Hyponatremia is the most common abnormality of sodium metabolism in patients with cancers.

It is a common paraneoplastic phenomenon accounting for approximately 70 % of malignancy-related cases of small cell lung cancer (SCLC). Lymphoma, thymoma, mesothelioma, Ewing’s sarcoma, and a variety of carcinomas including squamous cell carcinoma of the head and neck, have all been associated with the development of SIADH. Moreover, ectopic antidiuretic hormone (ADH) secretion has been described in neuroendocrine tumor s presenting as hyponatremia due to the syndrome of inappropriate ADH secretion. Other malignancies associated with paraneoplastic SIADH are gastrointestinal (esophageal, gastric, pancreatic, colon), gynecological , breast cancer, prostate, bladder, sarcomas, thymoma, adrenal, skin (melanoma), brain (primary and metastatic) and hematological (lymphoma, leukemia, multiple myeloma).

In contrast to hypovolemic hyponatremia caused by gastrointestinal losses, excessive diuresis, adrenal insufficiency, salt wasting nephropathy and cerebral salt wasting (all of which may be encountered in cancer patients) cause euvolemic hyponatremia.

Malignant hyponatremia may be caused by arginine-vasopressin imbalance within the syndrome of inadequate secretion of antidiuretic hormone (SIADH), or by hyper secretion of the atrial natriuretic peptide (ANP). The syndrome of SIADH is a disorder of sodium and water balance, which is characterized by hypotonic euvolemic hyponatremia and brings dilution hyponatremia associated with water intoxication. These patients do not become hypervolemic because of the natriuretic mechanisms that are activated. This restores euvolemia, but worsens serum sodium levels. Together, these mechanisms cause euvolemia and dilutional hyponatremia. ADH causes excessive water resorption in the collecting ducts. This increased intravascular volume leads to increased renal perfusion along with a substantial decrease in proximal tubular absorption of sodium. ANP binds to a specific set of receptors, resulting in increased renal sodium excretion.

The symptoms of SIADH depend on the degree and rapidity of onset of hyponatremia and the developing time frame. In case of longer time frame (chronic), the clinical presentation of the patient can be marked with mild neurological symptoms including hyperreflexia, gain disturbances, headache, weakness, muscle cramps and memory difficulties. If the serum levels are lower than 125 mEq/L, but the time frame is short (e.g. within 48 h) symptoms of great concern are altered mental status, confusion, gait disturbance, seizures, respiratory collapse, stupor, even a coma and death due to plasma hypo-osmolality. Particularly, in acute hyponatremia, clinical manifestations are primarily neurologic (due to an osmotic shift of water into brain cells causing edema). On the other hand, with chronic hyponatremia, the brain generates endogenous osmoles to minimize intra cellular swelling.

Both clinical and laboratory parameters may aid in the determination of volume status. An euvolemic state is supported by the absence of orthostatic vital sign changes or edema and normal central venus pressure.

The symptoms of SIADH disappear after systemic chemotherapy, as well as the primary tumor responses to treatment rate.

Hyponatremia in patients with cancer is associated with longer hospital stay and higher mortality. The optimal therapy for paraneoplastic SIADH is treating the underlying tumor, which if successful, can normalize the sodium level in a matter of weeks.

Asymptomatic patients have a lower risk of neurologic symptoms, but can still develop osmotic demyelination syndrome in case of rapidly correction.

Oral medications that can be tried, at first glance, include oral urea which increases urinary solute and therefore enhances water secretion.

On the other hand, oral salt tablets can be administered in conjunction with furosemide, as furosemide decreases the sodium chloride re-absorption in the thick ascending limb of the loop of Henle, thereby enhancing the effect of the salt tablets.

The primary pharmacologic treatments that can also be used are demeclocycline and vasopressin receptor antagonists. Demeclocycline is a tetracycline derivative that induces diabetes insipidus by reducing the collecting tubules response to ADH.

Particularly, if restriction of fluid intake is not tolerated by the patients, the vasopressin antagonists provide an alternative symptomatic treatment of paraneoplastic SIADH.

Hyponatremia is associated with significant morbidity and mortality in cancer patients.

Successful treatment of the underlying tumor, accompanied by a restricted fluid intake in severe cases, will usually result in prompt disappearance of the paraneoplastic SIADH.

During and after the tumor treatment, plasma ADH may be useful as a tumor marker.

Pseudo hyponatremia with normal serum osmolality may occur in hyperlipidemia or extreme hyperproteinemia.

Paraneoplastic Cushing syndrome (CS) arises from tumor secretion of adrenocorticotropic hormone or corticotrophin-releasing factor. These factors result in production and release of cortisol from the adrenal glands.

Up to 50 % of small-cell lung cancer (SCLC) can be associated with ectopic ACTH production, but only 2–10 % have clinically significant disease.

Approximately 50–60 % of these paraneoplastic cases are neuroendocrine lung tumor s (small cell lung cancer and bronchial carcinoids). Neuroendocrine Tumors (NETs) associated with CS are often derived from the lung, thymus, hypothalamic tumors, pancreas, thyroid, chromaffin cell tumors (phaeochromocytomas, paragangliomas and neuroblastomas) and rarely from the ovary or prostate. Typically, bronchial carcinoids produce a clinical and biochemical syndrome that resembles pituitary dependent CS.

Hypertensive crises and profound loss of potassium may lead to cardiac and vascular complications, including ventricular arrhythmias. In addition, polyglobulia with thrombocytosis and leukocytosis are typical signs for ectopic ACTH production. Finally marked suppression of the immune system may cause severe infections, which easily can lead to septicemia.

Clinically, the condition features hypertension, hypokalemia, muscle weakness, and generalized edema. Weight gain with centripetal fat distribution is more common in no paraneoplastic than in paraneoplastic Cushing syndrome.

Potassium replacement and spironolactone remains insufficient and amiloroide–metyrapone combination that normalizes serum potassium level is given. On another hand, ketoconazole decreases both cortisol and ACTH levels in 38 % of the patients with ectopic ACTH secretion.

SCLC -ACTH secretion patients have poorer prognosis than patients with paraneoplastic SCLC SIADH.

The presence of pseudo hyperkalemia should be considered in every patient with marked leukocytosis or thrombocytosis, due to minor leakage of intracellular potassium from leukemic cells due to mechanical stressors or heparin-induced lysis of leukocytes during laboratory processing (sampling vacuum tubes).

As for glucose metabolism disturbance as paraneoplastic syndrome , hypoglycemia is the most common abnormality. This type of hypoglycemia has been noted in relation with excessive production of somatomedin.

Tumor-associated hypoglycemia occurs rarely and can be caused by insulin-producing islet-cell tumors and (paraneoplastic) extra pancreatic tumors. The latter, termed non–islet cell tumor hypoglycemia (NICTH), presents as recurrent or constant hypoglycemic episodes with glucose levels as low as 20 mg/dl and typically affects elderly patients with advanced cancer.

Although virtually any type of cancer may cause NICTH the most common etiologies are sarcomas, hepatocellular carcinoma and GI carcinomas.

Sweating, anxiety, tremors, palpitations, hunger, weakness, seizures, confusion and coma may present as symptoms. Occasionally, these hypoglycemic episodes can predate the diagnosis of the underlying tumor.