REVIEW

Sindromul secreţiei inadecvate de hormon antidiuretic (sindromul Schwartz-Bartter)

 The syndrome of inappropriate antidiuretic hormone secretion (Schwartz-Bartter syndrome)

Beatrice Bulai , Anda Cojocariu

First published: 03 aprilie 2018

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.42.1.2018.1553

Abstract

Paraneoplastic syndromes are a very important chapter in the practice of medical oncology. Their recognition may reveal an occult neoplasia to the oncologist (when occur as early manifestations of neoplasia), they can mimic a metastatic disease or, on the contrary, they can mask the complications of a cancer. Also, they may aggravate the clinical condition of the pacient, sometimes becoming lethal. We chose to discuss the syndrome of inappropriate antidiuretic hormone secretion (SI-ADH) from the group of paraneoplastic syn­dromes, for at least two considerations: the first is the large num­ber of cytostatics that can cause these syndromes, and the other is the clinical characteristics of SI-ADH,  that have as a particularity the absence of signs and symptoms in early stages and the severity of neurological manifestations in advanced stages – coma and death. The present article aims at: knowing the physiopathological mechanism of SI-ADH, the main associated neoplasia, the recognition of the clinical and paraclinical signs, the main criteria of diagnosis and differential diagnosis, and the principles of treatment.

Keywords
Schwartz-Bartter syndrome, symptoms, chemotherapy

Rezumat

Sindroamele paraneoplazice reprezintă un capitol foarte im­por­tant în practica oncologiei medicale, iar recunoaşterea acestora îi poate releva medicului oncolog o neoplazie ocultă (atunci când aceste sindroame apar ca manifestări precoce ale neoplaziei) ori pot mima boala metastatică sau, dimpotrivă, pot masca com­plicaţiile unui cancer şi, nu în ultimul rând, pot complica starea clinică a pacientului, devenind uneori letale. Am ales să dezbatem, din  grupul sindroamelor para­neo­pla­zi­ce, sindromul secreţiei inadecvate de antidiuretic (SI-ADH), din cel puţin două considerente: primul este numărul mare al citostaticelor care pot determina acest sindrom, iar al doilea este reprezentat de tabloul clinic al SI-ADH, ce are ca particularitate sărăcia semnelor şi simptomelor în fazele in­ci­piente şi gravitatea manifestărilor neurologice şi a injuriei asu­pra sistemului nervos central, ducând la comă şi deces, în sta­diile avansate. Articolul de faţă îşi propune: cunoaşterea me­ca­nis­mului fiziopatologic al SI-ADH, cunoaşterea prin­ci­palelor neoplazii asociate, recunoaşterea semnelor clinice şi paraclinice, cunoaşterea principalelor criterii de diagnostic, a diagnosticului diferenţial şi a principiilor de tratament.

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:

  • Serum sodium below 135 mEq/L.
  • Plasma osmolarity below 280 mOsm/L.
  • Urine osmolarity above 100 mOsm/L.
  • 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.

Bibliografie

  1. Gross P. Clinical management of SIADH. Ther Adv Endocrinol Metab. 2012; Apr; 3(2): 61–73.
  2. Pillai BP et al. Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder. Indian J Endocrinol Metab. 2011; Sep; 15(Suppl3): S208–S215.
  3. Baker M et al. Cyclophosphamide-Induced Severe Acute Hyponatremic Encephalopathy in Patients with Breast Cancer: Report of Two Cases. Case Rep Oncol. 2014 May-Aug; 7(2): 550–554.
  4. Salcedo I, Aguayo A, Zuñiga J. Syndrome of Inappropriate Antidiuretic Hormone Secretion in a Patient with a Nodular Lymphocyte-Predominant Hodgkin Lymphoma. A Case Report and Review of Literature. Journal of Hematology and Oncology Research. 2015; 2(1):1-6.
  5. Cyclophosphamide Side Effects. Available at: https://www.drugs.com/sfx/cyclophosphamide-side-effects.html 
  6. Sindovin. ANM. Available at: https://www.anm.ro/_/_PRO/pro_6751_30.08.06.pdf 
  7. Vincristine Side Effect. Available at: https://www.drugs.com/sfx/vincristine-side-effects.html 
  8. Syndrome of inappropriate antidiuretic hormone. Cancer Canadian Society. Available at: http://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/managing-side-effects/syndrome-of-inappropriate-antidiuretic-hormone/?region=on 
  9. Cyclophosphamide – BC Cancer. Available at: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Cyclophosphamide_monograph_1June2013_formatted.pdf 
  10. Sindroamele paraneoplazice – clasificare, diagnostic şi tratament. Suport de curs pentru rezidenţi. UMF „Grigore T. Popa” Iaşi. Available at: http://www.umfiasi.ro/Rezidenti/suporturidecurs/Facultatea%20de%20Medicina/Oncologie/oncologie%20medicala-%20tematica%20curs%20rezidenti/12.%20Sindr.%20Paraneoplazice.pdf 
  11. Hiponatremia. Suport de curs pentru rezidenţi. UMF „Grigore T. Popa” Iaşi. Available at: http://www.umfiasi.ro/Rezidenti/suporturidecurs/Facultatea%20de%20Medicina/Nefrologie/Cap.%2017%20-%20Hiponatremia.pdf