A case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) with low plasma concentrations of antidiuretic hormone.

A 66-year-old Japanese man presented with persistent hyponatremia without polydipsia and polyuria. Laboratory examination showed serum sodium of 117 mEq/l, plasma osmolality 239 mosm/kg, urine sodium 108 mEq/l, urine osmolality 577 mosm/kg, and normal levels (less than 2.0 pg/ml) of serum antidiuretic hormone (ADH). ADH release was regulated normally with changes in plasma osmolality. No obvious cause for the syndrome of inappropriate secretion of ADH (SIADH) could be detected. However, 20 months later, the patient had bouts of hematuria and was found to have cancer of the urinary bladder. Increased renal sensitivity to ADH was suspected as the underlying mechanism of SIADH.     

Inappropriate secretion of antidiuretic hormone in isolated adrenocorticotropin deficiency.

A 62-year-old man was admitted because of nausea and vomiting. Severe hyponatremia with renal sodium loss was found. Endocrinological studies revealed that the patient had isolated adrenocorticotropin (ACTH) deficiency and secondary adrenocortical insufficiency. Furthermore, an inappropriate secretion of antidiuretic hormone (ADH) in relation to the low plasma osmolality was observed at an early stage of hyponatremia. Hydrocortisone therapy effectively corrected his hyponatremia. Following the correction of hyponatremia, the value of free water clearance increased and the level of the plasma ADH decreased. Thus, the present case indicates that ACTH deficiency can cause the syndrome of inappropriate secretion of ADH.     

Ectopic Cushing's syndrome due to concurrent corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secreted by malignant gastrinoma.

Ectopic Cushing's syndrome due to various malignancies is not uncommon. However, a few cases of ectopic Cushing's syndrome caused by corticotropin-releasing hormone (CRH), or CRH with adrenocorticotropic hormone (ACTH) have been reported. A 28-year-old woman presented with acute upper gastrointestinal bleeding caused by an active ulcer, located atypically in the 2nd portion of duodenum. Further work-up revealed high gastrin levels and abdominal computed tomography (CT) scans showed a large pancreatic head mass with multiple liver metastases. The serum cortisol and ACTH levels were checked due to hypokalemia with metabolic alkalosis and recent amenorrhea. Cortisol and ACTH were both highly elevated with pituitary hyperplasia and elevated CRH. The existence of ectopic ACTH and CRH in the liver biopsy was also demonstrated immunohistochemically. Since an operation was not feasible, chemotherapy was conducted using paclitaxel and etoposide. These two drugs were chosen according to the IN VITRO chemotherapy response assay to maximize the treatment. This report demonstrates concurrent ACTH- and CRH-related ectopic Cushing's syndrome caused by malignant gastrinoma with multiple liver metastases that was treated with marginal success using a multidisciplinary medical approach.     

In vitro release and biosynthesis of tumor ACTH in ectopic ACTH producing tumors.

Tumor tissues obtained from 4 patients with the ectopic ACTH syndrome were studied for release and synthesis of tumor ACTH, using an in vitro incubation system. The effect of various agents on release of tumor ACTH was evaluated in three cases; beta-MSH released and adenosine 3',5'-monophosphate (cyclic AMP) formed in the tissue were determined in one. Biosynthetic experiments using labeled amino acid incorporation were performed in two cases. Secretion of tumor ACTH was significantly stimulated in all cases by crude rat median eminence extract which was also effective in stimulating beta-MSH secretion associated with elevated tissue cyclic AMP levels in one. Addition of cyclic AMP and dibutyryl cyclic AMP caused a significant increase in release of both tumor ACTH and beta-MSH in one. Biogenic amines (norepinephrine and serotonin) markedly elevated tussie cyclic AMP levels without a corresponding increase of hormone release in one. Incorporation experiments revealed that 3H- or 14C-phenylalanine was incorporated into immunoreactive ACTH of a larger molecular size (big ACTH) in both cases by chromatographic procedures. However, biological activity of big ACTH was found to be undetectable by an in vivo steroidogenic assay. A mild tryptic digestion of the big forms resulted in the appearance of little ACTH to which the major radioactive peak shifted. These data suggest that the mechanism of release of tumor ACTH and beta-MSH is very similar to that of the pituitary, and that intracellular cyclic AMP may in part play some role in release of both hormones. It is also suggested that some ectopic ACTH producing tumors predominantly synthesize big ACTH, a possible precursor of ACTH, with less bioactivity.     

Symptomatic hyponatremia as a presenting sign of hypothalamic-pituitary disease: a syndrome of inappropriate secretion of antidiuretic hormone (SIADH)-like glucocorticosteroid responsive condition

Hyponatremia associated with high urine osmolality is usually caused by inappropriate secretion of antidiuretic hormone. However, secondary hypoadrenalism is also accompanied by hyponatremia and with features indistinguishable from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). As secondary hypoadrenalism requires a specific treatment, a high index of suspicion and appropriate hormonal testing are required to differentiate between these two entities. We retrospectively studied 10 patients with a previously undiagnosed hypothalamic-pituitary disease who presented with an acute symptomatic hyponatremia. Mean age (+/-SD) was 65.1+/-8.4 yr. Mean serum sodium was 120.7+/-2.9 nmol/l and urinary osmolality, 453.9+/-74 mosmol/kg. Serum creatinine, urea and uric acid were low. Mean serum morning cortisol was low, 104.0+/-55.2 nmol/l. High-dose ACTH test showed adequate increment of serum cortisol in 3 out of 7 patients tested. Two of these 3 patients did not respond adequately to the low-dose ACTH test. Endocrine evaluation disclosed partial or complete hypopituitarism in all 10 patients. Six patients had pituitary macroadenomas, one had a craniopharyngioma, one patient had a large aneurysm of the internal carotid with sellar destruction and two others had empty sella. Treatment by fluid restriction did not affect serum sodium levels significantly. In contrast, all patients achieved normal sodium when treated by glucocorticosteroid. Central hypoadrenalism should be considered in any patient presenting with hyponatremia with high urine osmolality. Low-dose ACTH test should be performed and followed by appropriate endocrine and imaging studies. Hyponatremia in these patients is promptly corrected by glucocorticosteroid replacement.     

Severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone developed as initial manifestation of human herpesvirus‐6–associated acute limbic encephalitis after unrelated bone marrow transplantation

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo‐SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus‐6–associated post‐transplantation acute limbic encephalitis (HHV‐6 PALE) after allo‐SCT. A 45‐year‐old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus‐mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV‐6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV‐6 PALE, and close monitoring of serum sodium levels in high‐risk patients for HHV‐6 PALE is necessary for immediate diagnosis and treatment initiation.     

Idiopathic, sustained, inappropriate secretion of ADH with associated hypertension and thirst.

A 15 year old girl presented with excessive thirst and hypertension (170/110 mm Hg). Biochemical investigations revealed serum sodium 118 meq/liter, serum osmolality 238 mosmol/liter, urine sodium 90 meq/liter, urine osmolality 700 mosmol/liter, persistenly elevated serum antidiuretic hormone (ADH) levels (5.8 to 11.9 pg/ml) and no obvious cause for the hypertension. The hypertension is, at least in part, volume-related, diminishing with fluid restriction. Features of gross water intoxication (e.g., confusion, coma) have not occurred. The etiology of the inappropriate secretion of ADH is not obvious but is not thought to be due to "resetting of osmoreceptors" as evidenced by failure to maximally dilute urine following a water load test and persistently elevated serum ADH levels. A similar patient described by Epstein and associates in 1962 is presently well with persistent features of inappropriate secretion of ADH.     

Plasma atrial natriuretic hormone levels in patients with the syndrome of inappropriate antidiuretic hormone secretion

This study explored whether atrial natriuretic hormone (ANH) might be involved in the escape from salt and water retention that occurs in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Sixteen patients with low serum Na+ concentrations [123 +/- 1 (+/- SE) mmol/L] were studied. Each patient excreted urine that was hyperosmolar (mean, 391 +/- 4 mosmol/kg) in relation to serum osmolality (mean, 258 +/- 4 mosmol/kg). Sodium excretion (81 +/- 20 mmol/L) also was inappropriate to the low serum Na+ level. The probable causes of SIADH were head trauma (4), pneumonia (5), lung cancer (3), and chlorpropamide therapy (4). In the nontumor patients, plasma and/or urinary vasopressin (AVP) concentrations were in the normal range, but inappropriate for serum osmolality. Urinary AVP values of 50 pg/mL or more (greater than 46 pmol/L) were found in the three tumor patients. The mean plasma ANH concentration was 6-fold higher than that in normal subjects [296 +/- 51 vs. 51 +/- 13 pg/mL (100 +/- 20 vs. 17 +/- 4 pmol/L); P less than 0.01]. Six SIADH patients were studied again after brief (1-3 days) water restriction. Although serum osmolality increased in each, their plasma AVP concentrations decreased very little, and urinary AVP excretion and plasma ANH did not change. These results indicate that plasma ANH levels are markedly increased in patients with SIADH. Their increased ANH secretion may antagonize water retention resulting from the inappropriate AVP secretion.     

ACTH-secreting medullary carcinoma of the thyroid presenting a severe idiopathic osteoporosis and senile purpura: report of a case and review of the literature.

A 64-yr-old female presented with severe osteoporosis and easy bruisability of over 2-yr duration. Biopsy of a neck mass revealed medullary carcinoma of the thyroid. Subsequently, lymphangitic pulmonary metastases were demonstrated which had been present radiographically for at least 4 yr. Basal serum calcitonin was markedly elevated and increased during calcium infusion. The diagnosis of ectopic ACTH syndrome was first entertained when hypokalemic alkalosis was observed during evaluation of her carcinoma. Elevated urinary 17-hydroxycorticosteroids, 17-ketosteroids, plasma cortisol, and immunoreactive plasma ACTH levels were documented. Adrenal steroidogenesis seemed to suppress on high dose dexamethasone. The primary tumor and its metastases contained high concentrations of immunoreactive ACTH and beta-melanocyte-stimulating hormone. Hepatic metastases contained extremely high concentrations of calcitonin. In contrast to the usual presentation of the ectopic ACTH syndrome as primarily hypokalemic alkalosis and glucose intolerance, patients with relatively benign and indolent ACTH-secreting tumors, such as certain cases of medullary carcinoma of the thyroid, may present with more typical signs and symptoms of Cushing's syndrome. The more pronounced cushingoid features in this latter group presumably reflects a more prolonged period of exposure to elevated glucocorticoid levels. Ten cases of ACTH-secreting medullary carcinoma of the thyroid from the literature are discussed. Extopic ACTH production by such tumors should be considered in the evaluation of patients with Cushing's syndrome or unexplained severe osteopenia.     

Cushing's syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin

Adrenal phaeochromocytoma rarely causes ectopic ACTH syndrome. We describe a 44-yr-old hypertensive woman who was Cushingoid and markedly pigmented. Laboratory studies indicated severe hypokalaemia, abnormal liver function tests, and random serum cortisols greater than 1660 nmol/L. Urinary catecholamines were markedly increased. An abdominal computed tomography scan showed a 4-cm left adrenal mass and an hypertrophied right adrenal. ACTH levels were elevated at 200 pmol/L, but ACTH precursors, which cross-react in the ACTH assay, were more highly elevated at 1625 pmol/L. The tumor cells cultured in vitro also secreted ACTH precursors, whereas ACTH levels were undetectable. Because the patient was highly pigmented, we measured circulating concentrations of alpha-MSH, which were undetectable and certainly insufficient to stimulate melanogenesis, suggesting that tumorderived ACTH precursors or ACTH were responsible for the pigmentation. A laparoscopic adrenalectomy resulted in remission of the Cushing's syndrome and dramatic reduction in the pigmentation. Before operation, treatment of the patient with metyrapone and replacement dexamethasone decreased cortisol from more than 1660 to less than 20 nmol/L. Surprisingly, this resulted in a decrease in ACTH precursors to 100 pmol/L and ACTH to 9.0 pmol/L. In vitro treatment of the tumor cells with dexamethasone for 24 or 40 h increased ACTH precursor secretion. In summary, this phaeochromocytoma causing Cushing's syndrome secreted primarily ACTH precursors, which seemed to cause the marked pigmentation. In vivo and in vitro evidence suggests that glucocorticoids induced ACTH precursor secretion.     

The syndrome of inappropriate antidiuretic hormone secretion (SIADH): pathophysiologic mechanisms in solute and volume regulation.

1. Studies on eight patients were performed to clarify the mechanism(s) of altered sodium metabolism and volume regulation in SIADH. The mechanism controlling water excretion was also studied to determine whether there is evidence that altered osmoregulation may be the basis for inappropriate ADH secretion in some patients. 2. These studies show that cumulative sodium balance and aldosterone secretion rates in patients with SIADH are negatively correlated with water intake. There is also a negative correlation between aldosterone secretion and urinary sodium excretion. In the absence of normal urine diluting ability, this increased excretion of sodium becomes a mechanism that allows an increased quantity of water to be excreted despite the persistence of an ADH effect on the renal tubules. 3. Within the range of hyponatremia observed in our studies, changes in serum sodium concentration were accounted for by changes in solute and water balance. One patient, who was potassium deficient during the studies, retained large quantities of sodium and potassium that could not be accounted for by an increase in either serum osmolality or body weight. These observations suggest that intracellular osmotically active solute is either lost or "inactivated" in some manner as intracellular potassium is replenished. 4. Marked impairment of urine diluting ability was demonstrated in all patients. However, two patients with SIADH associated with pulmonary tuberculosis exhibited graded responses to water loading, which suggests that ADH secretion may have been suppressed as serum osmolality was progressively reduced. Whether this can be attributed to a basic alteration or "re-setting" or osmoreceptor function, or is merely an indication that greater than normal reductions of serum osmolality are required to inhibit potent nonosmotic stimuli, remains to be determined.     

ADH (anti-diuretic hormone), aldosterone (PA) and renin activity (PRA) in patients with respiratory failure

Plasma ADH, PA and PRA in patients with respiratory failure (RF) were studied. RF patients were divided into 4 groups, i.e. acute RF (ARF) and chronic RF (CRF), with or without hypercapnia. The levels of these hormones were significantly higher in RF than those in control subjects, moreover, they were markedly elevated in ARF than those in CRF. In multiple regression analysis, ADH correlated with PaO2, pH and PRA in RF patients, but correlated with serum osmolality in control subjects. It was considered that ADH in RF was affected by the direct effect of blood gases and circulatory disorder. The mechanism of elevated PA and PRA in RF probably was mediated through restriction of intake of water and Na, reduction of renal blood flow and decreased ACE often occurred in RF. Abnormally elevated hormones are more often recognized in edematous patients than in nonedematous patients. It was suggested that many patients with RF develop heart failure or edema due to hormonal abnormalities.     

Hyponatremia of hypothyroidism. Appropriate suppression of antidiuretic hormone levels.

A hypothyroid, 72-year-old woman with idiopathic hypopituitarism manifested severe hyponatremia, plasma hypoosmolality, and inappropriately elevated urine osmolality suggestive of a syndrome of inappropriate antidiuretic hormone secretions. The hyponatremia did not respond to demeclocycline hydrochloride, and antidiuretic hormone (ADH) levels measured by a specific radioimmunoassay were appropriately suppressed. Subsequent replacement therapy with levothyroxine sodium resulted in correction of the hyponatremia. Thus, both direct assay as well as hormone blockade failed to show an action of ADH in mediating the water retention.     

β-ENDORPHIN AND β-MSH IN HUMAN PLASMA

The aim of this study was to establish whether or not a peptide with chromatographic and immunological properties of beta-endorphin exists in human plasma. Using direct chromatography under conditions designed to minimize generation of beta-endorphin and beta-MSH from beta-LPH, we invariably found a peptide with beta-endorphin immunoreactivity eluting in the position of beta h-endorphin on gel chromatography in samples of plasma from patients with elevated ACTH and LPH levels. beta-MSH was only found in the plasma of one patient with the ectopic ACTH syndrome.     

Usefulness of FDG-PET in detecting an ADH-secreting tumor: a case report

We report a case of a 41-year-old woman who was diagnosed as having the syndrome of inappropriate secretion of ADH (SIADH). There was no evidence of any disorders of the central nervous system, lung diseases, or drugs causing SIADH. Positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) was performed and indicated a tumor of the uterine cervix. After resection of the tumor, both serum sodium level and serum osmolarity were normalized concomitantly with a decrease in serum ADH level. This is the first case report suggesting the usefulness of a FDG-PET scan to detect an occult cancer responsible for SIADH. It seems plausible that FDG-PET may be helpful in the diagnosis of other ectopic hormone-producing tumors such as ectopic ACTH-producing tumors that cause Cushing's syndrome.     

Posttraumatic neurogenic hyponatremia with late onset

Ten months following a severe head injury, a 26-year-old man developed a syndrome of inappropriate secretion of antidiuretic hormone (ADH) with a grand mal seizure occurring after an increased intake of non alcoholic beverages. The water loading test was negative but the sorbitol infusion test was positive. In the basal state, plasma concentration of ADH was inappropriate to plasma osmolality. ADH has also been measured during dynamic tests (infusions of sorbitol and of normal saline; complete and partial water restriction; propranolol and diphenylhydantoin treatments). In spite of the poor sensitivity of these measurements when ADH concentrations are low, our results indicate that the plasma osmolality threshold at which ADH secretion is inhibited was probably reset at a level lower than normal.     

PITUITARY ACTH DEPENDENT CUSHING''S SYNDROME DUE TO ECTOPIC PRODUCTION OF A BOMBESIN-LIKE PEPTIDE BY A MEDULLARY CARCINOMA OF THE THYROID

A 41-year-old man presented with Cushing's syndrome and the biochemical features of ectopic ACTH production. Investigation revealed mediastinal metastases from a medullary carcinoma of the thyroid. The peripheral plasma contained grossly elevated levels of bombesin-like immunoreactivity (irBombesin) as well as calcitonin; blood sampling via a venous catheter confirmed a gradient of irBombesin, but not of ACTH, in the mediastinal vein draining the tumour. On extraction the tumour contained a bombesin-like peptide, but not vasopressin or corticotrophin releasing factor and only very low levels of ACTH; immunohistochemical studies showed positive immunostaining for bombesin and calcitonin but none for ACTH or CRF. No ACTH was released from dispersed tumour cells in vitro. However an extract of the tumour stimulated ACTH release in vitro from perifused dispersed rat anterior pituitary cells. This is the first reported case of Cushing's syndrome due to ectopic production of a bombesin-like peptide, causing excessive pituitary ACTH secretion.     

Ektope Hormonsekretion bei neuroendokrinen Tumoren

Ectopic hormone production is a rare complication in neuroendocrine tumors. Tumors producing corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) are most commonly observed, leading to the classical symptoms of Cushing’s syndrome. Additionally, a very low percentage of neuroendocrine tumors can produce growth hormone-releasing hormone (GHRH) leading to classical features of acromegaly. Moreover, ectopic antidiuretic hormone (ADH) secretion has been described in neuroendocrine tumors presenting as hyponatremia due to the syndrome of inappropriate ADH secretion. Other ectopic hormone secretions, such as paraneoplastic gonadotropin release are rarely observed. Ectopic hormone secretion is not usually associated with a detectable pituitary mass and diagnosis is based on the measurement of circulating peptides. This is frequently assisted by imaging techniques, such as somatostatin receptor scintigraphy. Therapeutically a curative approach is the primary goal but in advanced tumors palliative treatment aims to control symptoms with the help of specific antihormonal compounds, such as somatostatin analogues.     

Occult pulmonary malignancy in syndrome of inappropriate ADH secretion with normal ADH levels

Although the syndrome of inappropriate ADH secretion (SIADH) has many causes, principally pulmonary, central nervous system or neoplastic disease, and drugs, patients may present with SIADH in whom the etiology is not readily evident. We measured serum ADH levels in such an individual in both the eunatremic and water-loaded states and found levels to be undetectable despite failure to dilute the urine. A small oat cell pulmonary carcinoma was ultimately diagnosed with lung tomograms and cytology. Following a partial response to water restriction, demeclocycline was effective in producing a water diuresis that restored the serum sodium concentration to normal. Patients with clinical SIADH but low serum ADH levels can harbor a malignant or benign process that, notwithstanding the low ADH levels, may still remain responsive to demeclocycline, suggesting either neoplastic production of a biologically-active, immunologically-inactive ADH-like peptide, or increased renal tubular sensitivity to ADH.     

Cushing''s syndrome secondary to ectopic ACTH secretion from metastatic breast carcinoma

Breast carcinoma is a rare cause of ectopic ACTH syndrome. There are only two previously reported cases in which ACTH secretion is documented. We describe the case of a 56-year-old woman who presented with clinical and biochemical features of ectopic ACTH syndrome in the setting of metastatic breast carcinoma. Despite aggressive management of her ectopic ACTH syndrome, her course was complicated by opportunistic infection, respiratory failure and death. Immunostaining of the breast metastases for ACTH was positive and in situ hybridization revealed proopiomelanocortin gene expression. This is the first reported case of ectopic ACTH syndrome associated with metastatic breast cancer in which the technique of in situ hybridization has been used to confirm the breast cancer metastases as the source of ectopic ACTH secretion.