Pituitary puzzles: a perplexing headache
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1 Pituitary puzzles: a perplexing headache Thomas Upton* Steven Soule Department Of Endocrinology Christchurch Hospital, Christchurch, New Zealand
2 Declaration of Interests Novo Nordisk sponsorship, Diabetes Postgraduate Weekend, 2014
3 Christchurch, New Zealand
4 The year 2007 Caucasian female, 59 years Acute presentation Severe headaches increasing 3/12 Gradual decline in energy 2 years
5 Extensive medical history Chronic sinusitis inflammatory infiltrate maxillary sinus Haematuria thin basement membrane disease Hypertension Hyperlipidaemia Non-alcoholic fatty liver disease
6 Examination BP 130/85 sitting 105/85 standing Respiratory, abdominal NAD Euthyroid Visual fields normal Muscle strength normal
7 Initial investigations Full blood count normal Na, K normal Creatinine normal CRP 12 (<5) Urinalysis Red cells, no protein, no casts
8 Initial investigations CT head abnormal pituitary fossa MRI requested
9 Pituitary MRI
10 Pituitary function Synacthen test Cortisol (>550) FT4 index 38 (55-160) TSH 0.46 ( ) FSH 4.1 (>17) LH 0.05 (>11) Prolactin 520 (80-530) IGF-1 40 ug/l (66-236, SDS -3.2) Anterior hypopituitarism
11 What next?
12 Tumours Inflammatory lesions (hypophysitis) Hypertrophy Cysts Infection
13 Tumours Adenoma Functioning Non-functioning Germ cell tumours Others Meningioma Astrocytoma Glioma, ependyoma Craniopharyngioma Lymphoma Metastases Patient s MRI Pituitary lymphoma Invasive prolactinoma Renal cell carcinoma
14 Hypertrophy Primary hypothyroidism Han et al. Acta Neurochir (Wien) Normal hypertrophy Chanson et al. J Clin Endocrinol Metab 2001.
15 Infection and cysts Abscess Craniopharyngioma
16 Hypophysitis Rare inflammatory disorder <1% of sellar masses
17 Hypophysitis Aetiology primary secondary Anatomic location adenohypophysitis infundibuloneurohypophysitis panhypophysitis Histopathology
18 Primary hypophysitis Autoimmune 1:7 million incidence >750 cases reported Caturegli P, Iwama S. J Clin Endocrinol Metab 2013.
19 Lymphocytic hypophysitis Female predominance : 6:1 Onset 35yr, 45yr Pregnancy/post-partum (60%) Headache very common Sellar compression, hypopituitarism, DI, hyperprolactinaemia Association with autoimmune diseases Caturegli et al. 2011
20 Secondary hypophysitis Systemic diseases GPA (Wegener s) tuberculosis sarcoid syphilis Langerhans cell histiocytosis
21 Secondary hypophysitis Immunomodulatory drugs interferon ipilimumab
22 Ipilimumab hypophysitis Faje et al. J Clin Endocrinol Metab, 2014
23 Further investigations ANCA negative Calcium normal CXR unremarkable CT chest ground glass opacity, stable
24 Summary 59-year-old female Panhypophysitis Hypopituitarism No underlying cause
25 Progress Prescribed hydrocortisone 15-30mg per day Thyroxine commenced Developed thirst and polyuria partial cranial DI confirmed Headache resolved
26 Follow-up MRI Initial Six weeks later
27 However
28 3 months later Weight gain Muscle weakness Blurred vision
29 what was going on?
30 Answer in a bottle Hydrocortisone Prednisone Up to 40mg prednisone per day!
31 Progress Prednisone reduction Return of headache Recurrent pituitary swelling
32 Progress Pituitary biopsy planned Acute admission extreme headache Dexamethasone given Headache better within 24 hours Biopsy abandoned
33 Presentation +6 weeks prednisone Prednisone resumed Withdrawal of steroids
34 Progress Azathioprine Poorly tolerated Prednisone weaned slowly
35 2009 Unilateral submandibular swelling and local lymphadenopathy Stone et al. N Engl J Med, 2012, 366:539-51
36 Submandibular swelling Fine needle aspirate chronic sialadenitis Gland excised extensive atrophy areas of hyalinised fibrosis heavy lymphocytic and plasmacytic infiltration
37 Submandibular histology IgG4-related systemic disease Extensive atrophy of the acini, areas of hyalinised fibrosis Heavy lymphocytic and plasmacytic infiltration Multiple IgG4 positive plasma cells per high power field
38 IgG4 Least abundant IgG antibody Wide variation in normal range stable for any individual Associated with immune disease pemphigus vulgaris idiopathic membranous GN
39 IgG4-related systemic disease Not recognised until 2003 autoimmune pancreatitis extrapancreatic manifestations
40 Pathogenesis Multiple immune-mediated mechanisms T and B cell lymphocytic infiltrate Th2 response, Treg activation cytokines plasma cells IgG4, fibrosis Up to 40% have allergic diseases asthma, chronic sinusitis
41 Multiple organ involvement May be evident at diagnosis Evolve over months or years
42 Stone et al. N Engl J Med, 2012
43 IgG4-related systemic disease Histopathology key for diagnosis tumefactive mass dense lymphoplasmacytic infiltrate immunostaining for IgG4 Elevated plasma IgG4 supports diagnosis may be normal even with active disease often falls with treatment Response to corticosteroids is characteristic Relapse frequent
44 IgG4 hypophysitis Clinically described 2004, pathology year-old Chinese male blurred vision and hypogonadism pituitary mass - positive for IgG4 history of pancreatitis IgG4 positive Approximately 30 cases reported
45 Characteristics 16 detailed cases with IgG4 systemic disease Mean age 65.3 (40-75) Male predominance (13/16, 81%) 12/16 Asian, 1/16 Caucasian Constitutional symptoms common Multiple anterior pituitary deficits 10/16 (63%) Diabetes insipidus 9/16 (56%) 15/16 response to steroids, 1/16 AZA Caputo et al. Pituitary, 2014.
46 Criteria for diagnosis 1: Pituitary histopathology Mononuclear infiltration lymphocytes/plasma cells >10 IgG4-positive cells per high-power field 2: Pituitary MRI Sellar mass and/or thickened pituitary stalk 3: Biopsy-proven involvement in IgG4-positive lesions other organs other organs 4: Serology Increased serum IgG4 (>140mg/dl, 1.4g/L) 5: Response to glucocorticoids Shrinkage of pituitary mass/symptom improvement Diagnosis met if any of the following is fulfilled: Criterion 1 Criteria 2 and 3 Criteria 2, 4, and 5 Leporati et al. J Clin Endocrinol Metab. 2011, 96:
47 Outcome Partial recovery pituitary function Disease in remission IgG4 normal
48 Summary Hypophysitis rare cause of sellar masses consider systemic disease IgG4-related disease autoimmune, multiple organs involved tumefactive infiltration with IgG4-producing plasma cells IgG4 hypophysitis diagnosed on clinical, radiological, pathological criteria most reported cases adult Asian males hypopituitarism typical rapid clinical improvement with steroids
49 References Bando H, Iguchi G, Fukuoka H et al. The prevalence of IgG4-related hypophysitis in 170 consecutive patients with hypopituitarism and/or central diabetes insipidus and review of the literature. Eur J Endocrinol 2014, 170: Caputo C, Bazargan A, McKelvie PA et al. Hypophysitis due to IgG4-related disease responding to treatment with azathioprine: an alternative to corticosteroid therapy. Pituitary 2014, 17: Caturegli O, Iwama S. From Japan with love: another tesserae in the hypophysitis mosaic. J Clin Endocrinol Metab 2013, 98: Caturegli P, Newschaffer C, Olivi A et al. Autoimmune hypophysitis. Endocrine Reviews 2005, 26: Faje A, Sullivan R, Lawrence D et al. Ipilimumab-induced hypophysitis: A detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 2014: DOI: doi: /jc Goyal M, Kucharczyk W, Keystone E.. Granulomatous hypophysitis due to Wegener's granulomatosis. Am J Neuroradiol 2000, 21: Han L, Wang J, Shu K et al. Pituitary tumorous hyperplasia due to primary hypothyroidism. Acta Neurochir (Wien) 2012, 154: Howlett T, Levy M, Robertson I. How reliably can autoimmune hypophysitis be diagnosed without pituitary biopsy? Clin Endocrinol (Oxf.) 2010, 73: Koiso, Akutsu H, Takano S et al. Malignant lymphoma in the parasellar region. Case Rep Med 2014, DOI: /2014/ Liu F, Li G, Leporati P, Landek-Salgado MA, Lupi I et al. IgG4-related hypophysitis: a new addition to the hypophysitis spectrum. J Clin Endocrinol Metab 2011, 96: Yao Y et al. Diagnosis and management of pituitary abscess: experiences from 33 cases. Clin Endocrinol (Oxf.) 2011, 74: Kamisawa T, Funata N, Hayashi Y et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003, 38: Stone J, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012, 366: Wong S, Lam W, Wong W et al. Hypophysitis presented as inflammatory pseudotumour in immunoglobulin G4-related systemic disease. Hum Pathol 2007, 38:
50 Acknowledgements Dr Steve Soule, Department of Endocrinology, Christchurch Hospital A/Prof Penny Hunt, Department of Endocrinology, Christchurch Hospital
51 Could this be GPA? T1 T1 > contrast T1 > 6wk prednisone Goyal et al. Am J Neuroradiol 2000.
52
53 Exceptions
54 Excretion of water
55
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