Abstract
Summary
IgG4-related disease is a multiorgan disorder in which nodules and hypertrophic lesions are observed simultaneously, or separately, in areas including the pancreas, liver, lungs, salivary glands, thyroid glands, and pituitary glands. IgG4-related hypophysis is one of several IgG4-related diseases and is characterized by pituitary gland and pituitary stalk thickening, various degrees of hypopituitarism, and increased serum IgG4 levels. Steroid therapy is effective for patients with IgG4-related hypophysis, but the reported effectiveness of steroid therapy for restoring pituitary function differs between studies. Following an episode of autoimmune pancreatitis 10 years prior, enlargement of the pituitary gland and stalk along with panhypopituitarism and polyuria developed in a 73-year-old male. A high serum IgG4 level and biopsy of the submandibular gland showing infiltration of IgG4-positive plasma cells led to a clinical diagnosis of IgG4-related hypophysitis. Prednisolone treatment reduced the swelling of the pituitary gland and stalk and improved anterior pituitary function. Although arginine vasopressin secretion remained insufficient, polyuria was relieved and kept in remission even after prednisolone treatment was completed. This is the first reported case in which prednisolone was able to maintain both normal anterior pituitary function and remission of polyuria caused by IgG4-related hypophysitis. IgG4-related hypophysitis has previously been associated with a relapse of symptoms during treatment. However, the patient reported in this case study remained in remission for over 3 months after completion of steroid treatment and should be monitored closely for changes in pituitary function.
Learning points
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Steroid therapy is the first-line therapy for pituitary dysfunction and pituitary stalk swelling in IgG4-related hypophysitis.
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In this case, although posterior pituitary function remained insufficient, polyuria was relieved and kept in remission for over 3 months even after prednisolone treatment was completed.
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IgG4-related hypophysitis has been associated with the relapse of symptoms during steroid tapering, and changes in pituitary function and symptoms should be monitored closely.
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When we encounter cases of adrenal insufficiency and polyuria during observation of autoimmune pancreatitis or other IgG4-related disease, we should consider the possibility of IgG4-related hypophysitis in mind.
Background
IgG4-related disease is a multiorgan disorder in which nodules and hypertrophic lesions are observed either simultaneously or separately. These nodules and lesions develop as a result of significant infiltration and fibrosis caused by lymphocytes and IgG4-positive plasma cells (1). The affected organs are systemic, with the pancreas, salivary glands, kidneys, lacrimal glands, and aorta being the most commonly affected tissues. In 235 reported cases of IgG4-related diseases, enlargement of the pituitary was rare, with an incidence of 3% or less (2). In a report of 50 Japanese patients with IgG4-related hypophysitis (IgG4-RH), 40 patients exhibited anterior pituitary hypofunction while 35 patients were observed with central diabetes insipidus, which is a measure of posterior pituitary hypofunction. In certain cases, recovery of some anterior pituitary function was observed. In most cases, diabetes insipidus was not improved. We treated a case where IgG4-associated pituitary inflammation developed during follow-up for autoimmune pancreatitis. The patient received steroid treatment, which was able to maintain remission of polyuria and pituitary dysfunction caused by IgG4-related hypophysitis.
Case presentation
A 73-year-old male individual visited our hospital with rapidly worsening fatigue and polyuria. At the age of 62, the patient had developed acute pancreatitis with abdominal pain and was diagnosed with autoimmune pancreatitis due to elevated IgG4 levels. The patient did not require steroid therapy for pancreatitis, and the symptoms resolved with only infusion therapy and antibiotics. Therefore, biopsy was not needed. After discharge, the patient was followed up regularly at the Department of Gastroenterology without medication, and his IgG4 levels remained between 1000 and 1400 mg/dL.
Edema and polyuria were observed 1 week prior to his visit to our hospital. After admission, blood tests revealed hyponatremia (serum sodium level: 128 mEq/L) and low levels of cortisol and thyroid-stimulating hormone (TSH). Due to these findings, we chose to examine his pituitary function.
At the time of hospitalization, the patient was 160 cm tall, weighed 54.2 kg, and his consciousness was clear. The patient’s body temperature was 37.5°C, his blood pressure was 140/98 mm Hg, and his heart rate was 88 bpm. Edema of the face and legs was observed. No thyroid enlargement (goiter) or tenderness was observed and no significant abnormalities were found in the patient’s chest and abdomen. Further, he had also complained of xerostomia and ocular dryness.
Investigations
Laboratory tests revealed hyponatremia (128 mEq/L) and low urine osmolality (242 mOsm/kg). The patient’s daily urine volume was approximately 3.1 L/day. His white blood cell count was 104 × 102/μL, and the proportion of eosinophils was 30.5%. Basal endocrine laboratory tests showed high levels of prolactin whilst adrenocorticotrophic hormone (ACTH) and growth hormone levels were within the reference range. Low levels of the other pituitary hormones were found (Table 1). Computed tomography showed no change in pancreatic atrophy compared to 4 months prior, but enlarged lymph nodes were observed in the bilateral neck, upper clavicle, mediastinum, and pulmonary gate. In addition, soft shadows were observed around the aorta, superior mesenteric artery, and retroperitoneum. Magnetic resonance imaging (MRI) showed swelling of the pituitary gland, pituitary stalk, and the right submandibular gland (Fig. 1). A lack of T1 signal hyperintensity in the posterior pituitary gland was observed. Bitemporal hemianopia was observed in the visual field test. The patient’s serum IgG4 level was high, at 2060 mg/dL. These results met the diagnostic criteria for IgG4-RH.
Clinical characteristics of the study patients.
Parameter | Value |
---|---|
WBC, /μL | 10400 |
Eo, % | 30.5 |
RBC, ×104/μL | 402 |
Hb, g/dL | 12.3 |
Platelet, ×104/μL | 21.4 |
AST, U/L | 30 |
ALT, U/L | 8 |
AMY, U/L | 25 |
TP, g/dL | 9.5 |
Alb, g/dL | 3.4 |
CK, U/L | 47 |
Na, mEq/L | 128 |
K, mEq/L | 4.0 |
Cl, mEq/L | 93 |
BUN, mg/dL | 7.0 |
Cre, mg/dL | 0.94 |
CRP, mg/dL | 2.3 |
IgG, mg/dL | 4014 |
IgG4, mg/dL | 2060 |
IgE, IU/mL | 1300 |
TSH, μIU/mL | 0.44 |
FT4, ng/dL | 0.60 |
ACTH, pg/mL | 9.3 |
Cortisol, μg/dL | 1.3 |
PRL, ng/mL | 18.88 |
GH, ng/mL | 0.17 |
IGF-1, ng/mL | 12 |
AVP, pg/mL | 0.8 |
Urine osmolality, mOsm/kg | 242 |
Serum osmolality, mOsm/kg | 246 |
Urine Na, mEq/L | 113 |
Urine K, mEq/L | 82 |
Urine Cre, mg/dL | 33.05 |
Image studies of the case. Magnetic resonance images show how the enlarged pituitary and pituitary stalk (arrows) have reduced in size from (A) before treatment to (B) after treatment. Computed tomography shows the enlarged cervical lymph nodes (arrows) (C) before treatment and (D) after treatment, when they have also reduced in size. Computed tomography shows the improvement in retroperitoneal fibrosis (arrows) from (E) before treatment to (F) after treatment.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0007
Pituitary provocative tests were performed to assess pituitary function (Fig. 2). As the pituitary gland was enlarged and the patient was experiencing severe malaise, insulin tolerance and thyrotropin-releasing hormone (TRH) tests were not performed. In contrast, corticotropin-releasing hormone (CRH) and luteinizing hormone-releasing hormone tests were performed. The basal ACTH level (2.5 pg/mL) was low and the patient’s peak ACTH level was 92.0 pg/mL, more than double the basal level. His peak cortisol level was 5.5 μg/dL. Both basal and peak luteinizing hormone (LH) levels were below the test’s sensitivity levels. The basal follicle-stimulating hormone (FSH) level was low, at 0.46 mIU/mL, with a peak level of 1.21 mIU/mL. A rapid ACTH test was performed and showed basal and peak cortisol levels of 0.7 μg/dL and 7.5 μg/dL, respectively. The cortisol response decreased in the rapid ACTH loading test. In the CRH loading test, ACTH responded normally, but the peak cortisol level was low at 5.5 μg/dL compared to the increase in ACTH. It was unclear whether primary or hypothalamic hypoadrenocorticism was present because an insulin tolerance test was not performed. A growth hormone-releasing peptide-2 test was performed, revealing a peak growth hormone level of 1.31 ng/mL. As a result of these observations, severe adult growth hormone deficiency was diagnosed. The patient showed insufficient secretion of arginine vasopressin (AVP), with a corresponding increase in serum sodium levels after hypertonic saline infusion. After administration of vasopressin, urinary osmolality increased to more than 300 mOsm/kg. Thus, we diagnosed central diabetes insipidus.
Comparison of pituitary provocative tests on admission (before treatment; days 6–15) and after treatment (days 219–229). CRH test: ACTH secretion was normal on admission and after treatment (A), but cortisol secretion on the admission was low, which improved after treatment (B). LHRH test: LH and FSH secretion was low on admission and improved after treatment, but peak LH level remained below normal (C, D). A TRH test was performed only after treatment: TSH secretion was found to be normal (E). GHRP2 test: GH secretion was low on admission and after treatment. Compared to levels on admission, GH secretion improved significantly (F). Hypersaline infusion test: AVP secretion did not increase despite serum sodium levels increasing after hypertonic saline infusion on admission and after treatment (G). ACTH, adrenocorticotrophic hormone; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRP2, growth hormone-releasing peptide 2; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0007
Due to the difficulty of performing a pituitary biopsy, a biopsy of the right mandibular gland was not performed until the patient’s 12th day in hospital. Storiform fibrosis and lymphocytic phlebitis were not observed, but the number of IgG4-positive plasma cells far exceeded the 100 per high-pass filter, and the IgG4/IgG-positive plasma cell ratio was over 80% (Fig. 3). Based on the relevant diagnostic criteria (3), we diagnosed IgG4-RH.
Histological section of the right mandibular gland. Hematoxylin and eosin (A) and IgG4 immunohistochemical staining (B). Storiform fibrosis and lymphocytic phlebitis were not observed, but the number of IgG4-positive plasma cells was far in excess of the 100 per high-pass filter (A). The IgG4/IgG-positive plasma cell ratio was over 80% (B).
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0007
Treatment
The prednisolone dosage for initial treatment of IgG4-related diseases is typically 30–40 mg/day in Japan (3). In most cases, the dosage is decreased by 5 mg/day every 2 weeks, and the maintenance dosage is kept at 5–10 mg/day for 3–6 months. For our patient, we administered an initial dosage of 30 mg/day and decreased it by 5 mg/day every 2 weeks to 20 mg/day. Thereafter, the dosage decreasing interval was extended from 2 weeks to 1 month, without any maintenance therapy. Prednisolone administration was concluded 204 days after hospitalization, without any associated increase in IgG4 levels. We prescribed desmopressin for the diabetes insipidus and levothyroxine for the pituitary hypothyroidism. Administration of these two therapies was concluded 186 and 204 days after hospitalization, respectively (Fig. 4).
Clinical course of the patient. Initial prednisolone dosage for treatment was 30 mg/day. This was decreased by 5 mg/day every 2 weeks to 20 mg/day. The dosage decreasing interval was then extended from 2 weeks to 1 month. PSL administration was concluded 204 days after hospitalization. HYD, hydrocortisone; PSL, prednisolone.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0007
Outcome and follow-up
After the start of steroid therapy, the patient’s malaise, polyuria, edematous, xerostomia, and ocular dryness rapidly improved. Moreover, chest and abdomen computed tomography showed no enlarged lymph nodes or retroperitoneal fibrosis 218 days after hospitalization. An MRI of the pituitary showed no enlargement of the gland. However, the lack of a T1 signal hyperintensity in the posterior lobe of the pituitary gland was still observed (Fig. 1). Visual field, thyroidal and adrenocortical function, and IgG4 levels improved to within the reference range. However, gonadal function and growth hormone secretion were improved but remained outside the reference range (Table 2).
Basal endocrine laboratory tests after steroid therapy.
Parameter | Reference range | Before treatment (day 1) | After treatment (day 218) |
---|---|---|---|
ACTH, pg/mL | 7.2-63.3 | 9.3 | 30.1 |
Cortisol, μg/dL | 7.07-19.6 | 1.3 | 10.9 |
TSH, μIU/mL | 0.5-5.0 | 0.44 | 2.54 |
FT4, ng/dL | 0.9-1.7 | 0.6 | 1.11 |
PRL, ng/mL | 3.58-12.7 | 18.88 | 30.04 |
GH, mg/mL | 0-2.47 | 0.17 | 0.29 |
IGF-1, ng/mL | 54-190 | 12 | 55 |
AVP, pg/mL | 0-2.8 | 0.8 | <0.4 |
Pituitary provocative tests were performed to assess pituitary function 7 months after the start of treatment (Fig. 2). A TRH test was performed. The basal TSH level was within the reference range and the peak TSH level was more than 6 μIU/mL, which was within normal levels. A CRH test revealed that the basal ACTH level was within the reference range, and that the peak ACTH level was more than double the basal level. The peak cortisol level was more than 18 μg/dL, which is considered a normal reaction. After performing a luteinizing hormone-releasing hormone test, the peak FSH level was more than 1.5 times the level on admittance to the hospital, while the basal LH level was low, and peak LH level was less than five times the level on admittance. Pituitary hypogonadism was observed, but the secretion of both LH and FSH was improved. Peak growth hormone level was 5.56 ng/mL. Severe adult growth hormone deficiency was still present, but secretion was significantly improved compared to the pre-treatment peak level of 1.31 ng/mL. After desmopressin administration was concluded, daily urine volume was approximately 1.3 L/day, and urine osmolality and serum sodium level were normal, at 432 mOsm/kg and 143 mEq/L, respectively. However, AVP secretion was insufficient, corresponding to an increase in serum sodium levels after hypertonic saline infusion. A pituitary MRI continued to show a lack of high-intensity signal of the neurohypophysis on T1 weighted images (Fig. 1).
After the discontinuation of steroids, diabetes insipidus remained in remission for over 3 months, but the IgG4 level gradually increased (day 218; 46.9, day 254; 81.8, day 309; 133.0 mg/dL). At 137 days after termination (day 352), IgG4 levels had increased to 146 mg/dL, and prednisolone was restarted at 30 mg/day because of the increasing urine volume. Since then, the patient’s urine volume has decreased and IgG4 levels were improved, remaining in the range of 30–40 mg/dL.
Discussion
IgG4-RH is one member of the IgG4-related diseases and is characterized by a combination of dense infiltration of IgG4-positive plasma cells into the pituitary gland, thickening of the pituitary stalk, diffuse infiltration of lymphocytes into the pituitary, fibrosis with a storiform pattern, and increased serum IgG4 levels (4). IgG4-RH occurs in less than 3% of patients with IgG4-related diseases (5), but in recent years, its prevalence has been suggested to be underestimated (6). In addition, the involvement of various organs throughout the clinical course of IgG4-RH has been noted, with retroperitoneal fibrosis being the most common (38%), followed by interstitial pneumonia (28%), Mikulicz’s disease and autoimmune pancreatitis (24%), and lymph node swelling (18%). A small proportion of patients (14%) exhibit only hypophysitis (6). A report of 13 cases of IgG4-RH concomitant with autoimmune pancreatitis showed that the median duration from the onset of autoimmune pancreatitis to the onset of IgG4-RH was 2.5 years, and three patients were diagnosed with IgG4-RH more than 10 years after the diagnosis of autoimmune pancreatitis (6). IgG4-RH is reported to be highly responsive to steroid therapy. Glucocorticoids are the first-line treatment for symptoms associated with pituitary enlargement, and 30–40 mg/day of prednisolone is recommended as the initial dosage (3). Steroid therapy has resulted in reduced pituitary mass and pituitary stalk enlargement in many cases (7) and one study demonstrated a significant reduction in pituitary gland and pituitary stalk enlargement on posttreatment MRI scans in 69 of 71 patients treated with steroids (8). However, the effectiveness of steroid therapy for pituitary function varies between reports. Some studies have reported that steroid therapy resulted in improved anterior pituitary function (5, 7), but the improvement in posterior pituitary function was poor (5). Immunosuppressive drugs such as rituximab have been used in cases where steroids were ineffective or caused side effects (5). Tapering of steroids or immunosuppressive drugs for treatment of IgG4-RH requires careful consideration because of the possibility of reoccurrence of the disease or reenlargement of the pituitary (9).
Thus, while pituitary swelling and anterior pituitary function can be improved by steroid therapy, diabetes insipidus – a posterior pituitary function – is rarely improved. Among 115 cases with IgG-RH who developed diabetes insipidus, only five improved after treatment: three were treated with rituximab, one with cyclophosphamide, and one with postpartum IgG4-RH (5). No similar cases to that of our patient have been reported in the literature, where diabetes insipidus resolved without derivative desmopressin (DDAVP) and remained in remission for over 3 months after completion of single-agent steroid therapy.
The mechanism of remission of posterior pituitary dysfunction due to hypophysitis is unclear. It has been suggested that any reversible change resembling lymphocytic hypophysitis or very weak damage to the pituitary stalk might be associated with self-limiting diabetes insipidus and transient thickening of the pituitary stalk or that increased renal sensitivity to vasopressin might be associated with remission of diabetes insipidus (10).
Our patient was referred to our department with a chief complaint of rapidly worsening fatigue and polyuria during the observation course of autoimmune pancreatitis. We diagnosed IgG4-RH based on clinical and endocrine test findings, IgG4 levels, and the results of a submandibular gland biopsy. After steroid therapy, IgG4 levels gradually decreased; pituitary enlargement, polyuria, and urinary osmolality improved; and the steroid dosage was tapered off. No recurrence of symptoms happened during the course of the treatment. We reevaluated pituitary function and found that anterior, but not posterior, function improved after completion of the steroid therapy. However, even though ADH secretion remained decreased, the symptoms of diabetes insipidus disappeared without DDAVP.
IgG4-related hypophysitis frequently presents as panhypophysitis, destroying pituitary hormones in a different order from that of lymphocytic hypophysitis (8). The differing patterns of impaired hormones could be attributed to different locations of inflammation in the pituitary grand. Our patient presented with panhypophysitis; therefore, there was impairment of both anterior and posterior pituitary hormones. It is possible that some changes to the pituitary stalk or infundibulum may have partially affected the posterior pituitary hormones in this case.
Several case reports showed the decrease of IgG4 levels during the course of steroid treatment reflected the improvement of the symptoms of IgG4-RH, including DI, and this case also showed similar course. Thus, we think IgG4 level could be the useful clinical indicator when we monitor symptomatic improvement of DI, and also determine whether steroid administration should be stopped or resumed.
This is the first case in which prednisolone was able to maintain remission of both anterior pituitary function and polyuria caused by IgG4-related hypophysitis. In previous reports, IgG4-related hypophysitis has been associated with relapse of symptoms during steroid tapering. By contrast, this case remained in remission for over 3 months after the completion of steroid treatment and should therefore continue to be monitored closely for changes in pituitary function and recurrence of symptoms.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the case study reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written consent was obtained from the patient for publication of this case report.
Author contribution statement
MK and MF drafted the manuscript. YO reviewed the manuscript. SI and HI supervised this work. All authors provided care to the patient and contributed to the final version of the manuscript.
Acknowledgements
We thank Dr Tetsuhiro Kitamura for his medical advice. We would like to thank Editage (www.editage.com) for English language editing.
References
- 1↑
Stone JH, Zen Y, & Deshpande V. IgG4-related disease. New England Journal of Medicine 2012 366 539–551. (https://doi.org/10.1056/NEJMra1104650)
- 2↑
Inoue D, Yoshida K, Yoneda N, Ozaki K, Matsubara T, Nagai K, Okumura K, Toshima F, Toyama J, Minami T, et al.IgG4-related disease: dataset of 235 consecutive patients. Medicine 2015 94 e680. (https://doi.org/10.1097/MD.0000000000000680)
- 3↑
Takagi H, Iwama S, Sugimura Y, Takahashi Y, Oki Y, Akamizu T, & Arima H. Diagnosis and treatment of autoimmune and IgG4-related hypophysitis: clinical guidelines of the Japan Endocrine Society. Endocrine Journal 2020 67 373–378. (https://doi.org/10.1507/endocrj.EJ19-0569)
- 4↑
Takahashi Y. Mechanisms in endocrinology: autoimmune hypopituitarism: novel mechanistic insights. European Journal of Endocrinology 2020 182 R59–R66. (https://doi.org/10.1530/EJE-19-1051)
- 5↑
Amirbaigloo A, Esfahanian F, Mouodi M, Rakhshani N, & Zeinalizadeh M. IgG4-related hypophysitis. Endocrine 2021 73 270–291. (https://doi.org/10.1007/s12020-021-02714-0)
- 6↑
Kanie K, Bando H, Iguchi G, Shiomi H, Masuda A, Fukuoka H, Nishizawa H, Fujita Y, Sakai A, Kobayashi T, et al.IgG4-related hypophysitis in patients with autoimmune pancreatitis. Pituitary 2019 22 54–61. (https://doi.org/10.1007/s11102-018-00930-y)
- 7↑
Shimatsu A, Oki Y, Fujisawa I, & Sano T. Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocrine Journal 2009 56 1033–1041. (https://doi.org/10.1507/endocrj.k09e-277)
- 8↑
Shikuma J, Kan K, Ito R, Hara K, Sakai H, Miwa T, Kanazawa A, & Odawara M. Critical review of IgG4-related hypophysitis. Pituitary 2017 20 282–291. (https://doi.org/10.1007/s11102-016-0773-7)
- 9↑
Nishi N, Takeshima K, Morita S, Iwakura H, Nishi M, & Matsuoka T. Deterioration of pituitary function without relapse after steroid therapy for IgG4-related hypophysitis. Endocrinology, Diabetes and Metabolism Case Reports 2021 21–0029. (https://doi.org/10.1530/EDM-21-0029)
- 10↑
Takahashi M, Otsuka F, Miyoshi T, Ogura T, & Makino H. An elderly patient with transient diabetes insipidus associated with lymphocytic infundibulo-neurohypophysitis. Endocrine Journal 1999 46 741–746. (https://doi.org/10.1507/endocrj.46.741)