Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion.

We have studied the effects of demeclocycline on the water metabolism of a patient with the syndrome of inappropriate antidiuretic hormone (ADH) secretion who presented with a serum sodium concentration of 110 meq/litre. Free water clearance was studied before, during, and after treatment with demeclocycline. This study shows that demeclocycline (900 mg/day) can at least partially inhibit the action of ADH in the setting of tumor-induced ADH secretion, with the production of a reversible, partial nephrogenic diabetes insipidus, and with few or no side effects. Demeclocycline may be useful in the treatment of chronic inappropriate ADH 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.     

Pathophysiologic and pharmacologic alterations in the release and action of ADH

The physiologic factors involved in vasopressin (ADH) release and action are reviewed with emphasis on the interaction between osmotic and volume stimuli to the discharge of ADH. Abnormalities in reception of stimuli to ADH release, and in the impaired synthesis and release of ADH, are reviewed in relation to the causes of diabetes insipidus, and information on the biochemical changes which have been described in patients with nephrogenic diabetes insipidus is also discussed. We summarize the pathologic lesions and associated diseases found in 54 of our patients with diabetes insipidus. Criteria for establishing the diagnosis of diabetes insipdus are reviewed with emphasis on the dehydration test, including the importance of measuring plasma osmolality at the conclusion of water deprivation. Treatment of diabetes insipidus is briefly discussed with emphasis on the use of DDAVP and oral agents. The syndrome of inappropriate ADH secretion (SIADH) is reviewed including our experience with 39 patients. The differential diagnosis of SIADH, including the value of water loading and the measurement of ADH levels, is discussed. We comment on treatment of these patients including the use of investigational drugs. Lastly, we review the pharmacologic features and clinical relevance of some drugs which alter the release and action of ADH.     

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.     

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.     

Hyponatremia and antidiuresis syndrome

Antidiuretic hormone (ADH), or arginine vasopressin (AVP), is primarily regulated through plasma osmolarity, as well as non-osmotic stimuli including blood volume and stress. Links between water-electrolyte and carbohydrate metabolism have also been recently demonstrated. AVP acts via the intermediary of three types of receptors: V1a, or V1, which exerts vasoconstrictive effects; pituitary gland V1b, or V3, which participates in the secretion of ACTH; and renal V2, which reduces the excretion of pure water by combining with water channels (aquaporin 2). Antidiuresis syndrome is a form of euvolaemic, hypoosmolar hyponatraemia, which is characterised by a negative free water clearance with inappropriate urine osmolality and intracellular hyper-hydration in the absence of renal, adrenal and thyroid insufficiency. Ninety percent of cases of antidiuresis syndrome occur in association with hypersecretion of vasopressin, while vasopressin is undetectable in 10% of cases. Thus the term “antidiuresis syndrome” is more appropriate than the classic name “syndrome of inappropriate ADH secretion” (SIADH). The clinical symptoms, morbidity and mortality of hyponatraemia are related to its severity, as well as to the rapidity of its onset and duration. Even in cases of moderate hyponatraemia that are considered asymptomatic, there is a very high risk of falls due to gait and attention disorders, as well as rhabdomyolysis, which increases the fracture risk. The aetiological diagnosis of hyponatraemia is based on the analysis of calculated or measured plasma osmolality (POsm), as well as blood volume (skin tenting of dehydration, oedema). Hyperglycaemia and hypertriglyceridaemia lead to hyper- and normoosmolar hyponatraemia, respectively. Salt loss of gastrointestinal, renal, cutaneous and sometimes cerebral origin is hypovolaemic, hypoosmolar hyponatraemia (skin tenting), whereas oedema is present with hypervolaemic, hypoosmolar hyponatraemia of heart failure, nephrotic syndrome and cirrhosis. Some endocrinopathies (glucocorticoid deficiency and hypothyroidism) are associated with euvolaemic, hypoosmolar hyponatraemia, which must be distinguished from SIADH. Independent of adrenal insufficiency, isolated hypoaldosteronism can also be accompanied by hypersecretion of vasopressin secondary to hypovolaemia, which responds to mineralocorticoid administration. The causes of SIADH are classic: neoplastic (notably small-cell lung cancer), iatrogenic (particularly psychoactive drugs, chemotherapy), lung and cerebral. Some causes have been recently described: familial hyponatraemia via X-linked recessive disease caused by an activating mutation of the vasopressin 2 receptor; and corticotropin insufficiency related to drug interference between some inhaled glucocorticoids and cytochrome p450 inhibitors, such as the antiretroviral drugs and itraconazole, etc. SIADH in marathon runners exposes them to a risk of hypotonic encephalopathy with fatal cerebral oedema. SIADH treatment is based on water restriction and demeclocycline. V2 receptor antagonists are still not marketed in France. These aquaretics seem effective clinically and biologically, without demonstrated improvement to date of mortality in eu- and hypervolaemic hyponatraemia. Obviously treatment of a corticotropic deficit, even subtle, should not be overlooked, as well as the introduction of fludrocortisone in isolated hypoaldosteronism and discontinuation of iatrogenic drugs.     

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.     

Ectopic production of antidiuretic hormone (adh), adrenocorticotrophic hormone (ACTH) and beta-melanocyte stimulating hormone (beta-MSH) by an oat cell carcinoma of the lung.

A 61 year old woman presented with profound hyponatremia and markedly low serum osmolality. Urine osmolality was greater than the serum osmolality, an abnormality that was corrected by water restriction, suggesting inappropriate ADH secretion. Although there were no physical signs of Cushing's syndrome, her serum potassium level was low and markedly elevated levels of plasma and urine corticosteroids were not altered by the administration of large amounts of dexamethasone, suggesting the ectopic ACTH-MSH syndrome. Plasma levels of immunoreactive ACTH and beta-MSH were elevated. At autopsy, a metastastic oat cell carcinoma of the lung, not detected antemortem by chest roentgenograms and bronchoscopy, was found. Immunoreactive ADH, ACTH and beta-MSH were detected in the primary tumor and in metastases to the liver. beta-MSH was also detected in the spleen, in which metastases were observed. This is the first documented case of the simultaneous production of ADH, ACTH and beta-MSH by neoplastic tissue associated with clinical manifestations of the syndrome of inappropriate ADH secretion and the ectopic ACTH-MSH syndrome.     

Hyponatremia in intracranial disorders

Hyponatremia is a common electrolyte disturbance following intracranial disorders. Hyponatremia is of clinical significance as a rapidly decreasing serum sodium concentration as well as rapid correction of chronic hyponatremia may lead to neurological symptoms. Especially two syndromes leading to hyponatremia in intracranial disorders need to be distinguished, as they resemble each other in many, but not all ways. These are the syndrome of inappropriate ADH secretion (SIADH) and the cerebral salt wasting syndrome (CSW). The syndrome of inappropriate ADH secretion is characterized by water retention, caused by inappropriate release of ADH, leading to dilutional hyponatremia. The cerebral salt wasting syndrome on the other hand, represents primary natriuresis, leading to hypovolemia and sodium deficit. SIADH should be treated by fluid restriction, whereas the treatment of CSW consists of sodium and water administration. However, in the literature there is abundant evidence that hyponatremia in intracranial diseases is mostly caused by CSW. Therefore, treatment with fluid and salt supplementation seems indicated in patients with intracranial disorders who develop hyponatremia and natriuresis.     

Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

The syndrome of inappropriate ADH secretion (SIADH), also recently referred to as the "syndrome of inappropriate antidiuresis", is an often underdiagnosed cause of hypotonic hyponatremia, resulting for instance from ectopic release of ADH in lung cancer or as a side-effect of various drugs. In SIADH, hyponatremia results from a pure disorder of water handling by the kidney, whereas external Na+ balance is usually well regulated. Despite increased total body water, only minor changes of urine output and modest edema are usually seen. Renal function and acid-base balance are often preserved, while neurological impairment may range from subclinical to life-threatening. Hypouricemia is a distinguishing feature. The major causes and clinical variants of SIADH are reviewed, with particular emphasis on iatrogenic complications and hospital-acquired hyponatremia. Effective treatment of SIADH with water restriction, aquaretics, or hypertonic saline + loop diuretics, as opposed to worsening of hyponatremia during parenteral isotonic fluid administration, underscores the importance of an early accurate diagnosis and careful follow-up of these patients.     

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.     

Inappropriate ADH secretion-induced hyponatremia and associated with paroxetine use

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRI) are the most common antidepressants prescribed for elderly people. Although they are generally better tolerated than other antidepressant treatment classes, they can be responsible for potentially life-threatening hyponatremia, related to syndrome of inappropriate antidiuretic hormone secretion (SIADH). OBSERVATION: A 64 years-old woman was hospitalized for cognitive function alteration and vomiting after introduction of paroxetine for depressive symptoms. Serum investigations revealed hyponatremia (121 mmol/l) with low plasma osmolarity and normal natriuria consistent with diagnosis of SIADH. Hyponatremia was reversible after paroxetine withdrawal. DISCUSSION: Hyponatremia induced by SIADH is a serious but underestimated complication of SSRI treatment. This complication occurs in the elderly people within the first month of treatment. Monitoring of the serum sodium concentration during the first month of treatment is recommended for older patients.     

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.     

Syndrome of recurrent increased secretion of antidiuretic hormone following multiple doses of vincristine

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been recognized to occur following treatment with vincristine. None of the reports have provided information regarding its potential for recurrence on further challenge with vincristine (VCR), an agent generally required for repeated use in patients with malignancies. Symptomatic hyponatremia and SIADH that occurred 8 days following administration of VCR in a child with acute lymphatic leukemia was documented with specific radioimmunoassay of urinary ADH levels. The further occurrence of recurrent elevations in ADH excretion 8-10 days following repeated treatment with VCR was also observed. However, SIADH was prevented by prophylactic rigorous fluid restriction. The occurrence of SIADH following VCR therefore does not preclude the further safe usage of this drug.     

Syndrome of inappropriate antidiuretic hormone secretion associated with meningeal infiltration of tumor cells and elevated interleukin-1 beta and interleukin-6 in cerebrospinal fluid of a patient with adult T-cell leukemia

A 73-year-old man with acute adult T-cell leukemia (ATL) in remission was re-admitted to our hospital due to drowsiness, headache, and bilateral knee joint pain on May 17, 1998. On admission, examinations revealed decreased serum sodium concentration (112 mEq/l), low plasma osmotic pressure (259 mOsm/l), and elevated antidiuretic hormone(5.6 pg/ml). Cerebrospinal fluid examination showed an increased number of abnormal flower-like lymphocyte (951/microliter). Brain computed tomography and magnetic resonance imaging found no abnormality in the hypothalamus or pituitary gland. These findings yielded a diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH). Though ATL patients typically exhibit a variety of clinical symptoms, SIADH is rarely one of the complications. Further investigation showed that IL-1 beta and IL-6 concentrations were increased in spinal fluid but not in serum. Recently, it has been reported that exogeneous IL-6 is an inducer of ADH secretion, and that primary ATL cells and HTLV-I infected cell lines can produce IL-6. In this case, we speculated that IL-6 produced by ATL cells that infiltrated a cerebral lesion may have played an important role in the development of SIADH.     

Syndrome of inappropriate secretion of antidiuretic hormone associated with amyotrophic lateral sclerosis in respiratory failure

A 65-year-old man who had muscle weakness and dysarthria was admitted for investigation of motor neuron disease. He had lost 12 kg of weight in 6 months. Neurological findings disclosed upper and lower motor neuron disturbances with normal sensory nerve function, and needle electromyography showed a neurogenic pattern. Laboratory findings on admission demonstrated dilutional hyponatraemia due to an excessive secretion of antidiuretic hormone (ADH). Based on these findings, the patient was diagnosed as having the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with amyotrophic lateral sclerosis (ALS). During the night of first hospital day, the patient complained of severe dyspnoea, and mechanical ventilation was commenced. Following the mechanical ventilation, plasma ADH levels and serum sodium concentration were normalized. We propose that respiratory failure secondary to the atrophy of respiratory muscle might be responsible for the development of SIADH.     

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.     

Atrial natriuretic peptide in children with pneumonia

Atrial natriuretic peptide (ANP) has known natriuretic, diuretic, and vasodilatatory effects. It is synthesized and stored in the atrial cells. Stretching of the atrial muscle fibers during an increase in venous return sets a response of ANP release into the blood stream. High levels of ANP were measured in a number of lung diseases. Pneumonia in children is frequently accompanied by the hyponatremia of the syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH). High levels of ANP were found among patients with SIADH. Our objective was to determine if ANP plasma levels are altered in children with pneumonia, and to evaluate a possible correlation between severity of pneumonia and ANP levels. Blood samples from 28 children diagnosed with pneumonia were collected. Plasma ANP levels were determined by radioimmunoassay and compared to levels in 25 children without pneumonia. ANP levels in the pneumonia group (mean +/- SD, 16.02 +/- 11.69 pg/ml) increased significantly (P < 0.01) compared to levels in the control group (mean +/- SD, 7.44 +/- 9.29 pg/ml). Children in the pneumonia group also exhibited low levels of plasma sodium (mean +/- SD, 134.88 +/- 2.5 mmol/l) compared to levels in children without pneumonia (mean +/- SD, 139.77 +/- 4.15 mmol/l) (P < 0.01). There was no correlation between ANP plasma levels and severity of pneumonia. In conclusion, ANP levels in children with pneumonia, as in other lung diseases, are increased. High ANP levels may play a role in maintaining water and electrolyte equilibrium during a state of inappropriate ADH secretion accompanying pneumonia.     

Effect of ADH1B genotype on alcohol consumption in young Israeli Jews

BACKGROUND: The alcohol dehydrogenase 1B (ADH1B) genotype affects the risk for alcoholism, with elevated prevalence of a protective allele in Jews. Alcohol consumption is increasing among younger Israeli Jews, reflecting environmental influences. We investigated whether the relationship of ADH1B genotype with alcohol consumption differed between younger and older adult Israelis. METHODS: Israeli community residents aged 22 to 65 participated in a structured interview that included questions on the maximum number of drinks on an occasion (Maxdrinks). The ADH1B genotype was determined for 68 participants and dichotomized into nonprotective (ADH1B(*)1/1) and protective (ADH1B(*)1/2 or ADH1B(*)2/2) genotypes. Using Maxdrinks as the dependent variable, Poisson's regression was used to test an age x genotype interaction. RESULTS: The ADH1B genotype interacted significantly with age (p=0.01) in a Poisson's model with Maxdrinks as the outcome. Among participants >or=33 years, Maxdrinks was low and unrelated to the ADH1B genotype. Among participants <33 years with ADH1B(*)1/2 or ADH1B(*)2/2, Maxdrinks was also low (mean, 2.6 drinks) but among those with ADH1B(*)1/1, Maxdrinks was substantially higher (mean, 6.2 drinks). CONCLUSION: Maximum lifetime drinking among younger adult Israelis without genetic protection exceeded thresholds for risky and unsafe drinking (>or=5 drinks). Environmental influences promoting greater drinking among younger Israelis may particularly affect those with the nonprotective, more common ADH1B genotype.