PRIMARY GRANULOMATOUS HYPOPHYSITIS PRESENTING WITH SECONDARY HYPOTHYROIDISM

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1 Case Report PRIMARY GRANULOMATOUS HYPOPHYSITIS PRESENTING WITH SECONDARY HYPOTHYROIDISM Bana Antonios, MD 1 ; Kais Antonios 1 ; Terri Washington, MD, FACE 2 ; Maha Abboud, MD, FACE 2 ABSTRACT Objective: We present a case of a 45-year-old woman with history of Graves disease treated with thyroidectomy who developed panhypopituitarism due to granulomatous hypophysitis. Methods: The details of the case presentation, evaluation, diagnosis, and treatment are reviewed. On routine follow-up visits for thyroid condition, the patient complained of symptoms of hyperthyroidism, despite being on a previously adequate dose of levothyroxine. Work-up led to the diagnosis of hypophysitis. Results: The patient responded to corticosteroid therapy, but 5 months later, magnetic resonance imaging of the brain showed recurrence of the disease. Eventually, the patient underwent partial transsphenoidal hypophysectomy, later developed recurrence of disease, and had total hypophysectomy. The postoperative pathology report was consistent of granulomatous hypophysitis. Conclusion: Granulomatous hypophysitis is an uncommon inflammatory disease affecting the pituitary. It is commonly misdiagnosed as a macroadenoma because of its clinical presentation. (AACE Clinical Case Rep. 2018;4:e329-e333) Submitted for publication September 8, 2017 Accepted for publication February 10, 2018 From 1 Tishreen University of Latakia, Syria, and 2 Elmhurst Memorial Hospital, Elmhurst, Illinois. Address correspondence to Dr. Terri Washington, 1200 South York Street, Suite 3150, Elmhurst, IL twashi@att.net. DOI: /ACCR To purchase reprints of this article, please visit: See accompanying article, p. e350. Abbreviations: FT4 = free thyroxine; GH = granulomatous hypophysitis; LH = lymphocytic hypophysitis; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone CASE REPORT Hypophysitis is a rare inflammatory process of the pituitary gland that mimics pituitary macroadenomas. It can be idiopathic or manifest as a part of a systemic autoimmune disease. Granulomatous hypophysitis (GH) and lymphocytic hypophysitis (LH) are the most common subtypes reported in literature (1-3). We present a case of a 45-year-old female with past medical history of hypothyroidism after total thyroidectomy for Graves disease and surgical history of hysterectomy. On presentation, she complained of hyperthyroid symptoms (e.g., fatigue, excess sweating, hot flashes, presyncope, weight loss, and headaches), despite being on a previously adequate levothyroxine dose. Two months prior, her thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were normal. Her physical exam was unremarkable except for a surgically absent thyroid. Laboratory evaluation revealed TSH <0.006 mu/l (normal range, 0.34 to 5.6 mu/l) and FT4 of 1.1 ng/dl (normal range, 0.58 to 1.64 ng/dl); thus, her levothyroxine dose was decreased. Despite this, she continued to have symptoms and low TSH. Secondary hypothyroidism was suspected, as TSH was undetectable and FT ng/dl off levothyroxine. Severe headache, insomnia, and worsening fatigue developed, so imaging was done and magnetic resonance imaging (MRI) revealed a large bilobed enhancing pituitary mass with suprasellar extension and thickening of the pituitary stalk (Fig. 1). Laboratory results showed low am cortisol, estrogen, follicle-stimulating hormone (FSH), insulin-like growth factor AACE CLINICAL CASE REPORTS Vol 4 No. 4 July/August 2018 e329

2 e330 Primary Granulomatous Hypophysitis, AACE Clinical Case Rep. 2018;4(No. 4) 1, and a high prolactin. Her ophthalmologic examination reported normal visual acuity, color vision, peripheral vision, and eye movements. Hydrocortisone was started due to acute adrenal insufficiency, because the am cortisol was 3.4 µg/dl (normal range, 10 to 20 µg/dl). Cabergoline was started for hyperprolactinemia given mild prolactin elevation and involvement of the pituitary stalk on MRI. Levothyroxine was restarted, and estrogen patch was given to treat menopause symptoms. Her laboratory results prior to treatment are shown in Table 1. The patient was referred to neurosurgery for evaluation and possible surgical treatment. Neurosurgery suspected lymphocytic hypophysitis based on the MRI findings and initially recommended high-dose dexamethasone, which was weaned over the course of 2 months. Her symptoms improved and headaches decreased significantly. Repeat MRI 2 months after steroid therapy showed resolution, with normal pituitary volume and midline pituitary stalk. She was weaned off cabergoline, estrogen, and hydrocortisone, and only levothyroxine was maintained to see if hormone levels would normalize with steroid treatment. Five months later, her symptoms returned, and MRI revealed interval enlargement of the pituitary gland, measuring cm with extension into the suprasellar chiasm (Fig. 1 and 2). The patient underwent a transsphenoidal partial hypophysectomy. Pathology findings showed fragments of the normal pituitary tissue, with lymphocytic infiltration and scattered noncaseating granulomas. The inflammatory infiltrate was composed of T cells and monocytes/macrophages, with scattered B cells and plasma cells. The diagnosis of granulomatous hypophysitis was made (Fig. 3). Postsurgical findings included permanent diabetes insipidus; levothyroxine was continued, and hydrocortisone and estrogen replacement were restarted for panhypopituitarism. The headache returned after 1 month, with recurrence of hypophysitis. MRI showed enlargement of the pituitary and thickening of the pituitary stalk measuring cm. She underwent total hypophysectomy via a transsphenoidal approach for definitive treatment. DISCUSSION Hypophysitis is a chronic inflammatory process of the pituitary gland that is rare and not fully understood. The estimated incidence is 1 per 9 million per year (1). It is believed to be either idiopathic or associated with other autoimmune disorders. Hypophysitis can be categorized histopathologically as LH, GH, xanthomatous hypophysitis, and plasmocytic hypophysitis, also known as IgG4- related hypophysitis (2,3). Mixed histology can be seen, however. Necrotizing hypophysitis has also been suggested as an additional variant, but only three cases have been reported in the literature (4,5). LH is the most common subtype, with over 390 cases reported. GH is the second most common, followed by xanthomatous and IgG4-related hypophysitis. LH occurs more often in women, with a 3:1 female to male predomi- Fig. 1. Initial magnetic resonance imaging findings. Total measurement was cm including the pituitary and suprasellar components. Fusifom involvement of the pituitary stalk with bulbous configuration measuring cm. Total cranial caudad length of the bilobed configuration measuring 2.1 cm in height. Localized mass effect was noted on the optic chiasm.

3 Primary Granulomatous Hypophysitis, AACE Clinical Case Rep. 2018;4(No. 4) e331 Hormone Table 1 Laboratory Work-up Before and After Corticosteroid Therapy Before dexamethasone Sept. 6, 2016 After dexamethasone & cabergoline Dec. 19, 2016 Normal range am Cortisol 3.4 µg/dl µg/dl Prolactin 87.7 ng/dl 0.8 ng/dl ng/ml FT ng/dl 0.94 ng/dl ng/dl IGF-1 94 ng/dl 151 ng/dl ng/dl FSH 0.4 µiu/ml miu/ml LH 0.2 µiu/dl IU/mL ACTH 6 pg/ml 6-58 pg/ml Abbreviations: ACTH = adrenocorticotropic hormone; FSH = folliclestimulating hormone; FT4 = free thyroxine; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone. Fig. 2. Coronal plane pictures showing recurrence of pituitary enlargement and pituitary stalk thickening after initial treatment with dexamethasone. nance and is often seen during the postpartum period. Granulomatous hypophysitis occurs equally in males and females (6-8). GH can be either primary or secondary. Primary GH is an isolated chronic inflammation of the pituitary gland, first described in 1917 as an immunogenic infiltration of the pituitary gland that leads to formation of noncaseating granulomas in the absence of systemic granulomatous disease. It causes pituitary enlargement that mimics a macroadenoma (6). Secondary GH can be due to an infection, systemic inflammatory disorders such as sarcoidosis, Wegener granulomatosis, Crohn disease, Takayasu arteritis, Cogan syndrome, or a side effect of some medications, mostly in those receiving immunotherapy for metastatic melanoma with anti-ctla4 and anti-pdi antibodies (3,5,8). Our patient s rheumatology evaluations, including DNA antibody, SSA/SSB antibodies, anti-smith/rnp antibody, JO-1 antibody, anti-nuclear antibody, and rheumatoid factor, were within normal limits. GH can present with a broad spectrum of symptoms, the most common being headaches. The headaches are severe, without relief with medication, as was seen with our patient. The headaches are caused by the enlarged pituitary mass, which can compresses the optic chiasm, leading to varied symptoms of visual impairments, such as blurred vision, double vision, or even loss of vision. Nausea and vomiting occur secondary to increased intracranial pressure and/or acute adrenal insufficiency. In such cases, emergency intervention is needed, with treatment of the mass or surgical intervention to relieve the pressure (3,7,9). Hyperprolactinemia can be seen with development of amenorrhea and galactorrhea. Our patient had a hyster-

4 e332 Primary Granulomatous Hypophysitis, AACE Clinical Case Rep. 2018;4(No. 4) Fig. 3. Pituitary lesion from patient s surgical resection showing granulomatous hypophysistis (10 magnification), with arrow showing a cluster of granulomas. ectomy and denied galactorrhea but did have a mildly elevated prolactin thought to be from involvement of the pituitary stalk. Panhypopituitarism and its symptoms result from the autoimmune attack on the gland and destruction of hormone-producing cells. Central diabetes insipidus is also common. Our patient had complaints of sweating, insomnia, heat intolerance due to undetectable FSH and estradiol, and weight loss, fatigue, and presyncope from secondary adrenal insufficiency given her low morning cortisol (5,7). Radiographic imaging with MRI aids in diagnosis because it reveals the pituitary mass. It is helpful as a noninvasive way to differentiate hypophysitis from pituitary adenomas. Gutenberg and colleagues (10) developed a scoring system for the radiologic features that help to distinguish the diagnosis of hypophysitis from pituitary adenomas. Radiographic features more specific to hypophysitis include: homogenous enhancement of the pituitary, diffuse symmetric gland enlargement, midline stalk thickening, and the absence of the posterior pituitary bright spot (10). Nevertheless, biopsy is needed for a definitive diagnosis. The most common histopathologic findings of primary GH include multinucleated giant cells, noncaseating granulomas, histiocytes, infiltration by numerous lymphocytes, and deposition of calcium (8). Treatment of GH is debatable because of the rarity of the disease, the lack of histologic confirmation in many cases, and the variable clinical presentation. Symptoms from pituitary mass effect, such as the optic chiasm compression, cranial nerve palsies, and severe headache, are general indications for treatment of hypophysitis. Given the benign course of the disease and the fact that some case reports demonstrated a response to high-dose steroids, it is preferable to start with conservative treatment instead of pituitary surgery. Medical therapy with high-dose steroids and close radiologic observation are recommended for initial management (11). High-dose glucocorticoids help with symptoms such as headaches by reducing inflammation and thus decreasing the size of the pituitary mass (3,12). Dopamine agonists such as bromocriptine or cabergoline have been used in patients suffering from visual field deficits and hyperprolactinemia. However, the impact of these agents on the course of the disease is unknown. Our patient s symptoms did improve with high-dose dexamethasone treatment. However long-term use of high-dose steroids is not desirable and can be detrimental to patients, given unwanted side effects. Other immunosuppressive agents such as methotrexate, azathioprine, rituximab, infliximab, cyclosporine, and mycophenolate mofetil have been utilized in a small number of patients with hypophysitis with some success (5,9). Transsphenoidal resection is a minimally invasive procedure that is both diagnostic and therapeutic in refractory cases or cases presenting with severe headaches, cranial nerve damage, and optic chiasm compression. Neurosurgeons try to preserve some normal tissue to prevent the total loss of pituitary function, as was

5 Primary Granulomatous Hypophysitis, AACE Clinical Case Rep. 2018;4(No. 4) e333 done in this case. In some instances, the pituitary gland regains its function after the procedure, but long-term hormone replacement therapy is almost always required (7,8,11). Postsurgically, methylprednisone is given to reduce the swelling and inflammation and as a part of hormonal replacement (8). After initial steroid treatment, the patient did not want to try medication again because of side effects and opted instead for surgical treatment. Partial hypophysectomy was done, but due to recurrence, she eventually underwent a total hypophysectomy for definitive treatment. This case is noteworthy because of the recurrence of the disease, which is a rare occurrence that has been reported with LH but not GH. Two cases of recurrent LH have been reported that were treated with low-dose stereotactic radiotherapy. This is a noninvasive option of treatment in recurrent LH and corticosteroid-resistant cases of LH. Unfortunately, there is no experience with stereotactic radiotherapy in the management of postsurgical recurrence of GH (3,13). CONCLUSION Our patient, initially thought to be hyperthyroid due to medication, actually developed panhypopituitarism from GH. Primary GH is an uncommon inflammatory disease affecting the pituitary. It is often misdiagnosed and has a varied clinical presentation. Pathology is important to distinguish between subtypes of this inflammatory process in the pituitary. Patients present with multiple anterior pituitary hormone deficiencies, and treatment involves hormone replacement therapy. Glucocorticoids are used as initial treatment, but the disease can wax and wane, so definitive diagnosis is made by surgical resection, as presented here. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Khare S, Jagtap VS, Budyal SR, et al. Primary (autoimmune) hypophysitis: a single centre experience. Pituitary. 2015;18: Tashiro T, Sano T, Xu B, et al. Spectrum of different types of hypophysitis: a clinicopathologic study of hypophysitis in 31 cases. Endocr Pathol. 2002;13: Xu Y, Lou L, Wang TH, et al. Granulomatous hypophysitis: experience with eight surgical cases of a single center. Chin Neurosurg J. 2016;2:3. 4. Al-Haddad S, Fandino R, Scheithauer BW, Galvis L, Syro LV, Kovacs K. Necrotizing granulomatous hypophysitis presenting as a sellar mass. Endocr Pathol. 2011;22: Faje A. Hypophysitis: evaluation and management. Clin Diabetes Endocrinol. 2016;2: Caturegli P, Newschaffer C, Olivi A, Pomper MG, Burger PC, Rose NR. Autoimmune hypophysitis. Endocr Rev. 2005;26: Chung CH, Song MS, Cho HD, et al. A case of idiopathic granulomatous hypophysitis. Korean J Intern Med. 2012;27: Shi J, Zhang JM, Wu Q, Chen G, Zhang H, Bo WL. Granulomatous hypophysitis: two case reports and literature review. J Zhejiang Univ Sci B. 2009;10: Gundgurthi A, Kharb S, Garg MK, et al. Combined granulomatous and lymphocytic hypophysitis presenting as pituitary incidentaloma in a middle-aged woman. Indian J Endocrinol Metab. 2012;16: Gutenberg A, Larsen J, Lupi I, Rohde V, Caturegli P. A radiologic score to distinguish autoimmune hypophysitis from nonsecreting pituitary adenoma preoperatively. Am J Neuroradiol. 2009;30: Elgamal ME, Mohamed RM, Fiad T, Elgamal EA. Granulomatous hypophysitis: rare disease with challenging diagnosis. Clin Case Rep. 2017;5: Kristof RA, Van Roost D, Klingmüller D, Springer W, Schramm J. Lymphocytic hypophysitis: non-invasive diagnosis and treatment by high dose methylprednisolone pulse therapy? J Neurol Neurosurg Psychiatry. 1999;67: Selch MT, DeSalles AA, Kelly DF, et al. Stereotactic radiotherapy for the treatment of lymphocytic hypophysitis: report of two cases. J Neurosurg. 2003;99: