Introduction
Paraneoplastic syndromes are a heterogeneous group of signs and symptoms associated with the evolution of malignant disease, but which are not the direct effect of the primary tumor, adenopathy or metastasis. These may precede or may develop in parallel with the neoplastic disease, and the effective treatment of neoplasia may lead to the disappearance of these syndromes. However, the patients with immune or neurological etiology are not predictably resolved after the treatment of the malignancy.
The syndrome of inappropriate antidiuretic hormone secretion (SI-ADH) – general data
Schwartz-Bartter’s syndrome (SI-ADH) is due to paraneoplastic ADH secretion. ADH – or arginine-vasopressin – is a peptide of nine amino acids secreted by the hypothalamus, with the function of maintaining plasma osmolarity (normal plasma osmolality is between 286 and 294 mOsm/l), acting on collector tubes to increase water permeability.
Associated malignancies. Among the neoplasms quoted in the medical literature as associating SI-ADH, small cell pulmonary bronchial cancer occupies the first place (approximately 75%), unlike the non-small lung cancer, in which this paraneoplastic syndrome occurs at a much lower rate (approximately 1%). Also, cases of secondary SI-ADH have been described after surgical manipulations in bronchial-pulmonary cancer (puncture, lobectomy, pneumomectomy). Other malignancies that associate SI-ADH are: mesothelioma, lymphoma, Ewing sarcoma, thymomas, primary brain tumors, head and neck cancer, digestive (gastric, duodenal, pancreatic) and genito-urinary cancers (bladder, prostate, uterus).
Regardless of the type and location of neoplasia, the syndrome can be determined by tumor lysis syndrome due to injury of the kidneys.
Schwartz-Bartter syndrome consists of: increased urinary osmolality, elevated urinary sodium, low serum osmolality, in a euvolemic patient, without edema, who is not hypotensive, with no renal, cardiac, adrenal, and thyroid dysfunction, and in the absence of diuretic treatment. This syndrome is much more common than the number of cases cited in the literature.
Clinical characteristics. Schwartz-Bartter’s syndrome is clinically described through all clinical manifestations of water intoxication that associates digestive manifestations (anorexia, nausea, vomiting), neuropsychiatric manifestations (euphoria, aggressiveness, mental confusion), to which seizures may be added when the plasma sodium concentration drops below 120mEq/l, a symptomatology that can culminate with the induction of coma due to cerebral edema. Most patients are asymptomatic. When it becomes manifest, the central nervous system toxicity is present, which is directly proportional to the intensity of the manifestations, so that in the initial stage patients suffer from fatigue, anorexia, headache, and discreet alteration of mental status. As the syndrome progresses, it associates delirium, convulsions, coma and rarely death; therefore, it is one of the oncological emergencies.
Bio-humoral changes are expressed by the dilutional hyponatremia (constant), natriuresis, urine hyperosmolarity, and serum hypoosmolality.
Diagnostic criteria:
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Serum sodium below 135 mEq/L.
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Plasma osmolarity below 280 mOsm/L.
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Urine osmolarity above 100 mOsm/L.
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Urine sodium above 20 mEq/L.
The differential diagnosis is made with: laboratory hyponatraemia, hyponatraemia associated with volume depletion as in vomiting, fluid sequestration, diarrhea, excessive sweating. Elevated urine sodium levels above 20mEq/l may be due to diuretics’ usage, salt loss, mineral deficiency, corticosteroid use, osmotic diuresis, metabolic alkalosis, renal tubular acidosis, hypothyroidism and hypocorticism. Also, the differential diagnosis must take into account the hyponatremia associated with volemic expansion with urine sodium less than 20 mEq/l from acute or chronic kidney failure.
Schwartz-Bartter syndrome and chemotherapy
In some rare cases, chemotherapy may reveal, contribute or aggravate this syndrome. Chemotherapeutic agents whose usage may cause or aggravate this syndrome are: cyclophosphamide, vincristine, vinorelbine, vinblastine, imatinib, interferon alpha and gamma, and methotrexate.
Cyclophosphamide. It was the first drug to show a ADH-like effect, in 1974. More recent studies have shown a direct toxic effect of cyclophosphamide or of its metabolites on renal collecting ducts, causing excessive water retention. The occurrence of the syndrome in patients treated with cyclophosphamide is closely correlated with the dose administered, most often occuring at higher doses (above 50 mg/kg), without excluding the possibility of the occurrence of the manifestation at low doses (less than 10 mg/kg).
Vinca alkaloids. One of the proposed mechanisms is its neurotoxic effect, by stopping the cells of the posterior hypothalamus in the metaphase, causing cell membrane rupture and the release of inadequately high concentrations of antidiuretic hormone. Another hypothesis is the direct tubular destruction in the proximal convoluted tubule, affecting the tubular reabsorption of phosphorus and chloride, resulting in a decrease in the concentration of these electrolytes in the blood, associated with SI-ADH hyponatraemia.
Hyponatremia is a well-known direct complication of the administration of cytotoxic drugs. Therefore, routine monitoring of electrolytes (plasma concentrations) is required.
Treatment
1. Removal of the tumor.
2. Symptomatic treatment is based primarily on water restriction (500 ml/24 h), osmotic diuresis (mannitol, urea – PEV). In case of failure, loop diuretics (furosemide) and lithium carbonate (900-1200 mg/24 h) and demeclocycline 600 mg/day (acting as an indirect antagonist of V2 receptor of the vasopresin in the kidney) are used.
In case of severe hyponatraemia with neurological manifestations, the treatment with hypertonic saline solution is instituted. In medical literature there are many recommendations for the correction of chronic hyponatraemia (installed in more than 48 hours), the limits being between 8 and 12 mEq/day. To lower the risk of pontine myelinolysis, most authors recommend a total dose of 8 mEq/day. Isotonic saline solution has no effect in increasing the plasmatic sodium levels. Salt tablets may be administered, their effect being potentiated by the administration of loop diuretics.
The administration of vasopressin receptor antagonists increases the diuresis, without interfering with sodium and potassium excretion, but it is recommended to avoid V2 receptor antagonists due to increased thirst sensation and high cost.
Conflict of interests: The authors declare no conflict of interests.