized by proliferation of

periaortic fibrous tissue with subsequent ureteral com-

pression, leading to hydronephrosis. Autoimmunity to

oxidized low-density lipoprotein and ceroid has been

reported to be involved in this condition [14–15]. Re-

cently, it has been reported that IgG4 might have a

pathological role in idiopathic retroperitoneal fibrosis

[16]. Because the efficiency of steroid therapy has

been established for this condition, early diagnosis and

treatment is essential to avoid fetal conditions such as

acute renal failure or pericardial fibrosis. It has been

reported that FDG-PET is useful to judge the exten-

sion of chronic periaortitis [17] or IgG4-related MFS

[5]. Thus, FDG-PET may become useful tool to detect

extra-pituitary lesions suspected of LAH or LIN.

Although it has been reported that an autoimmune

mechanism against anhydrase 2 or lactoferrin may be

involved in autoimmune pancreatitis [18], antigens in-

volved in IgG4-related MFS have not been identified.

Further studies are needed to elucidate the autoim-

mune mechanism of IgG4-related sclerosing disease.

In summary, we have reported the first case in

which the cause of CDI was IgG4-related MFS. IgG4

related sclerosing disease should be included in the

differential diagnosis of thickening of the pituitary

stalk with CDI and the search for extra-pituitary in-

volvement is essential for appropriate management.

Reference

1. Kamisawa T, Okamoto A (2006) Autoimmune pancre-

atitis: proposal of IgG4-related sclerosing disease. J

Gastroenterol 41: 613–625.

2. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N,

Akamatsu T, Fukushima M, Nikaido T, Nakayama K,

Usuda N, Kiyosawa K (2001) High serum IgG4

concentrations in patients with sclerosing pancreatitis.

N England J Med 344: 732–738.

3. Kamisawa T, Funata N, Hayashi Y, Tsuruta K,

Okamoto A, Amemiya K, Egawa N, Nakajima H

(2003) Close relationship between autoimmune pancre-

atitis and multifocal fibrosclerosis. Gut 52: 683–687.

4. Kamisawa T, Okamoto A, Funata N (2005) Clinico-

pathological feature of autoimmune pancreatitis in rela-

tion to elevation of serum IgG4. Pancreas 31: 28–31.

5. Tanabe T, Thusima K, Yasuo M, Urushihata K,

Hsnaoka M, Koizumi T, Fujimoto K, Kubo K, Uehara

T, Shigematsu S, Hamano H, Kawa S (2006) IgG4-

associated multifocal systemic fibrosis complicating

sclerosing sialadenitis, hypophysitis, and retoroperito-

neal fibrosis, but lacking pancreatic involvement.

Intern Med 45: 1243–1247.

6. Wong S, Lam WY, Wong WK, Lee KC (2007)

Hypophysitis presented as inflammatory pseudotumor

in immunoglobulin IgG4-related systemic disease. Hum

Pathol 38: 1720–1723.

7. Yamamoto M, Takahashi H, Ohara M, Suzuki C,

Naishiro Y, Yamamoto H, Shinomura Y, Imai K

(2006) A case of Mikulicz’s disease (IgG4-related

plasmacytic disease) complicated by autoimmune

hypophysitis. Scand J Rheumatol 35: 410–411.

8. Imura H, Nakao K, Shimatsu A, Ogawa Y, Sando T,

Fujisawa I, Yamabe H (1993) Lymphocytic infundibu-

loneurohypophysitis as a cause of central diabetes

insipidus. N Engl J Med 329: 683–689.

9. Kojima H, Nojima T (1989) Diabetes insipidus caused

by lymphocytic infundibulohypophysitis. Arch Pathol

Lab Med 113: 1399–1401.

10. Gartman JJ, Jr., Powers SK, Fortune M (1989)

Pseudotumor of the sellar and parasellar areas. Neuro-

surgery 24: 896–901.

11. Kishimoto M, Okimura Y, Kimura K, Mizuno I, Iguchi

G, Fumoto M, Takahashi Y, Kanda F, Kaji, H, Abe H,

Hanioka K, Chihara, K (2000) Multifocal fibrosclerosis

as a possible cause of panhypopituitarism with central

diabetes insipidus. Endcr J 47: 335–342.

12. Amagasa M, Yuda F, Kojima H, Noshita N, Sato S

(2001) Natural course of lymphocytic infundibulo-

neurohypophysitis. Clin Neuropathol 20: 229–232.

13. Noble SC, Chander WF, Lloyd RV (1886) Intracranial

extension of orbital pseudotumor; A case report.

Neurosurgery 18: 798–801

14. Parums DV, Brown DL, Mitchinson MJ (1990) Serum

antibodies to oxidized low-density lipoprotein and

ceroid in chronic periaortits. Arch Pathol Lab Med

114: 383–387.

15. Parums DV, Chadwick DR, Mitchinson MJ (1986)

The location of immunoglobulin in chronic periaortitis.

ISAKA et al.728

Atherosclerosis 61: 117–123.

16. Hamano H, Kawa S, Ochi Y, Unno H, Shiba N, Wajiki

M, Nakazawa K, Shimojo H, Kiyosawa K (2002) Hy-

dronephrosis associated with retroperitoneal fibrosis

and sclerosing pancreatitis. Lancet 359: 1403–1404.

17. Salvarani C, Pipitone N, Versari A, Vaglio A, Serafini

D, Bajocchi G, Salvo D, Buzio C, Greco P, Boiardi L

(2005) Positron emission tomography (PET): evalua-

tion of chronic periaortitis. Arthritis Rheum 53: 298–

303.

18. Okazaki K, Uchida K, Ohana M, Nakase H, Uose S,

Inai M,Matsushima Y, Katamura K, Ohmori K, Chiba

T (2000) Autoimmune-related pancreatitis is associated

with autoantibodies and a Th1/Th2-type cellular im-

mune response. Gastroenterology 118: 573–581.