Background

Granulomatosis with polyangiitis (GPA) is a disorder formerly known as Wegener granulomatosis. Its hallmark is necrotizing vasculitis with granulomatous inflammation. It involves primarily small and medium-sized vessels with a predilection for the upper and lower airways. Necrotizing glomerulonephritis is common [1]. The current definition was formed in 2012 by the Chapel Hill Conference for Consensus Criteria [2].

GPA belongs to a group of anti-neutrophil cytoplasmic antibody (ANCA)-positive diseases called ANCA-associated vasculitis, although ANCA testing may be negative in 10–20% of cases [3].

Research led to the identification of different subsets of ANCA-positive diseases. Anti-proteinase 3 activity (PR3-ANCA) is most common in GPA, while patients with microscopic polyangiitis and Churg–Strauss syndrome are most often anti-myeloperoxidase ANCA (MPO-ANCA) positive [4].

GPA occurs in a systemic and a localized form. ENT involvement occurs in up to 90% of individuals. The sinonasal area is most commonly affected [5,6,7]. Otologic involvement is the second most common presentation [8, 9]. Localized forms of GPA with involvement of the ear and/or the upper respiratory tract have been described, especially in younger patients [10]. Dysfunction of the central nervous system is common at some point of the disease; the result can be dysfunction of cranial nerves II, VI, and VII, but also endocrine involvement of the pituitary gland [11,12,13,14]. Severe headache is the most common nonendocrine symptom of hypophysitis. Chiasmal syndrome and ocular paresis may occur due to the increased sellar mass. Isolated DI centralis may occur as an endocrine symptom and is characterized by deficient secretion of arginine vasopressin (AVP), leading to clinical symptoms of polyuria and polydipsia. More frequently, combined hormonal insufficiency of the anterior and posterior pituitary occurs. Hypogonadotropic hypogonadism, secondary hypothyroidism, and potentially life-threatening secondary adrenal insufficiency are the most frequent endocrine disorders of the anterior pituitary, at least in patients with primary hypophysitis, in contrast to the finding of vulnerable gonadal and growth hormone axis and more robust adrenal and thyroid axes in patients with pituitary adenoma [15]. However, data on hypophyseal function of patients with secondary hypophysitis due to GPA are scarce.

We present the case of a patient with localized, severe granulomatosis with polyangiitis with otitis media, facial nerve palsy, and pituitary dysfunction resulting in DI.

This case is presented according to the CARE guidelines [16].

Additionally, a comprehensive systematic review of existing literature was performed to examine how often and to what extent hypophyseal dysfunction and ENT involvement occur in patients with GPA.

Case presentation

The patient is a white German male of 29 years of age who presented with otalgia and serous otorrhea (Figs. 1, 2) to the otolaryngology resident on call in the ER of the Charité University Hospital in Berlin in November 2018. The patient reported having had these symptoms for 1 month. He had visited an otolaryngology clinic in October 2018 with facial nerve palsy with House–Brackmann score (HB) < III. At the clinic, treatment was started with i.v. antibiotics and prednisolone as well as tympanocentesis with insertion of T-tubes. Audiometric analysis revealed combined sensorineural and conductive hearing loss on the right side and conductive hearing loss on the left side (Fig. 3). A computed tomography (CT) scan report on his temporal bone described fluid retention on the mastoid on both sides, possibly with osteolysis. Routine laboratory analysis including human immunodeficiency virus and hepatitis showed slightly elevated C-reactive protein (34.9 mg/l) but no further anomalies. On microbiologic testing, the middle ear fluid revealed biological flora without detection of pathogens.

Fig. 1
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Left ear of the patient 1 day after presentation to our clinic with visible serous otorrhea after insertion of Titan tubes

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Fig. 2
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Right ear of the patient 1 day after presentation to our clinic with visible serous otorrhea after insertion of Titan tubes

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Fig. 3
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Audiometric analysis on 26/11/2018, showing mixed hearing loss on the right side with Fletcher index of 80 dB and conductive hearing loss on the left side with Fletcher index of 40 dB

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Facial nerve function normalized and otorrhea decreased after receiving treatment. The patient was discharged after 7 days with middle ear tubes in situ.

Upon presentation to the ER, facial nerve function was still abnormal with HB score of II, and extensive serous otorrhea persisted. The middle ear ventilation tubes were in situ. The patient also reported increased fluid intake of 9 L per day and weight gain of 12 kg in 7 weeks.

Laboratory analysis showed positive c-ANCA at 87.0 U/ml with increased anti-PR3 activity in combination testing. Anti-MPO activity was negative.

On the basis of this testing, a diagnosis of granulomatosis with polyangiitis was established.

A magnetic resonance imaging (MRI) scan of the brain showed slight widening of the pituitaries infundibulum and unclear inhomogeneity between the anterior and posterior pituitary (Figs. 4, 5).

Fig. 4
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Coronal imaging of the hypophysis on a 3-T T1-weighted MRI image

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Fig. 5
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Saggital imaging of the hypophysis on a 3-T T1-weighted MRI image

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Clinical and laboratory evaluation of the anterior pituitary function did not indicate insufficiency of the somatotropic, gonadotropic, thyrotropic, or corticotropic axis. In addition, serum prolactin was within the reference range.

Plasma sodium concentration was 144 mmol/l with plasma osmolality of 300 mosm/kg. In a water deprivation test, urine osmolality increased insufficiently from 131 to 418 mosm/kg. Measurement of hypertonic saline-stimulated plasma copeptin (2.63 pmol/l) confirmed the diagnosis of DI.

Treatment for GPA was successfully started with 1 g rituximab i.v., and ANCA values decreased to 22.2 U/ml at 4 months after discharge and finally to 13.4 U/ml in October 2019 (Additional file 1).

Discussion

GPA is a variable disease that may present with a complex set of symptoms [11,12,13,14]. The patient in our case presented with otalgia, otorhea, facial nerve dysfunction, hearing loss, and polydipsia. Upon presentation to our department, the posterior pituitary gland function was already affected. While the resulting increase in fluid intake was not seen as a burden by the patient, medical history showed that symptoms of DI had existed before otologic involvement. Referral to specialists in endocrinology and rheumatology was sought after the diagnosis of GPA.

A comprehensive systematic PubMed search was performed using the search term ‘Wegener granulomatosis AND pituitary dysfunction OR granulomatosis with polyangiitis AND pituitary dysfunction OR Wegener granulomatosis AND diabetes insipidus OR granulomatosis with polyangiitis AND diabetes insipidus’. The article references were scanned for additional literature, resulting in a total of 65 articles. All case reports with confirmed diagnosis of GPA in addition to diabetes insipidus were included. Articles published in foreign language (other than English or German) and for which no full text was available were excluded. In total, 39 articles were selected for analysis after applying inclusion and exclusion criteria.

The 39 selected articles described 61 different cases for analysis (Table 1). ENT involvement in patients with GPA was very common, with 43 patients reported to have any ENT area affected (72%). Sinonasal disease was very common, with 21 patients affected (35%). Otologic complaints were less common, being reported in nine patients (15%). Two of the selected case series, representing a total of 17 patients, did not specify the involved subarea. This may result in underestimation of the total percentage of patients affected per subarea.

Table 1 Published articles with patients matching our inclusion criteria, with publication date and site of ENT involvement
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Of the 61 cases, 36 (59%) experienced at least one symptom of anterior pituitary dysfunction. Hyperprolactemia was the most common hormonal dysbalance (n = 20, 33%), while hypothyroidism (n = 15, 25%) and hypogonadism (n = 14, 23%) ranked second and third. Panhypopituitarism was relatively uncommon and occurred in eight (13%) patients.

Most of the patients examined in this study had an established diagnosis of GPA before developing symptoms suggestive of DI (n = 33, 54%). The majority of patients (n = 35, 57%) developed ENT symptoms suggestive of GPA earlier than symptoms suggestive of DI. In 11 cases of this subgroup (31%), the ENT symptoms occurred days to months before DI symptoms. In 18 cases (51%), ENT symptoms developed years prior to diagnosis. Six cases (17%) did not include a timeframe for the occurrence of the symptoms.

DI was diagnosed before the diagnosis of GPA in 17 cases (28%). In this subgroup, the symptoms of DI developed days to month before diagnosis of GPA in three (18%) cases and years before diagnosis of GPA in another three (18%) cases. The other cases did not offer a timeframe (Table 2).

Table 2 Evaluation of pituitary function tests and latency of occurrence of symptoms per case
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Among the reviewed articles, only one report matched our patient’s complaints of therapy-resistant otitis media, facial nerve paralysis, sensorineural hearing loss, and DI [42]. Although GPA can occur as a very limited localized disease, e.g., as antibiotic-resistant otitis media with or without mastoiditis [51,52,53], we want to highlight that GPA can also occur with a combination of involved localized areas, as described herein. The current case, as well as the cases reviewed, highlight the complexity of this disease.

This review supports previous research and suggests that more than 70% of patients with GPA and DI have symptoms in the field of otolaryngology [6]. We found that ENT-related symptoms might occur more often before symptoms of DI. These results might explain why early involvement of ENT specialists was found to result in substantially increased survival [54].

In line with our findings, in many of the cases reviewed, patients experienced ENT symptoms at least 1 year before symptoms of DI occurred. Sinonasal disease is the most common manifestation in the head and neck area, but other symptoms occur frequently. The otolaryngologist has to manage acute and chronic symptoms, so knowledge about the different forms of the disease is fundamental.

The specific enlargement of the pituitary infundibulum on MRI is the result of involvement of the stalk and the hypothalamus in patients with DI [55, 56]. These images allow for distinction from other pathologies affecting the gland. While panhypopituitarism occurred in only a few patients, our study suggests that anterior pituitary dysfunction is slightly more common than anticipated before [27, 29]. Even with these numbers, it may be possible that gland dysfunction is underdiagnosed due to the blunted response when treated with corticosteroids, which most patients with GPA receive during the course of their disease. Hyperprolactemia, hypothyroidism, and hypogonadism are the most common abnormalities in our study. Care by the attending physician in regard to possible dysfunction of pituitary gland function is important, especially because several patients developed DI years after diagnosis of GPA. If polydipsia and polyuria are present, tests for anterior pituitary gland function must be performed.

Conclusion

This case demonstrates a relatively rare occurrence of DI in a patient with GPA and demonstrates the difficulty of diagnosing the disease. All healthcare professionals involved in the diagnostic process of the disease must have knowledge about its possible variable course. This is especially important since delayed diagnosis can lead to significant morbidity and possibly mortality, while appropriate treatment options exist [57].