Isolated Adrenocorticotropic Hormone Deficiency Diagnosed After the Cessation of Glucocorticoid Therapy for Eosinophilic Esophagitis: A Case Report

Isolated adrenocorticotropic hormone deficiency (IAD) is a rare pituitary disorder that can cause adrenal insufficiency. However, due to its nonspecific symptoms, its diagnosis is often difficult and may be delayed. Patients with IAD require lifelong glucocorticoid (GC) replacement therapy. Contrastingly, GC-induced secondary adrenal insufficiency is a reversible condition that arises when patients receiving GC therapy reduce their GC dosage or discontinue therapy. Differentiating between IAD and GC-induced secondary adrenal insufficiency is clinically crucial. We report a unique case that required differentiation between these two conditions. A 71-year-old Japanese woman presented with symptoms of adrenal insufficiency after discontinuation of GC therapy for eosinophilic esophagitis. We conducted detailed interviews and repeated the endocrinological examinations. We concluded that her symptoms were owing to IAD rather than GC-induced secondary adrenal insufficiency. She began a lifelong hydrocortisone replacement therapy. This case suggests that when caring for patients undergoing GC therapy, it is important to consider the possibility of coexisting IAD and arrange endocrinological examinations if signs of adrenal insufficiency arise during the gradual reduction of GC treatment.


Introduction
Isolated adrenocorticotropic hormone deficiency (IAD) is a relatively rare pituitary disorder of unknown etiology with reported prevalence rates of 1.9-7.3cases per 1,000,000 in Japan [1].It leads to secondary adrenal insufficiency (SAI) and presents with nonspecific symptoms such as generalized fatigue, loss of appetite, and weight loss, often causing delays in diagnosis [2].Moreover, eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus mediated by antigens, with the most frequently studied factors being food allergens, and its prevalence has steadily increased in recent years [3,4].The treatment options for EoE can include proton pump inhibitors, corticosteroids, and biologics [4].
Herein, we present a case of IAD diagnosed after the cessation of glucocorticoid (GC) therapy for EoE.The clinical course was complicated by masking of IAD symptoms with GC therapy for EoE.The diagnosis of IAD was established through meticulous interviews and endocrinological assessments.

Case Presentation
A 71-year-old Japanese woman presented with fatigue, loss of appetite, nausea, dysphagia, and precordial pain that gradually began in early October 2022 and prompted her to seek medical attention at a local clinic.Her medical history included ovarian cyst surgery.Her mother had a family history of thyroid surgery.However, no other endocrine disorders were reported.She had no history of smoking or alcohol consumption.Esophagogastroduodenoscopy (EGD) was performed at a local clinic, raising the suspicion of esophageal candidiasis, for which she was prescribed oral miconazole.However, her symptoms did not improve and she was referred to our hospital.Upon admission, EGD and endoscopic biopsy were conducted, which resulted in a diagnosis of EoE (Figures 1, 2).Treatment commenced with oral vonoprazan (20 mg/day) and topical budesonide therapy (800 μg/day).Nevertheless, as her symptoms showed minimal improvement, topical budesonide was discontinued six days after its initiation, and oral prednisolone (30 mg/day) was started, leading to rapid amelioration of her condition.The following week, topical budesonide therapy was  Oral prednisolone treatment was discontinued in January 2023.In late March 2023, topical budesonide therapy was also discontinued.After cessation of oral prednisolone, the patient experienced symptoms of bilateral shoulder-to-upper arm pain, general fatigue, and loss of appetite, which led to readmission in mid-May.
Low levels of adrenocorticotropic hormone (ACTH) and cortisol were observed; hence, the patient was transferred to our division.

Parameter
She tested positive for thyroid peroxidase antibody (4.7 IU/mL) and thyroglobulin antibody (1,310 IU/mL).Dynamic tests assessing pituitary hormone secretion revealed normal release of TSH, GH, and PRL, with age-appropriate release of luteinizing hormone and follicle-stimulating hormone.However, ACTH release was notably absent upon stimulation with corticotropin-releasing hormone (CRH) (Tables 2, 3).Decreased cortisol response was observed during the rapid ACTH stimulation test (Table 4).In the insulin tolerance test, no response of ACTH or cortisol was observed (Table 5).There were no apparent abnormalities on brain magnetic resonance imaging (Figure 3).Computed tomography of the chest and abdomen revealed no abnormalities in the heart, lungs, liver, spleen, pancreas, kidneys, or adrenal glands.Human insulin (four units) was injected intravenously in the morning (9 am).
N.M.: not measured.Based on these findings, the patient was diagnosed with SAI.She started taking 15 mg/day of hydrocortisone orally, and her fatigue, loss of appetite, and pain in the shoulders and upper limbs improved rapidly.On day 42 after the transfer, the patient was discharged.As her symptoms began several weeks after the discontinuation of oral prednisolone, it was uncertain whether her SAI stemmed from GC-induced SAI or pre-existing IAD.In mid-November 2023, four months post discharge, a rapid ACTH stimulation test and CRH stimulation test were conducted to confirm the diagnosis.During these tests, hydrocortisone (10 mg/day) was administered orally.In the rapid ACTH stimulation test, the cortisol response decreased (Table 6), whereas ACTH release was absent in the CRH stimulation test (Table 7).Human corticotropin-releasing hormone (CRH, 100 µg) was injected intravenously in the morning (9 am).
These findings were similar to the initial stimulation test results, supporting a diagnosis of IAD.When reviewing her medical history again, it was noted that she had easily become fatigued and had quit her job as a staff member at a grocery store because of her fatigue approximately one year before being diagnosed with EoE.This suggests the presence of adrenal insufficiency before EoE treatment.Therefore, we concluded that the patient developed IAD before the onset of EoE, and the symptoms of IAD became apparent in conjunction with the onset of EoE.Treatment with GCs for EoE unintentionally improved her symptoms of IAD; however, the cessation of GC therapy led to the recurrence of IAD symptoms.After the stimulation tests, hydrocortisone replacement therapy was continued.During outpatient follow-up, no recurrence of symptoms was observed.

Discussion
We encountered a case of an older adult woman who was diagnosed with IAD after treatment for EoE (Figure 4).We concluded that the patient had pre-existing IAD before the onset of EoE.Symptoms of IAD became more evident after the onset of EoE and were inadvertently alleviated by GC therapy; however, the symptoms resurfaced upon cessation of the treatment and disappeared again with hydrocortisone replacement therapy.

FIGURE 4: Clinical course.
The use of glucocorticoids to treat eosinophilic esophagitis unintentionally improved symptoms of IAD.However, once oral prednisolone was stopped, the symptoms reappeared.After the diagnosis of IAD, initiation of oral hydrocortisone replacement therapy immediately ameliorated the symptoms.
This case highlights two important points.Firstly, it underscores the significance of distinguishing between GC-induced SAI and IAD in patients who have discontinued GC therapy.Secondly, it emphasizes the importance of meticulously assessing the clinical course during the differentiation process.
GCs are widely used owing to their anti-inflammatory and immunosuppressive properties.However, a notable drawback of GC therapy is the suppression of the hypothalamic-pituitary-adrenal (HPA) axis, potentially resulting in GC-induced SAI [5].Daily administration of 20 mg or more of hydrocortisone or its equivalents for longer than three weeks may be associated with the suppression of ACTH secretion [6].In this case, oral prednisolone treatment was administered for approximately two months and was discontinued several weeks before the onset of adrenal insufficiency symptoms.Therefore, it was necessary to differentiate between GC-induced SAI and IAD.If it had been GC-induced SAI, there was a possibility that the secretion of ACTH may have recovered after a certain period [5].Typically, the HPA axis recovers within four weeks after discontinuing continuous GC usage [5], although in some instances, it may take longer than six months [7].Therefore, we conducted stimulation tests eight months after the cessation of GC treatment for EoE.In this case, no signs of recovery of ACTH secretion were observed, leading to the diagnosis of IAD.Furthermore, IAD is an extremely rare condition.Conversely, numerous patients undergo GC therapy under various conditions, raising the possibility that some may have pre-existing IAD.Generally, if diseases treated with GCs improve and clinicians decide to taper them, they must plan for a gradual reduction in the GC dose to prevent GC-induced SAI.However, if the patient has IAD, the secretion of ACTH and cortisol never recovers, even with careful tapering.These patients must undergo GC replacement therapy for life.Therefore, this differentiation is crucial.It is essential to consider the possibility of IAD and schedule endocrinological investigations if symptoms of adrenal insufficiency emerge during the gradual tapering of GC therapy.
Furthermore, in understanding the clinical course of this case, it was crucial to carefully confirm the medical history of the patient.This allowed us to ascertain that symptoms of IAD were also present at the onset of EoE.
Conversely, IAD is a rare endocrine disorder characterized by reduced or absent production of ACTH in the pituitary gland, leading to SAI.ACTH secretion is impaired in IAD, although other pituitary hormones are normally secreted and there are no structural abnormalities in the pituitary gland [9].Moreover, patients with IAD typically exhibit vague symptoms, including fatigue, loss of appetite, unintentional weight reduction, and a tendency to develop hypoglycemia [5].In this case, at the onset of EoE, the patient presented with local symptoms such as dysphagia and precordial pain, as well as systemic symptoms including fatigue, loss of appetite, and nausea.Systemic symptoms are relatively rare in patients with EoE.This suggests that the patient may have developed IAD before the onset of EoE.Furthermore, the medical history indicated increased fatigue approximately one year before the onset of EoE providing further evidence supporting this hypothesis.
In this unique case, the symptoms of pre-existing IAD were masked by GC therapy for EoE, and upon discontinuation of GC therapy, the symptoms reappeared.We confirmed the diagnosis by reassessing the patient's medical history and repeating stimulation tests.

FIGURE 1 :
FIGURE 1: EGD performed in November 2022.EGD findings showed an esophageal ulcer (white arrows) and severe inflammation of the mucosa.EGD: esophagogastroduodenoscopy.

FIGURE 3 :
FIGURE 3: Brain MRI performed in June 2023.Sagittal T1-weighted plain MRI showed no abnormality in the pituitary gland (yellow arrow).MRI: magnetic resonance imaging.