Panhypopituitarism and Abducens Nerve Palsy due to IgG4-Related Disease (IgG4-RD) in a Middle-Aged Man: A Case Report

Introduction: Pituitary is an essential gland which produces several vital hormones. These hormones orchestrates the complex regulatory functions of many other endocrine glands. Damage to pituitary gland can be presented by one or several hormone deficiency. This damage may be a result of following etiologies: mass lesion, post radiation and surgery, infiltrative and autoimmune lesions (like lymphocytic hypophysitis, neurosarcoidosis, IgG4-related disease (IgG4-RD) and hemochromatosis), infection/abscess, infarction (like Sheehan syndrome) and other causes. Hypophysitis is a rare pituitary inflammatory disorder with an incidence of 1 in 10 million [1], [2], [3], [4]. Histologic subtypes of hypophysitis are including: lymphocytic, granulomatous, xanthomatous, and plasmacytic (IgG4-related). This case report presents the clinical, radiologic, and pathologic characteristics of this rare condition in a male patient.Case Presentation: A 42 years married male was referred to Tehran Imam Khomeini Hospital Center because of long lasting headache. He had a history of headache since four years ago. He also complained of blurred vision and polyuria and mild nausea and fatigue during these years. He also complained of infertility and decrease in libido. Hypothyroidism and hypertension was diagnosed 2 years ago. The patient s drug history was included Levothyroxine 0.1 mg and Losartan 25 mg per day and Testosterone injections. He was treated with prednisolone 5mg per day since 2017 after brain MRI which revealed enlarged pituitary gland, low signal intensity area around pituitary gland in T2, cavernous sinus involvement, thickening of pituitary stalk and poor enhanced area around pituitary. MRI finding was suggestive of lymphocytic hypophysitis. During follow/up he noticed increasing headache, dizziness and nausea and new-onset diplopia. Patient was admitted for further evaluation. On physical examination, he was completely alert and oriented with stable vital signs. In neurologic examination impairment of left lateral rectus muscle was detected which caused diplopia especially at lateral gaze. His laboratory examination showed: WBC: 8700, HGB: 13, Platelet: 248000, Urea: 33 mg/dl, Creatinine:0.9 mg/dl, Na: 135 meq/L, K: 3.7meq/L, urine SG:1005,HBA1C:7.5% , AST:15 U/L, ALT:22 U/L, ALP:153 U/L ,Ca:8.6 mg/dl p:4.2 mg/dl, 25OH vitD:15 ng/ml, ESR:55 mm/h , CRP: 36mg, LH: 0.1 mIU/ml, FSH<0.1 mIU/ml, Prolactin: 3.1 ng/dl, TSH<0.004 mIU/L, FT4:1.9 ng/dl, Anti TPO: negative, Testosterone: 3.2ng/ml, IGF1:102 ng/ml, Cortisol: 2.5 mic g/dl, ACTH:7.6 pg/ml, AFP:1.58 mic g/L, BHCG<1.20 mIU/ml, ACE Level:20 IU/L (13.3-63) and IgG Subclass 4: 2327 mg/L (62-1127).Chest CT scan showed a 42*16 mm pericardial cyst lateral to right atrium without any evidence of pulmonary sarcoidosis. He underwent transsphenoidal pituitary biopsy which detected pituitary cells infiltrated by dense population of lymphocyte and plasma cells. Histomorphologic finding was consistent with Lymphocytic Hypophysitis but IHC study of pituitary specimen confirmed the diagnosis of IgG4 Related autoimmune hypophysitis . (figure 3)Discussion: Hypophysitis, or inflammatory process of pituitary gland are categorized into 4 subtypes [5]. Autoimmune or lymphocytic hypophysitis is a rare inflammatory disease known by diffuse polyclonal lymphocytic infiltration with predominance of T cells (particularly CD4) and eventual destruction of the pituitary tissue manifested by various degrees of pituitary dysfunction [6]. Confirmatory diagnosis of autoimmune hypophysitis is essentially established on histopathology of the resected specimen, in which lymphocyte and plasma cell infiltration is seen [5]. Lymphocytic hypophysitis is a rare entity that may mimic pituitary adenoma and occurs mostly in women in the peripartum period [7]. When lymphocytic hypophysitis is seen in men, headache and decreased libido are the most common presenting symptoms [8]. The occurrence of central diabetes insipidus (CDI) in patients with lymphocytic hypophysitis seems to be due to autoimmune hypothalamic involvement rather than an expansion of the pituitary inflammatory process [9]. However Tashiro T. et al [10] believed that spread of inflammation from the infundibuloneurohypophysis to the adenohypophysis was the main cause of this concomitance [11,12]. Identical ultrastructural features have been noted between lymphocytic hypophysitis and granulomatous hypophysitis suggesting that both of these conditions could represent the same autoimmune disease at different ends of the range [13]. Immunoglobulin G4-related disease (IgG4-RD) is a systemic relapsing and remitting fibro-inflammatory condition characterized by infiltration of tissue with IgG4 positive plasma cells [14, 15, 16]. Leporati et al [17] devised 5 criteria to establish a diagnosis of IgG4-related hypophysitis. IgG4-RD are new recognized infiltrative disease that affect almost every organ of the body, with preference for the pancreas, salivary gland, orbital tissue, lung, thyroid and kidney. A few article mostly in Japan described these diseases.This patient had an increased serum IgG4 level (232.7 mg/dl) and a MRI showed thickened pituitary stalk. No sign of pancreatic, salivary or other organ involvement was detected but he was suffering from TPO-negative hypothyroidism that is suggestive of IGG4 related thyroid dysfunction. IHC examination of the specimen is necessary for diagnosis because histopathology may not confirm the diagnosis of IgG4 related hypophysitis as was in our case. Association between IgG4-RD and pericardial involvements like pericardial thickening and chronic constrictive pericarditis has been reported in a few articles [18, 19] but there is no association between IgG4-RD and pericardial cyst in the literature.IgG4-RD can involve cranial nerves. Involvement of II, VI, VII cranial nerves was reported [20]. Our patient had VI cranial nerve palsy.Glucocorticoid and Rituximab therapy has been suggested in these patients [21]. Despite of using long –term glucocorticoid, our patient symptoms especially headache did not subside. Conclusion: Here we report an interesting case of IgG4 related autoimmune disease presenting with anterior and posterior hypophysitis (panhypopituitarism and DI) and 6th cranial nerve palsy and hypothyroidism. The diagnosis of IgG4-related hypopysitis must be considered in patients with pituitary stalk thickness and other organ involvement such as Anti TPO-negative hypothyroidism.