732 Alvarez, Cordido, Sacriscin Postgrad Med J: first published as 10.1136/pgmj.73.865.732 on 1 November 1997. Downloaded from due to lymphocytic hypophysitis in a patient with retroperitoneal fibrosis

A Alvarez, F Cordido, F Sacristan

Summary of 130/70 mmHg and body temperature of We present a 78-year-old woman with 37°C. Cardiopulmonary auscultation showed clinical acute hypopituitarism in whom a systolic murmur and bilateral rales. There pathologic findings showed lymphocytic was marked tenderness after percussion of the hypophysitis and retroperitoneal fibrosis. right costovertebral area. Laboratory blood Lymphocytic hypophysitis should be in- tests revealed an erythrocyte count of cluded in the differential diagnosis of 3.1 x 1012/1, haemoglobin 6.0 mmol/l, haema- hypopituitarism at any age. The associa- tocrit 0.267, leucocyte count 8.7 x 109/1, urea tion with idiopathic retroperitoneal fibro- 34.1 mmol/l, creatinine 335.9 mmol/l, potas- sis suggest an autoimmune origin for this sium 5.5 mmol/l, sodium 135 mmol/l and entity. glucose 6.1 mmol/l. The urinary sediment presented abundant white blood cells and Keywords: hypopituitarism, lymphocytic hypophysi- bacteria. Chest X-ray showed a right pleural tis, retroperitoneal fibrosis effusion. Renal sonogram showed bilateral nephrolithiasis, high-grade right obstructive uropathy, and atrophic right kidney. The Hypopituitarism is most frequently due to a initial diagnosis was urinary tract infection pituitary tumour, other common causes being complicating obstructive uropathy. Empiric surgery, pituitary radiation therapy and pitui- antibacterial treatment was prescribed (aztreo- tary apoplexy. Less common causes ofpituitary nam). Her condition worsened with vomiting, insufficiency include , progressive decline in mental status and head trauma, internal carotid artery aneurysm hypotension. Physical examination revealed and infiltrative diseases that affect the hypotha- blood pressure of 90/50 mmHg and dehydra- lamus or pituitary.' tion, without focal neurologic deficits. Re- Lymphocytic hypophysitis is being increas- peated blood laboratory tests showed ingly recognised as a cause of hypopituitarism, haemoglobin 5.6 mmol/l, haematocrit 0.251, usually presenting in women during late leucocyte count 7.67 x 109/1, urea 22.2 mmol/ pregnancy or the postpartum period. It is 1, sodium 144 mmol/l, potassium 5.7 mmol/l, characterised by lymphocytic infiltration and glucose 1.9 mmol/l. Urine sodium was destruction of the anterior . 49 mmol/l and urine potassium 57 mmol/l. http://pmj.bmj.com/ Depending on the stage of the disease, the A presumptive diagnosis of acute adrenal gland may be enlarged due to inflammatory insufficiency was established and the patient infiltrate, or small and atrophic, with fibrosis. received high-dose hydrocortisone. Serum Patients may show symptoms of an expanding cortisol (before the steroid therapy) was intrasellar mass or different degrees ofpituitary 179 mmol/l (reference range 138-690 mmol/ dysfunction.2 1). The thyroid-stimulating hormone level was We report on a woman with lymphocytic 1.2 mU/l (reference range 0.25-4 mU/l) and on October 2, 2021 by guest. Protected copyright. Juan Canalejo Hospital, La Corufia, hypophysitis presenting with clinical signs of the free thyroxine was 7 pmol/l (reference Spain acute hypopituitarism and idiopathic retro- range 11 - 24 pmol/l). With these hormonal Department of peritoneal fibrosis, probably of autoimmune results and the highly stressful situation of the Pathology origin. Lymphocytic hypophysitis should be patient, a diagnosis of hypopituitarism was A Alvarez included in the differential diagnosis of hypo- made. No stimulation test could be per- F Sacristan pituitarism at any age. The association with formed. A computed Department of tomographic study did Endocrinology idiopathic retroperitoneal fibrosis suggests an not show evidence of a hypothalamus-pitui- F Cordido autoimmune origin for this entity. tary mass. After an initial clinical and bio- chemical improvement, with normalisation of Department of Case report serum glucose and electrolyte levels, the Ciencias de la Salud patient died seven days later due to broncho- I, University of la A 78-year-old woman was admitted to the aspiration. Corufia, La Corufia, Spain hospital because of right flank pain during the An autopsy performed four hours after death F Cordido previous two weeks and renal failure. The showed a normal brain (1050 g) and an patient had a 10-year history of bilateral atrophic pituitary gland, hard in consistency Correspondence to obstructive uropathy with bilateral lithiasis and white-grey in colour. The thyroid was Augusto Alvarez Garcia, Servicio de Anatomia and secondary renal atrophy. She was allergic small (6.2 g), as were the adrenal glands (joint Patol6gica, Hospital Juan to penicillin and had previous diagnoses of weight 5 g) and ovaries. There was a retro- Canalejo, Las Jubias 84, renal insufficiency and chronic anemia. She 15006 La Coruna, peritoneal fibrous mass with a diameter of Espana had never been pregnant. Physical examina- 5.3 cm, involving iliac vessels, both ureters and Accepted 20 March 1997 tion disclosed general pallor, blood pressure the right kidney hilium. Kidneys were atrophic, Lymphocytic hypophysitis 733

Figure 1 The posterior pituitary gland normal in Causes of secondary retroperitoneal size, showed no altera- fibrosis Postgrad Med J: first published as 10.1136/pgmj.73.865.732 on 1 November 1997. Downloaded from tions (left), while the ante- * drugs: methysergide, methyldopa, ergot rior part (right) is atrophic alkaloids and by dense fibrous tis- * inflammation adjacent to an abdominal sue (arrows) (HE origi- aneurysm nal x 40) * malignant tumours * retroperitoneal injuries: haemorrhage, infection, or radiation z * peri-arteritis nodosa * autoimmune disease 'T ll * tuberculosis te. l * sarcoidosis lA * biliary tract disease * gonorrhoea * ascending lymphangitis from the lower extremities

Figure 2 Close view of the anterior pituitary gland with slight oedema and moderate lymphocy- tic infiltration surround- ing (arrows) the residual Summary points parenchyma (HE origi- nal x 400) * lymphocytic hypophysitis should be considered k.... a cause of hypopituitarism at any age * it presents as an intrasellar mass during the last months ofpregnancy or early postpartum, or as hypopituitarism at any age * the pituitary can be enlarged or small in size * the aetiology of lymphocytic hypophysitis is probably autoimmune. Autoimmune pathogenesis is supported by coexistence with idiopathic retroperitoneal fibrosis

with pyelo-calyceal dilatation and coraliform lithiasis. The right kidney weighed 40 g and the left 130 g. Other necropsy findings included an increase in the weight of both lungs (600 g each) due to bilateral bronchopneumonia, and Discussion left ventricular hypertrophy due to subaortic stenosis. Hypopituitarism without a pituitary tumour or

Microscopically, the posterior pituitary previous pituitary-directed therapy could be http://pmj.bmj.com/ gland was normal. Parenchymal fibrosis was due to , empty sella syn- found in the anterior pituitary gland (figure 1), drome, head trauma, internal carotid artery with slight oedema and a moderate T-pheno- aneurysm and infiltrative diseases affecting the type lymphocytic infiltration (CD3+) , with hypothalamus or the pituitary.' plasmatic cells and few eosinophils (figure 2). Lymphocytic hypophysitis is a rare entity, No germinal centres, giant cells or granulomas with approximately 60 reported cases, predo-

were observed. The histologic appearance of minantly affecting females and usually present- on October 2, 2021 by guest. Protected copyright. the fibrous retroperitoneal mass was similar to ing during late pregnancy or the first 14 that of the anterior pituitary gland, with months thereafter.3 It presents as an intrasellar collagen tissue and a scattered infiltrate of T- mass during the last three months ofpregnancy phenotype lymphocytes (CD3+) and polyclo- or early postpartum period, or as postpartum nal plasmatic cells. Isolated germinal centres hypopituitarism ofvariable degree.2 The loss of were observed. Lymphocytic infiltrates and pituitary function is often out of proportion to fibrosis were not observed in the thyroid, the degree of pituitary enlargement. Depend- adrenal glands or ovaries. ing on the phase of the disease, the pituitary gland can be enlarged, normal or small in size. Somatotropic and gonadotropic function are more likely to be preserved than corticotropic Causes of hypopituitarism or thyrotropic function, unlike the findings in hypopituitarism due to a sizeable pituitary * adenoma.' It has been reported 4 that anti- * pituitary surgery pituitary antibodies can be found in the serum * pituitary radiation therapy of 75% of women with the empty sella * pituitary aplopexy syndrome. It is conceivable that in some cases * empty sella syndrome * head trauma the empty sella syndrome may represent a final * infiltrative disease stage of lymphocytic hypophysitis.' In addition, * internal carotid artery aneurysm in some cases of the empty sella syndrome, * lymphocytic hypophysitis there is evidence of resolution of pituitary enlargement caused by previously unrecog- 734 Alvarez, Cordido, Sacristain

nised hypophysitis.3 The real incidence of this Because of the occasional presence of anti- entity, therefore, may be greater than currently pituitary antibodies, a lymphoid infiltration recognised. Some cases of idiopathic hypopi- similar to that seen in autoimmune thyroiditis Postgrad Med J: first published as 10.1136/pgmj.73.865.732 on 1 November 1997. Downloaded from tuitarism in men and postmenopausal women and the presence of activated lymphocytes may also be due to lymphocytic inflammation. interdigitated with pituicytes, the concept of Moreover, the spectrum of lymphocytic hypo- lymphocytic hypophysitis as an autoimmune physitis may include cases of idiopathic iso- disease became firmly stabilised relatively lated adrenocorticotropin and TSH defic- early.4'8 In a third of the patients, lymphocytic iencies.5'6 hypophysitis is associated with other autoim- A definite diagnosis of lymphocytic hypo- mune diseases with similar histologic features: physitis requires histologic evidence of lym- lymphoid thyroiditis, lymphoid adrenalitis, phoid inflammatory infiltrate involving the atrophic gastritis, parathyroiditis and idio- adenohypophysis, with plasmatic cells, eosino- pathic retroperitoneal fibrosis.7'9"0 On the other phils, fibrosis and oedema, without granuloma hand, its high incidence in pregnant or and/or epithelioid cells.2 Lymphocytic hypo- puerperal women favours an autoimmune physitis probably progresses through various aetiology due to the high risk of autoimmune stages. Early on, the pituitary becomes oede- exacerbations in these periods. The present matous, inflamed, and enlarged, producing case had an inflammatory infiltrate affecting mass-like symptoms. Subsequently, the pitui- the retroperitoneal fibrous tissue with similar tary tissue is destroyed and replaced by immunologic phenotype and histologic. fea- fibrosis; the sellar mass spontaneously re- tures to the adenohypophysis tissue. These gresses, and symptoms of hypopituitarism data suggest that both entities had a similar develop. At this time the pituitary is usually pathogenic mechanism. shrunken and atrophic. The early stage may be In summary, lymphocytic hypophysitis subclinical, with no symptoms of pituitary should be included in the differential diagnosis mass but with ultimate development of post- of hypopituitarism, even if it appears in partum hypopituitarism. The case here re- nonpregnant women or older patients. It is ported exemplifies the atrophic phase of probably an autoimmune disease. lymphocytic hypophysitis with extensive fibro- sis and scanty lymphoid infiltrate, features found only in late stages and diagnosed at This work was supported by Xunta de Galicia autopsy.7 Investigation Grant XUGA 90004 A-95.

1 Vance ML. Hypopituitarism. N Engl J Med 1994; 330: 7 Sobrinho-Simoes M, Brandao A, Paiva ME, Vilela B, 1651-63. Fernandes E, Cameiro-Chaves F. Lymphoid hypophysitis 2 Cosman F, Post KD, Holub DA, Wardlaw SL. Lympho- in a patient with lymphoid thyroiditis, lymphoid adrenalitis, cytic hypophysitis. Report of 3 new cases and review of the and idiopathic retroperitoneal fibrosis. Arch Pathol Lab Med literature. Medicine 1989; 68: 240-56. 1985; 109: 230-3. 3 Garber JR, Hedley-Whyte ET. Case 25-1995. A 44-year-old 8 Levine S. Allergic adenohypophysitis: a new experimental woman with headache, blurred vision, and an intrasellar disease of the pituitary gland. Science 1967; 158: 1190- 1. mas. N Engl J Med 1995; 333: 441- 8. 9 Carpenter CCJ, Solomon N, Silverberg SG, et al. Schmidt's

4 Komatsu M, Kondo T, Yamauchi K, et al. Antipituitary syndrome (thyroid and ): a review of http://pmj.bmj.com/ antibodies in patients with the primary empty sella the literature and a report of fifteen cases including ten syndrome. J Clin Endocrinol Metab 1988; 67: 633 - 8. instances of coexistent diabetes mellitus. Medicine 1964; 43: 5 Burke CW, Moore RA, Rees LH, Bottazzo GF, Mashiter K, 153- 78. Bitensky L. Isolated ACTH deficiency and TSH deficiency 10 Paja M, Estrada J, Ojeda A, Ram6n y Cajal S, Garcia-Uria J, in the adult. I R Soc Med 1979; 7: 328 - 35. Lucas T. Lymphocytic hypophysitis causing hypopituitar- 6 Stacpoole PW, Interlandi JW, Nicholson WE, Rabin D. ism and , and associated autoimmune Isolated ACTH deficiency: a heterogeneous disorder. thyroiditis, in a non-pregnant woman. Postgrad MedJ7 1994; Medicine 1982; 61: 13-24. 70: 220-4. on October 2, 2021 by guest. Protected copyright.