Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) and Adrenal Insufficiency Induced by Rathke's Cleft Cyst: A Case Report

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1 Endocrine Journal 2000, 47 (4), Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) and Adrenal Insufficiency Induced by Rathke's Cleft Cyst: A Case Report HIROSHI IWAI, YASUHIRO OHNO, MADOKA HOSHIRO, MIKA FUJIMOTO, AKIYosxi NISHIMURA, YuzuRu KISHITANI* AND NoRImKo AOKI Second Department of Medicine, Kinki University School of Medicine, Osaka-Sayama , Japan *Department of Internal Medicine, Sakai Hospital, Kinki University School of Medicine, Osaka-Sayama , Japan Abstract. We report a case of a seventy-year-old woman with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and adrenal insufficiency induced by Rathke's cleft cyst. She experienced nausea, vomiting, diarrhea, and headache and disturbance of consciousness induced by hyponatremia at a serum sodium level of 100 meq/1. In spite of severe hyponatremia, urinary sodium excretion was not suppressed and serum osmolality (270 mosm/kg) was lower than urine osmolality (304 mosm/kg), and arginine vasopressin (AVP) remained within normal range. SIADH was diagnosed because she was free from other diseases known to cause hyponatremia such as dehydration, cardiac dysfunction, liver dysfunction, renal dysfunction, hypothyroidism, and adrenal insufficiency. Cranial computed tomographic (CT) scan and cranial magnetic resonance (MR) imaging showed a cystic lesion of approximately 2 cm in diameter in the pituitary gland. These images suggested that the cystic lesion was a Rathke's cleft cyst, which was the cause of SIADH. Water restriction therapy normalized her serum sodium concentration and improved her symptoms. After one year, she suffered from general fatigue, appetite loss, fever, and body weight loss (5 kg/2 months). She had neither hypotension nor hypoglycemia, but her serum sodium level was low and serum cortisol, ACTH, and urine free cortisol were very low. Therefore, secondary adrenal insufficiency was suspected and diagnosed by stimulation tests. After start of hydrocortisone replacement therapy (10 mg/day), her symptoms disappeared. In conclusion, Rathke's cleft cyst should be kept in mind as a potential cause in a patient with SIADH, hypopituitarism, and/or adrenal insufficiency. Key words: SIADH, Adrenal insufficiency, Rathke's cleft cyst (Endocrine Journal 47: , 2000) RATHKE'S cleft cyst is an epithelial cyst from a remnant of Rathke's pouch. The cyst is frequently found in autopsy cases (2-30%) [1-6], but it is usually small and rarely causes symptoms. However, there are both endocrinological and neurological symptoms associated with Rathke's cleft cyst in rare cases, including diabetes insipidus (DI), hypopituitarism, amenorrhea, galactorrhea, headache, and impairment of visual acuity and visual field defects [7]. Cases of secondary adrenal insufficiency caused by Rathke's cleft cysts are very rare [8-10], and cases in which Rathke's cleft cyst induced inappropriate secretion of pituitary hormone are heretofore unreported. We report here the first documented case of SIADH induced by Rathke's cleft cyst, followed by secondary adrenal insufficiency due to the enlargement. Received: February 1, 1999 Accepted: April 19, 2000 Correspondence to: Dr. Hiroshi IWAI, Second Department of Medicine, Kinki University School of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka , Japan Case Report A seventy-year-old woman visited a local clinic on August 29, 1996 with complaints of nausea, vomiting, diarrhea, and headache. She was admitted to

2 394 IWAI et al, the same institution on September 3 to screen for the cause of hyponatremia (serum sodium level of 115 meq/1). Though her symptoms were immediately improved by saline fluid replacement and symptomatic therapy against acute gastroenteritis and dehydration, she was admitted to our hospital on September 13 to care for disturbance of consciousness induced by hyponatremia (serum sodium level of 100 meq/1). On admission she had neither dehydration, nor ascites, nor edema, nor any other abnormal physical findings. Her past history was unremarkable. She was in severe hyponatremia at a serum sodium level of 118 meq/1. Since serum creatinine (Cr) was within normal range (0.5 mg/dl) and serum blood urea nitrogen (BUN) was low (5 mg/dl) (Table 1), severe renal dysfunction was excluded. At 4 days after water restriction therapy (1500 ml/day), serum osmolality was still low (270 mosm/kg), and osmolality of urine was higher (304 mosm/kg) than that of serum. Urine sodium excretion was not suppressed (26 meq/l) and plasma AVP concentration was in fact slightly elevated though within normal range. Plasma renin activity (PRA) and aldosterone were within normal range (Table 1), and human atrial natriuretic peptide (HANP) was high (56 pg/ml). These data indicated an increase of circulating blood volume. Serum cortisol, ACTH and urine free cortisol were within normal range (Table 2), but urinary level of 17-hydroxycorticosteroids (17-OHCS) was Table 1. Laboratory data on admission (September 1996) Table 2. Endocrinological data

3 SYMPTOMATIC RATHKE'S CLEFT CYST 395 slightly decreased (0.6 mg/day). Though GH and PRL were within normal ranges, basal levels of both LH and FSH were low, at 4.2 miu/ml and 11.6 miu/ml, respectively (Table 2). Though TSH, at a level of 1.1pU/ml, was within normal range ( pu/ml), levels of both free thyroxine (FT4) and free triiodothyronine (FT3) were mild low, at 0.8 ng/dl (normal range ) and 1.7 pg/ml (normal range ), respectively. Thyroid hormones and TSH were measured by radioimmunoassay. Pituitary dysfunction was suspected, and several stimulation tests were thus performed to accurately estimate pituitary function. On September 20, the responses of cortisol and ACTH to CRH were normal (Fig. 1-a). Cortisol response to ACTH and GH response to GRH were slightly suppressed and gonadotropin responses to LHRH were slightly suppressed and delayed. TSH response to TRH was normal (data not shown). Since the results of stimulation tests showed that there was mild hypopituitarism and the absence of either severe hypothyroidism or adrenal insufficiency, she was diagnosed as SIADH. Cranial CT scan performed on September 10, to examine for the cause of headache and SIADH showed a low-density area of approximately 2 cm in diameter in the pituitary gland. This area was lowintensity on the T1-weighted MR image and high-intensity on the T2-weighted MR image. The margin of the cystic lesion was regular, the inner space was homogenous (Fig. 2), and the cyst wall was not enhanced. Because there were no abnormal findings in cerebrospinal fluid (data not shown), infectious diseases of the central nervous system such as meningitis and encephalitis were excluded. To exclude the other malignant tumors and lung diseases, several tumor markers were examined and upper gastro-intestinal endoscopy, chest- and abdomen-ct, and systemic Ga scintigraphy were done. Neuron specific enolase (NSE), a marker for neuroendocrine tumors and lung small cell carcinoma, was slightly elevated, but the other tumor markers were within normal ranges and there were no abnormal findings on diagnostic imaging. The cystic lesion in the pituitary gland was implicated as a possible cause of SIADH because she was not on any medication and did not have a malignant tumor, lung disease, or disease of the central nervous system. After the start of water restriction therapy, her serum sodium level immediately normalized and her consciousness returned to an alert state. She was discharged when the absence of no recurrence was confirmed. In October 1997, she showed signs of gradually advancing general fatigue, appetite loss, moderate fever, and body weight loss (5 kg/2 months). She had neither hypotension nor hypoglycemia at that time, but serum sodium was low at 125 meq/l, and serum cortisol, serum ACTH, and urine free cortisol were very low, at 0.4 pg/dl, < 5 pg/ml, and < 10 ag /day, respectively (Table 2). Urine 17-OHCS was low (<0.2 mg/day) and serum aldosterone was with- Fig. 1. CRH stimulation tests. a. CRH stimulation test on September 20, The responses of cortisol and ACTH to CRH were normal. b. CRH stimulation test on October 27, The responses of cortisol and ACTH to CRH were blunted.

4 396 IWAI et al. Fig. 2. Cranial MR image on admission in November The cystic lesion in the pituitary gland shows as a low- and high-intensity area on T1- and T2-weighted cranial MR images, respectively. The margin was regular and the inner space was homogenous. in normal range (51 pg/ml). The basal levels of GH and gonadtropin were low, but PRL was elevated (Table 2). Though FT4 and FT3 were low, at 0.7 ng/dl (normal range ) and 1.8 pg/ml (normal range ), respectively, TSH levels were elevated at 5.5 ciiu/ml (normal range ). Thyroid hormones and TSH were measured by enzyme immunoassay at this time. Both anti-thyroglobulin antibody and anti-microsome antibody were negative. On October 27, 1997, the responses of ACTH and cortisol to CRH were very low (Fig. 1-b). Cortisol response to ACTH in rapid ACTH test and the responses of gonadtropins to LHRH were remarkably suppressed. GH response to GRH was slightly suppressed. On the other hand, TSH response to TRH was normal (data not shown). The patient was diagnosed as secondary adrenal insufficiency and slightly primary hypothyroidism. The size of the cystic lesion in the pituitary gland on the meglumine gadopentetate (Gd)-enhanced cranial MR image taken in October 1997 was 2.5 cm in diameter, which was larger than that in November 1996 (2 cm in diameter) (Fig. 3). In addition, there Fig. 3. Gd-enhanced cranial MR image in October Gd-enhanced MR image shows that both the margin and inner space of the cystic lesion in the pituitary gland in October 1997 were similar to that in November However, the size at the later date, 2.5 cm diameter, was larger than that in November 1996.

5 SYMPTOMATIC RATHKE'S CLEFT CYST 397 Fig. 4. Clinical course. In September 1996, she experienced hyponatremia-induced disturbance of consciousness due to SIADH. Water restriction therapy normalized her serum sodium level and improved her symptoms. In October 1997, symptoms such as general fatigue and appetite loss appeared gradually and her body weight lowered. Since she had insufficiency of ACTH and cortisol secretion, hydrocortisone replacement therapy was started. Consequently, her serum sodium level was normalized, her symptoms were improved, and her body weight was gradually restored. were no abnormal findings on abdomen-ultrasound and abdomen-ct scan. Therefore, her symptoms may have been induced by secondary adrenal insufficiency due to enlargement of the cyst. After start of hydrocortisone replacement therapy (10 mg/day), her symptoms of general fatigue, appetite loss and fever immediately disappeared and her body weight gradually increased (Fig. 4). She was informed of the risk that the cystic lesion might induce not only SIADH but also insufficiency of ACTH secretion, and accordingly was advised to submit to an operation for treatment of the cystic lesion. However, she has refused the operation and opted for a conservative therapy. To date she has had no recurrence of symptoms. Discussion This is a rare case of a patient who initially presented with hyponatremia due to SIADH induced by Rathke's cleft cyst and who one year later suffered from secondary adrenal insufficiency due to enlargement of the cyst. Though dehydration and dysfunction of heart, liver, and kidney were absent on admission and SIADH was suspected on laboratory data, adrenal insufficiency and myxedema had to be excluded to diagnose SIADH. The first episode of hyponatremia in the present case was not due to adrenal insufficiency because serum cortisol, ACTH, and urine free cortisol were all within normal ranges and the responses of ACTH and cortisol to CRH were normal. On admission thyroid functions, which were the findings of TSH within normal range, very mildlow FT4 and FT3, normal TSH response to TRH, and negative thyroid-antibody, showed that hypothyroidism was euthyroid sick syndrome and not severe, hence hypothyroidism was assumed not to cause hyponatremia. In fact, over one year after the initial diagnosis, serum sodium level was maintained within normal range by water restriction therapy. Therefore, SIADH was diagnosed. Since the patient was not on any medication and no

6 398 IWAI et al. ectopic AVP-producing tumors such as lung cancer, disease of the central nervous system and lung disease were found, it was considered that the cystic lesion in the pituitary gland might be a possible cause of SIADH rather than some other disease. Differential diagnosis for cystic lesion in the pituitary gland was various and included arachnoid cyst, Rathke's cleft cyst, pituitary adenoma, craniopharyngioma, etc. It is reported in an analysis correlating pathological findings of Rathke's cleft cysts with CT scan and MR imaging, that their images were very useful for diagnosis. The signal intensity of Rathke's cleft cyst on CT scan and MR imaging was shown to vary according to various fluid components secreted from the epithelial cells of the cyst wall. The content of this cystic lesion resembled cerebrospinal fluid (CSF) showing low-density on CT scan and low- and high-intensity on T1- and T2- weighted MR images, respectively. Although it was needed to exclude a cystic pituitary adenoma, the lack of enhancement of the cyst wall and homogeneous content of this cystic lesion implicated Rathke's cleft cyst [11-13]. As both thyroid autoantibodies and anti-pituitary autoantibody were negative and lymphocytic adenohypophysitis was excluded by MR image, autoimmune endocrine diseases were ruled out [14]. Endocrinological and neurological symptoms with Rathke's cleft cyst are generally associated with compression of the pituitary gland, pituitary stalk, optic nerve, or hypothalamus. The endocrinological symptoms include DI, hypopituitarism, amenorrhea, and galactorrhea, and the neurological symptoms include headache, impairment of visual acuity and visual field defects. DI, a disturbance of AVP secretion, is frequently found in patients with Rathke's cleft cyst and has a prevalence of 13-36% [7, 15]. Hypopituitarism accounts for most of the pituitary dysfunction induced by Rathke's cleft cyst and has a prevalence of about 40% [7]. Hyperprolactinemia-induced amenorrhea and galactorrhea stemming from disturbance of the secretion of prolactin-inhibiting factor (PIF) also frequently appears (prevalence of 7-25%) [7, 15]. In this case, it is likely that the large cystic lesion initially induced inappropriate secretion of AVP and then secondary adrenal insufficiency by compression of the pituitary gland or pituitary stalk. Besides, the patient showed hypogonadism and then hyperprolactinemia, all of which did not cause symptoms. In the future, further enlargement of the cystic lesion may induce visual disturbance. Though our patient opted for conservative therapy for treatment of the cystic lesion, an operation is still advisable. This is because the cystic lesion has gradually enlarged and induced severe endocrinological symptoms. On the other hand, it is reported that all neurological symptoms disappear and endocrinological symptoms improve at a frequency of 60% after transsphenoidal surgery for Rathke's cleft cyst [15]. Cases of secondary adrenal insufficiency caused by Rathke's cleft cysts are very rare [8-10]. In addition, cases of Rathke's cleft cyst inducing inappropriate secretion of pituitary hormones other than PRL have yet to be reported. This case suggests that physicians should remember the potential influence of Rathke's cleft cyst on secretion of pituitary hormones when SIADH, hypopituitarism, and adrenal insufficiency are encountered. References 1. Rasmussen AT (1929) Ciliated epithelium and mucussecreting cells in the human hypophysis. Anat Rec 41: Gillman T (1940) The incidence of ciliated epithelium and mucous cells in the normal Bantu pituitary. S Afr J Med Sci 5: Bayoumi ML (1948) Rathke's cleft and its cysts. Edinburgh Med J 55: Shanklin WM (1949) On the presence of cysts in the human pituitary. Anat Rec 104: Shanklin WM (1951) The incidence and distribution of cilia in the human pituitary with a description of microfollicular cysts derived from Rathke's cleft. Acta Anat 11: McGrath P (1971) Cysts of sellar and pharyngeal hypophyses. Pathology 3: Voelker JL, Campbell RL, Muller J (1991) Clinical, radiographic, and pathological features of symptomatic Rathke's cleft cysts. J Neurosurg 74: Wenzel M, Salcman M, Kristt DA, Gellad FE, Kapcala LP (1989) Pituitary hyposecretion and hypersecretion produced by a Rathke's cleft cyst pre-

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