Hyponatremia
Hyponatremia and cancer relationship
Hyponatremia is the most common electrolyte abnormality observed in cancer patients. In a retrospective cohort study from a comprehensive cancer center, hyponatremia (serum Na + < 137 mEq/L) was noted in 47% of hospitalized cancer patients [VO2]. In general, hyponatremia is categorized as mild (130–134 mEq/L), moderate (120–129 mEq/L), and severe (< 120 mEq/L), according to serum sodium concentrations. Hyponatremia has been linked to poor prognosis in several types of cancers, which include non-small cell lung cancer, pleural mesothelioma, renal cell carcinoma, gastrointestinal cancer, and lymphoma. , The risk of mortality increases with more severe hyponatremia. Moreover, low serum sodium concentrations have also been associated with poorer performance status in lung cancer patients. In addition, timely and effective corrections of serum sodium concentrations have been associated with improvement in prognosis for several cancers. ,
Symptoms
Symptoms of hyponatremia are caused primarily by osmotic swelling of brain cells and increased intracranial pressure (ICP). Severity of symptoms usually correlates with the degree of hyponatremia. Most patients with mild to moderate hyponatremia are asymptomatic. Severe hyponatremia, on the other hand, may cause nausea, vomiting, confusion, falls, movement disorders, seizures, and coma. Time course of the development of hyponatremia is another significant factor that determines the severity of symptoms. Chronic hyponatremia (onset > 48 hours) can be asymptomatic whereas acute hyponatremia can manifest as encephalopathy, especially in patients with malnutrition, hypokalemia, alcoholism, or advanced liver disease.
Pathophysiology
Hyponatremia is the result of imbalance between salt and water concentrations with relatively more total body water (TBW) than salt. Normal kidneys can eliminate up to 20 to 30 L of free water daily. Antidiuretic hormone (ADH) also known as arginine vasopressin ( AVP ) is the major hormone that regulates free water reabsorption by kidney tubules. ADH is a peptide hormone produced by the hypothalamus and transported to the posterior pituitary via nerve axons. It is released into the circulation from the posterior pituitary and binds to V2 receptors at the basolateral side of the collecting tubules in the kidney. Binding of ADH to V2 receptor activates adenylate cyclase and subsequent formation of cyclic adenosine monophosphate (cAMP). This leads to movement and fusion of specific vesicles that contain aquaporin 2 (AQ2) channels in the cytoplasm to the apical membrane of the collecting tubules. Once AQ2 channels are inserted, the apical membrane becomes permeable to water. Water moves from medullary renal space to the apical membrane and is then released into the circulation through the basolateral membrane ( Fig. 2.1 ). ADH release is stimulated by two mechanisms: osmotic and nonosmotic factors. The osmotic regulation of ADH occurs in the anterior hypothalamus as “osmoreceptor cells or osmostat” sense changes in extracellular fluid (ECF) osmolality. This is a tightly controlled system as an increase or decrease in ECF osmolality by 1% stimulates or suppresses ADH release respectively. Nonosmotic stimulation of ADH release occurs in the absence of changes in serum osmolality. Pain, emotional stress, nausea, and reduction in effective arterial blood volume (EABV) are some of the examples of nonosmotic stimuli, which tend to be very common in patients with cancer and those under treatment with various cancer therapies.
Approach to etiology of hyponatremia
Hyponatremia typically develops when there is disruption in the elimination of free water by kidneys, or when water shifts from the intracellular to extracellular space, both of which result in the dilution of extracellular sodium concentration. Several algorithms are considered acceptable when evaluating a patient with hyponatremia. The most commonly used algorithm incorporates both serum osmolality and urine sodium concentrations. We have adopted this approach for specific causes of hyponatremia in cancer patients ( Fig. 2.2 ).
The first step in a patient with hyponatremia is to check serum osmolality. Serum osmolality is normally tightly maintained between 280 to 290 mOsm/L. Using this range, hyponatremia can be classified as hyper-osmolar, iso-osmolar, and hypo-osmolar hyponatremia.
Hyper-osmolar hyponatremia
If serum osmolality increases because of an effective osmole other than sodium, then hyper-osmolar hyponatremia develops as the effective osmole causes water shift from intracellular to extracellular space. The most common example of this kind of hyponatremia is caused by hyperglycemia. For each 100 mg/dL increase in plasma glucose, above 150 mg/dL 1.6 to 2.4 mEq/L decrease is observed in serum sodium concentration. Hyperglycemia over time can also stimulate thirst and ADH secretion by causing low EABV secondary to osmotic diuresis.
Hypertonic mannitol infusion, which is used in the treatment of cerebral edema, or sucrose/maltose carrier used in intravenous immunoglobulin infusions can also increase serum osmolality and subsequent movement of water from intracellular to extracellular space.
Iso-osmolar hyponatremia
Hyponatremia in the setting of normal serum osmolality is called pseudohyponatremia . Pseudohyponatremia is caused by circulating excessive proteins or lipids, which reduce the water fraction of the serum. Because sodium is restricted to the water phase of the serum, laboratory methods that measure the sodium concentration per unit of total serum give falsely low measurement. However, analyzers that directly measure the sodium concentration or activity in the water phase of serum are not affected by this error. This measurement technique avoids dilution steps and is called direct potentiometry . Pseudohyponatremia in cancer patients can be seen with plasma cell dyscrasias (i.e., multiple myeloma, Waldenstrom macroglobulinemia) because of excessive paraproteins or in obstructive jaundice because of increased amount of abnormal lipoprotein, Lipoprotein X.
Another example of iso-osmolar hyponatremia is the use of glycine or sorbitol during hysteroscopy, transurethral resection of the prostate or laparoscopic surgeries as these isosmotic solutions may get systemically absorbed and cause the dilution of the extracellular sodium without changing the serum osmolality.
Hypo-osmolar hyponatremia
When serum osmolality is low, ADH release and subsequent hyponatremia can occur through nonosmotic stimuli of ADH. As reduction in EABV is one of the most common reasons of nonosmotic stimuli of ADH, evaluation of hypo-osmolar hyponatremia mandates assessment of volume status to differentiate the underlying causes. This type of hyponatremia can be further classified as hypervolemic , euvolemic , and hypovolemic .
Hypovolemic hypo-osmolar hyponatremia
Hypovolemic hypo-osmolar hyponatremia is characterized by both TBW and solute loss resulting in low EABV and nonosmotic stimuli of ADH. Solute loss could either be through kidneys or via gastrointestinal tract. Because of low EABV, the renin-angiotensin-aldosterone system is activated and urine sodium (UNa + ) of 20 mEq/L or less is observed as aldosterone mediates renal tubular reabsorption of sodium, to maintain tissue perfusion. However, in the cases of renal solute wasting, UNa + is expectedly greater than 20 mEq/L.
In cancer patients, vomiting and diarrhea resulting from chemotherapy are the main causes of gastrointestinal solute loss. On the other hand, renal salt wasting is a well-defined toxicity of platinum-based chemotherapy, especially, cisplatin. Other medications used by cancer patients include loop and thiazide diuretics, which can also cause renal sodium loss.
Another rare cause of hypovolemic hypo-osmolar hyponatremia is an entity described as cerebral salt wasting ( CSW ) syndrome. This is typically seen in patients with central nervous system (CNS) disease, particularly subarachnoid hemorrhage, less commonly CNS metastases. First described by Peters et al. in 1950, CWS syndrome is defined by the development of extracellular volume depletion caused by a renal tubular sodium transport abnormality in patients with intracranial disease and normal adrenal and thyroid functions. CWS has similar features to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) with high urine osmolality and high urine sodium concentration (UNa + > 20 mEq/L), but the main distinction lies in the volume status: SIADH is characterized by euvolemia, whereas CSW syndrome is a hypovolemic state. Two postulated mechanisms for CSW syndrome are the excess secretion of natriuretic peptides and the loss of sympathetic stimulation to the kidney. It is important to differentiate CSW syndrome from SIADH as treatment of these two conditions is completely different. Treatment of choice for SIADH is free water restriction, whereas it is isotonic fluid replacement in CSW syndrome. Fractional uric acid excretion (FE UA ) is one marker suggested to differentiate between CSW and SIADH. Initially, both conditions are associated with a low serum uric acid level and a high fractional excretion of uric acid. However, correction of hyponatremia normalizes FE UA to less than 10% in SIADH but not in CSW syndrome. Also patients with CSW may be hypotensive and orthostatic, whereas patients with SIADH are euvolemic and likely normotensive.
Euvolemic hypo-osmolar hyponatremia
Euvolemic hypo-osmolar hyponatremia is characterized by relatively more TBW than salt. This can be caused by three conditions: low solute intake, increased water intake or diminished water excretion. In euvolemic hypo-osmolar hyponatremia, because EABV is normal to slightly expanded, renin-angiotensin-aldosterone system is suppressed, and so the UNa + is always greater than 20 mEq/L. Low solute or salt intake in cancer patients is usually caused by loss of appetite. Primary polydipsia seen in psychogenic disorders is an example of relatively more water intake compared with salt. Because ADH stimulation is not the primary cause of hyponatremia in neither poor solute intake nor primary polydipsia, the urine is maximally diluted in the absence of ADH, and urine osmolality is less than 100 mOsm/kg.
Euvolemic hypo-osmolar hyponatremia can also develop because of excessive ADH. In the presence of ADH, urine cannot be maximally diluted and urine osmolality is 100 mOsm/kg or more. Excessive ADH can be seen in certain endocrinopathies, such as adrenal insufficiency or hypothyroidism. Adrenal insufficiency increases corticotropin-releasing hormone (CRH) mediated secretion of ADH as the inhibitory feedback on CRH by cortisol diminishes. Adrenal insufficiency occurs in cancer patients because of metastatic infiltration of adrenal glands or because of toxicity of cancer drugs, such as seen with immune checkpoint inhibitors promoting an immune response–mediated adrenalitis.
The exact mechanism of hyponatremia observed with hypothyroidism is not fully understood. It is suggested that hypothyroidism induces hyponatremia by impairment of water excretion either by increasing release of ADH or by reduction in glomerular filtration rate. The thyroid hormone normally inhibits central release of ADH, so hypothyroidism diminishes this inhibitory effect. In addition, in an animal study, it has been shown that thyroid hormone deficiency potentiates ADH effect on the kidney tubules by upregulation of AQ2 receptors.
The most common cause of euvolemic hypo-osmolar hyponatremia in a cancer patient is the SIADH. Table 2.1 summarizes common causes of SIADH in cancer patients. SIADH is more frequent in solid tumors, such as small cell lung cancer (SCLC) and head and neck cancers, but it has been associated with many types of malignancies in case reports. In the cases of SCLC and head and neck cancers, SIADH is actually caused by ectopic production of ADH.
| Cancers | SCLC, NSCLC, head & neck cancers, breast cancer, mesothelioma, lymphoma, Ewing sarcoma, thymoma, gastrointestinal cancers, urothelial cancers, renal cell carcinoma, prostate cancer, endometrial cancer |
| Chemotherapy | Vincristine, vinblastine, cyclophosphamide, ifosfamide, cisplatin, melphalan, interferon |
| Nonchemotherapy drugs | Vasopressin, desmopressin, opiates, SSRIs, TCAs, chlorpropamide, clofibrate, meperidine, barbiturates, carbamazepine, amiodarone, NSAIDs, ACE inhibitors, dopamine agonists, ecstasy |
| CNS diseases | Infections, mass, bleeding, trauma |
| Pulmonary diseases | Infections, mass, bleeding, positive pressure intubation, asthma, COPD |
| Miscellaneous | Pain, nausea |
Some of the cancer drugs, such as cyclophosphamide and the vinca alkaloids (vincristine, vinblastine) are well known to induce SIADH. These drugs show neurotoxic effects on the paraventricular and supraoptic neurons and alter the normal osmoreceptor control of vasopressin secretion. Cisplatin on the other hand can cause hyponatremia by both potentiating the effect ADH on the kidney tubules and causing renal salt wasting. Cancer patients also frequently use palliative medications, such as antidepressants, antiemetics, opioids, and nonsteroidal antiinflammatory medications that can either stimulate or potentiate ADH, causing a drug-induced form of SIADH.
ADH can also be produced in excess with nonosmotic stimuli because of pain, nausea, infiltrative processes of CNS and lungs with metastasis, infection, or bleeding. All of these conditions are common comorbidities in cancer patients and are likely the most frequent cause of hyponatremia in patients with an underlying malignancy.
Hypervolemic hypo-osmolar hyponatremia
Hypervolemic hypo-osmolar hyponatremia results from both TBW and salt increase, which usually manifest as an edematous state. Urine sodium (UNa + ) concentration is a helpful tool to differentiate between the various causes of hypervolemic hypo-osmolar hyponatremia. In cancer patients, cirrhosis caused by liver metastasis or hepatocellular carcinoma, hepatic sinusoidal obstruction syndrome (veno-occlusive disease) following hematopoietic stem cell transplantation (HSCT), and cardiomyopathy from chemotherapy or radiotherapy cardiotoxicity are common causes of hypervolemic hyponatremia. In addition, nephrotic syndrome seen with a number of paraneoplastic syndromes, graft-versus-host disease or because of cancer drugs as well as inferior vena cava and lymphatic compressions by tumor, capillary leak syndrome seen during engraftment phase of HSCT or because of interleukin-2/chimeric antigen receptor T-cell treatment are other examples of edematous hypervolemic hyponatremia with low effective blood volume. These conditions are characterized with UNa + of 20 mEq/L or less as the underlying process causing low EABV is the major stimulus for ADH release and renin-angiotensin-aldosterone system stimulation. On the other hand, kidney failure can impair tubular dilution of the urine and yield hypervolemic hyponatremia. In this case, UNa + concentration remains greater than 20 mEq/L.
Treatment of hyponatremia
Treatment of hyponatremia in the cancer patient depends on the etiology, severity, and presence or absence of symptoms. Hyponatremia symptoms develop mainly because of ICP from brain edema. When serum sodium concentration and therefore serum osmolality drops, water shifts from extracellular space to relatively hyperosmolar intracellular space of brain cells. Swelling of brain cells increases intracranial pressure as the skull is a nonexpanding cavity. Increases in intracranial pressure can lead to nausea, vomiting, confusion, ataxia, movement disturbances, seizures, respiratory failure and/or coma. Brain cells quickly adapt to surrounding hypotonicity and extrude solutes, such as sodium, potassium, and chloride in the first couple of hours. This is followed by brain cell extrusion of organic osmoles, such as glutamate, creatinine, and myoinositol to prevent brain edema. Adaptation is usually complete within 48 hours. If hyponatremia persists for more than 48 hours, it is defined as chronic hyponatremia , which mandates different therapy than “acute hyponatremia”. Rapid correction of chronic hyponatremia results in a life-threatening condition called osmotic demyelination syndrome ( ODS ). ODS occurs because regeneration of intracellular organic osmoles takes longer than the correction of extracellular hypo-osmolarity, resulting in further water shift from brain cells and subsequent cell shrinkage and myelin breakdown. It is now common practice to limit the rate of correction of chronic hyponatremia to less than 8 mEq/L in any 24-hour period. This limit is further decreased to 6 mEq/L in 24 hours for patients at high risk of osmotic demyelination. ODS risk is higher in patients with severe hyponatremia (serum Na + ≤ 105 mEq/L), malnutrition, hypokalemia, alcoholism, or advanced liver disease.
In contrast, acute symptomatic hyponatremia (onset < 48 hours) requires immediate correction with much less concern for ODS. Acute hyponatremia in the cancer patient may be seen occasionally following various surgical procedures. Patients during the postoperative period typically have increased ADH activity caused by multiple factors, such as pain, nausea, narcotics, and nonsteroidal antiinflammatory drugs. Nothing per oral status and use of hypotonic intravenous infusions also significantly contribute to hyponatremia during this time. Patients with acute hyponatremia and symptoms of ICP should be treated with a 100-mL bolus of 3% hypertonic saline, followed by up to two additional 100-mL doses (total dose of 300 mL) if symptoms persist over the course of 30 minutes.
Treatment options for chronic hyponatremia in cancer patients vary depending on the etiology. The initial step for deciding on the treatment choice is to evaluate serum osmolality. Hyperosmolar hyponatremia treatment is directed toward eliminating the underlying cause. In the case of hyperglycemia, lowering blood sugar, and in other cases eliminating the hyper-osmolar solute, such as mannitol, sucrose, or maltose corrects hyponatremia. Iso-osmolar hyponatremia, seen in those with plasma dyscrasias, caused by paraproteins, or in obstructive jaundice, caused by Lipoprotein X, does not warrant any specific treatment, as this is pseudohyponatremia caused by the laboratory method of serum sodium measurement.
On the other hand, hypo-osmolar hyponatremia requires treatment, especially when symptomatic ( Fig. 2.3 ). Severe symptomatic cases should be treated aggressively with 3% hypertonic solution for at least the first couple of hours to prevent neurologic complications. In general, 1 mEq/L per hour of increase in serum sodium concentration is targeted with hypertonic saline until symptoms subside. Increase in serum sodium concentration by 4 to 6 mEq/L has been suggested to be sufficient to improve serious symptoms of hyponatremia. This can be approximated by hourly administration of 3% hypertonic saline in the milliliter amount equal to the patient’s weight in kilogram (e.g., for a 70-kg patient, 70 mL/h of 3% hypertonic saline). Another formula that is commonly used to calculate the required amount of hourly hypertonic or isotonic saline infused to correct hyponatremia is called Androgue-Madias formula , which estimates the effect of 1 L of sodium infusate on serum sodium concentration with the subsequent calculation:
Changeinserumsodium=(Infusate Sodium+InfusatePotassium)-Serum Sodium / (Total Body Water+1)
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