Background

Arginine vasopressin deficiency (AVP-D), formerly known as central diabetes insipidus, is known to occur due to various causes such as malignant tumors, surgery, and inflammatory conditions. The correct diagnosis of the underlying disease in each case is important for deciding the treatment strategy [1]. Lymphocytic infundibulo-neurohypophysitis (LINH) is one of autoimmune disease and induces AVP-D. In recent years, anti-rabphilin-3A antibodies, which are autoantibodies targeting rabphilin-3A, a specific GTP-Rab3A binding protein present in the secretory granules of the posterior pituitary, have been identified as highly sensitive markers for LINH [2].

The onset of various endocrine disorders such as type 1 diabetes mellitus, subacute thyroiditis, Graves’ disease, and anterior pituitary inflammation that are considered to be related to autoimmunity have been reported following coronavirus disease 2019 (COVID-19) infection [3]. Additionally, the onset of such diseases has been documented following SARS-CoV-2 vaccination [4]. While some cases of developing pituitary inflammation and the consequent AVP-D following COVID-19 infection [5,6,7,8,9,10,11] or SARS-CoV-2 vaccination [12,13,14,15,16,17,18] were reported, the cases with proved detailed involvement of autoimmunity as the cause of these diseases were rare.

Here we report a case of a 75-year-old woman who developed AVP-D with positive anti-rabphilin-3A antibodies. The onset occurred 9 weeks after contracting COVID-19 infection and 5 weeks after receiving SARS-CoV-2 vaccination.

Case presentation

A 75-year-old woman with no apparent medical history or family history contracted COVID-19 infection on December 10, 2022, which resolved without the need for hospitalization, and initially, no sequelae were noted. Additionally, she had received four SARS-CoV-2 vaccinations: the first dose on July 10, 2021 (tozinameran; Pfizer-BioNTech, Lot No. FC9880), the second dose on July 31, 2021 (tozinameran; Pfizer-BioNTech, Lot No. EY0583), the third dose on March 10, 2022 (elasomeran; Takeda/Moderna, Lot No. 000048 A), and the fourth dose on August 17, 2022 (tozinameran; Pfizer-BioNTech, Lot No. FR1790). On January 5, 2023, she received her fifth dose of SARS-CoV-2 vaccination (tozinameran/famtozinameran; Pfizer-BioNTech, Lot No. GJ7139). Around February 10, she began experiencing polydipsia and polyuria. Although her primary care physician found no abnormalities on physical examination, she was referred to a post-COVID-19 sequelae outpatient clinic due to suspected psychogenic diseases, where she underwent further examination as an inpatient. During hospitalization, her water intake was approximately 3–4 L per day, and urine output was around 3 L per day, raising suspicion of AVP-D, which led to her admission to our hospital on October 2, 2023. Upon admission, she had a height of 146 cm and a weight of 56.3 kg, with no signs of dryness in the oral cavity. Her 24-hour urine output was 3900 mL/day, resulting in a urine volume per body weight of 69.2 mL/kg, indicating polyuria. Blood tests at admission revealed a serum sodium level of 146 mEq/L, an AVP concentration of 0.6 ng/mL indicating its decreased secretion, and a urine osmolarity of 224 mOsm/L (Table 1). Baseline hypothalamic-pituitary-adrenal axis values upon admission showed ACTH 15.7 pg/mL (reference range 7.2–63.3 pg/mL), cortisol 5.9 µg/dL (reference range 5.1–23.6 µg/dL). Both the three-part loading test (Table 2) and GH releasing peptide-2 (GHRP-2) loading test (Table 3) showed that the anterior pituitary hormone reserve was maintained.

Table 1 Endocrinological blood test results
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Table 2 CRH/TRH/LHRH dynamic tests
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Table 3 GHRP-2 test
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In the hypertonic saline infusion test, the responsiveness of plasma AVP decreased compared to the increase in serum Na levels. Additionally, after 120 min of the hypertonic saline infusion test, 5 units of exogenous vasopressin were administered, resulting in an increase in urinary osmolarity (from 322 to 491 mOsm/kg) and a decrease in urine output (from 5.4 to 3.5 mL/kg/hr) compared to pre-administration levels (Table 4). Subsequent administration of desmopressin (DDAVP) resulted in an increase in urine osmolarity, leading to the diagnosis of AVP-D. Serum levels of human chorionic gonadotropin β-subunit (β-hCG), α-fetoprotein (AFP), angiotensin I-converting enzyme (ACE), and immunoglobulin G4 (IgG4) were within normal ranges, and proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA) was negative (Table 1). MRI conducted for further investigation revealed loss of posterior lobe high signal intensity on T1-weighted images (Fig. 1A, B). Contrast-enhanced MRI demonstrated a thickened pituitary stalk measuring 3.5 mm with strong enhancement (Fig. 1C, D).

Table 4 Hypertonic saline infusion test and vasopressin test
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Fig. 1
figure 1

Pituitary magnetic resonance imaging (MRI) at first visit. (A) Sagittal view of plain MRI. (B) Coronal view of plain MRI. No high signal was observed in the posterior pituitary lobe. (C) Sagittal view of contrast-enhanced MRI. (D) Coronal view of contrast-enhanced MRI. Enlargement of the pituitary stalk (yellow arrowhead) and enhancement are evident. No pituitary tumor was observed

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Based on these findings, lymphocytic infundibulo-neurohypophysitis (LINH) was initially suspected. However, since the thickening of the pituitary stalk persisted even 8 months after symptom onset and it was atypical, we considered to perform a pituitary biopsy for histological confirmation. However, due to the patient’s advanced age and her desire to minimize surgical invasiveness, we opted to measure anti-rabphilin-3A antibodies, which are considered specific to LINH and the presence of serum anti-rabphilin-3A antibody was detected by western blotting (Fig. 2). It supported the diagnosis of LINH.

Fig. 2
figure 2

Measurement of anti-rabphilin-3A antibodies by Western blotting. Detection of anti-rabphilin-3A antibodies by Western blotting. Recombinant full-length human rabphilin-3A expressed in HEK293FT cells (RPH3A) or negative control (-) were probed with serum from the present case (patient) or from a patient who was diagnosed with LINH by biopsy previously (positive control patient). Recombinant full-length human rabphilin-3A expressed in HEK293FT cells was also probed with an anti-V5 antibody as a positive control (Anti-V5 antibody) in the first lane from the left. Arrowheads indicate the presence of anti-rabphilin-3A antibodies. Dashed arrowheads indicate the absence of anti-rabphilin-3A antibodies. A protein band of 76 kDa that appeared in RPH3A but not in that of negative control was considered to be positive for anti-rabphilin-3A antibodies. RPH3A, rabphilin-3A, TFs, transfections of full-length human rabphilin-3A gene

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For the treatment of AVP-D, oral DDAVP 60 µg/day was initiated, resulting in a decrease in urine output, and the patient continues to attend outpatient visits. We considered pharmacological doses of steroid treatment for hypophysitis, but we did not implement steroid therapy due to the absence of clinical symptoms such as headache or visual field disturbances, the limited expected efficacy in treating AVP-D, and concerns regarding the side effects of steroid administration in elderly patients. MRI imaging 12 months after the initial consultation did not detect new lesions persisted with stalk enlargement suggesting a stable course of LINH not likely any malignancies (Fig. 3A, B).

Fig. 3
figure 3

Pituitary MRI at the 12-month follow-up. (A)Sagittal view of contrast-enhanced MRI. (B) Coronal view of contrast-enhanced MRI. Compared with that at 8 months, the enlargement of the pituitary stalk (blue arrowhead) did not significantly change

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Materials and methods

Western blotting was conducted on serum obtained from the patient for detection of anti-rabphilin-3A antibodies, as reported previously [2]. A vector containing the full-length human rabphilin-3A gene was transfected into HEK293FT cells to produce recombinant human rabphilin-3A protein. Expression of recombinant human rabphilin-3A protein was confirmed using an anti-V5 antibody. As a negative control, the same vector without the rabphilin-3A gene was transfected into HEK293FT cells. A protein band presenting a size of 76 kDa, which corresponds to the molecular weight of rabphilin-3A, appeared in the lysate of cells transfected with the rabphilin-3A protein but not in that of control cells, which was considered to be positive for anti-rabphilin-3A antibodies, as reported previously.

Discussion and conclusions

The insights gained from this case indicate that measuring anti-rabphilin-3A antibodies is helpful to diagnosed LINH in cases with AVP-D occurring after COVID-19 infection and/or SARS-CoV-2 vaccination. Furthermore, in our case, pituitary stalk thickening can persist for over 8 months.

Hypophysitis has various etiologies, including lymphocytic, granulomatous, xanthomatous, necrotizing, IgG4-related systemic disease, and chemotherapy agents, apart from pregnancy-related causes. Therefore, the gold standard for the final diagnosis of hypophysitis including LINH is pituitary biopsy, however high patient invasiveness is a major clinical concern [19].

Sheen et al. recommend biannual follow-up pituitary MRI scans for a duration of two years in cases demonstrating pituitary stalk thickening to monitor the progression of the disease [20].

In our case, pituitary stalk thickening persisted even at 8 months after symptom onset, prompting the consideration of a pituitary biopsy for a definitive diagnosis of LINH, also to rule out malignant conditions such as Langerhans cell histiocytosis.　However, the evaluation of anti-rabphilin-3A antibodies targeting antigens specific to the posterior pituitary which are highly sensitive markers for LINH [21] was helpful for avoiding invasive pituitary biopsies.

Previous case reports suggest that both COVID-19 infection and SARS-CoV-2 vaccination could potentially trigger the onset of AVP-D.

There are seven reports of pituitary dysfunction accompanied by AVP-D following SARS-CoV-2 vaccination [12,13,14,15,16,17,18]. The majority of these cases were female, four cases presented only with AVP-D, and the time from vaccination to disease onset varied from 3 days to 8 weeks post-vaccination. [14,15,16,17,18]. Interestingly, pituitary stalk enlargement was frequently detected on MRI scans in 85% (6/7) (Table 5).

Table 5 Clinical, hormonal, and radiological findings in all patients who developed AVP deficiency after COVID-19 vaccination
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On the other hand, there are also seven reports of pituitary dysfunction accompanied by AVP-D after COVID-19 infection. Among the seven cases, only one case exhibited symptoms of pituitary anterior lobe dysfunction other than AVP-D. the time from infection to disease onset varied from 2 to 8 weeks. Unlike SARS-CoV-2 vaccination-related AVP-D, thickening of the pituitary stalk was only observed in 17% (1/6), (Table 6) [5,6,7,8,9,10,11]. In reports of long-term follow-up of idiopathic cases of AVP-D, 79.1% (34 of 43 patients) were detected to have pituitary stalk enlargement on MRI at the time of onset, and 93.0% (40 of 43 patients) up to 6 months thereafter [22]. Considering the frequency of pituitary stalk enlargement in both idiopathic AVP-D and SARS-CoV-2 vaccination-related AVP-D, it is presumed that SARS-CoV-2 vaccination-related AVP-D shares a similar pathophysiology with idiopathic AVP-D.

Table 6 Clinical, hormonal, and radiological findings in all patients who developed AVP deficiency after COVID-19 infection
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One potential contributor to pituitary inflammation following vaccination is the adjuvant-induced autoimmune (ASIA) syndrome, which is believed to overreact immune responses using adjuvants [23].

However, AVP-D due to vaccines other than the SARS-CoV-2 has been limited only with the older smallpox vaccine [24, 25], with no recent reports from other vaccines, suggesting a possible specific effect of adjuvants in the SARS-CoV-2 vaccine. Secondly, antigen cross-reactivity between SARS-CoV-2 spike protein antibodies and tissue proteins such as thyroid peroxidase protein has been known [26]. Although it is unknown for pituitary and hypothalamic cells, these cells may possess cross-reactivity to induce autoimmunity.

On the other hand, the following mechanism is considered for the development of AVP-D during COVID-19 infection: SARS-CoV-2 utilizes its spike protein to invade host cells via the Angiotensin converting enzyme 2 (ACE2) receptor [27]. The hypothalamus expresses ACE2 receptors and is thought to be a target for SARS-CoV-2, which may lead to AVP-D [28].

COVID-19 infection-related AVP-D may differ from idiopathic AVP-D in terms of its pathophysiology and imaging characteristics, such as those seen in LINH. There has been only one case of anti-rabphilin-3A antibody-positive AVP-D without pituitary stalk enlargement, which was considered to have resolved due to its chronic nature [29]. It is possible that this case did not initially present with pituitary enlargement. The measurement of anti-rabphilin-3A antibody has been predominantly conducted in cases with imaging characteristics. However, accumulation of cases for antibody measurements are needed for further investigation of the underlying causes, including COVID-19 infection-related AVP-D and cases without other imaging characteristics, to facilitate the advancement of etiological assessment.

In conclusion, it was presumed that the SARS-CoV-2 vaccine was the triggering factor in our case. Pituitary stalk enlargement and positive anti-rabphilin-3A antibodies may help in the diagnosis of AVP-D induced by SARS-CoV-2 vaccination. As testing for anti-rabphilin-3A antibodies becomes more widespread and data accumulates, it is anticipated that it will contribute to clarify the detail causes of such conditions.

We reported this adverse event related to the vaccine to Pfizer Japan.