Hyponatremia causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Causes

Causes of hyponatraemia

An abnormally low plasma sodium level is best considered in conjunction with the person's plasma osmolarity and extracellular fluid volume status.

Most cases of hyponatremia are associated with reduced plasma osmolarity. In fact, the vast majority of adult cases are due to increased vasopressin, i.e., anti-diuretic hormone (ADH). Vasopressin is a hormone that causes retention of water, but not salt. Hence, the patient with hyponatremia can be viewed as the patient with increased ADH activity. It is the physician's task to identify the cause of the increased ADH activity in each case.

In patients who are volume depleted, i.e., their blood volume is too low, ADH secretion is increased, since volume depletion is a potent stimulus for ADH secretion. As a result, the kidneys of such patients hold on to water and produce a very concentrated urine. Treatment is simple (if not without risk)  — simply restore the patient's blood volume, thereby turning off the stimulus for ongoing ADH release and water retention.

Some patients with hyponatremia have normal blood volume. In those patients, the increased ADH activity and subsequent water retention may be due to "physiologic" causes of ADH release such as pain or nausea. Alternatively, they may have the Syndrome of Inappropriate ADH (SIADH). SIADH represents the sustained, non-physiologic release of ADH and most often occurs as a side effect of certain medicines, lung problems such as pneumonia or abscess, brain disease, or certain cancers (most often small cell lung carcinoma).

A third group of patients with hyponatremia are often said to be "hypervolemic". They are identified by the presence of peripheral edema. In fact, the term "hypervolemic" is misleading since their blood volume is actually low. The edema underscores the fact that fluid has left the circulation, i.e., the edema represents fluid that has exited the circulation and settled in dependent areas. Since such patients do, in fact, have reduced blood volume, and since reduced blood volume is a potent stimulus for ADH release, it is easy to see why they have retained water and become hyponatremic. Treatment of these patients involves treating the underlying disease that caused the fluid to leak out of the circulation in the first place. In many cases, this is easier said than done when one recognizes that the responsible underlying conditions are diseases such as liver cirrhosis or heart failure — conditions that are notoriously difficult to manage, let alone cure.

Hyponatremia can result from dysfunctions of the mineralocorticoid aldosterone (i.e. hypoaldosteronism) due to adrenal insufficiency, congenital adrenal hyperplasia, and some medications.

It is worth considering separately, the hyponatremia that occurs in the setting of diuretic use. Patients taking diuretic medications such as furosemide (Lasix), hydrochlorothiazide, chlorthalidone, etc., become volume depleted. That is to say that their diuretic medicine, by design, has caused their kidneys to produce more urine than they would otherwise make. This extra urine represents blood volume that is no longer there, that has been lost from the body. As a result, their blood volume is reduced. As mentioned above, lack of adequate blood volume is a potent stimulus for ADH secretion and thence water retention.

A recent surge in death from hyponatremia has been attributed to overintake of water while under the influence of MDMA. Also, Almond et al.[1] found hyponatremia in as many as 13% of runners in a recent Boston Marathon, with life-threatening hyponatremia (serum Na below 120 mmol/L) in 0.6%. The runners at greatest risk of serious water intoxication had moderate weight gain during the race due to excessive water consumption (see reference). Siegel et al [2] recently found that in addition to over-zealous drinking, the cause of exercise-associated hyponatremia (EAH) is from an inappropriate secretion of the hormone arginine vasopressin, or antidiuretic hormone. This excess hormone secretion prevents the kidneys from excreting the excess water in the urine.

Pseudohyponatremia

Certain conditions that interfere with laboratory tests of serum sodium concentration (such as extraordinarily high blood levels of lipid or protein) may lead to an erroneously low measurement of sodium. This is called pseudohyponatremia, and can occur when laboratories use the flame-photometric and indirect (but not direct) ion-selective electrode assays.[3][4] This is distinct from a true dilutional hyponatremia that can be caused by an osmotic shift of water from cells to the bloodstream after large infusions on mannitol or intravenous immunoglobulin.

Hypoosmolar Hyponatremia

When the plasma osmolarity is low, the extracellular fluid volume status may be in one of three states:

Low Volume

Loss of water is accompanied by loss of sodium.

Treat underlying cause and give IV isotonic saline. It is important to note that sudden restoration of blood volume to normal will turn off the stimulus for continued ADH secretion. Hence, a prompt water diuresis will occur. This can cause a sudden and dramatic increase the serum sodium concentration and place the patient at risk for so-called "central pontine myelinolysis" (CPM). That disorder is characterized by major neurologic damage, often of a permanent nature.

Because of the risk of CPM, patients with low volume hyponatremia may eventually require water infusion as well as volume replacement. Doing so lessens the chance of a too rapid increase of the serum sodium level as blood volume rises and ADH levels fall.

Normal Volume

The cornerstone of therapy for SIADH is reduction of water intake. If hyponatremia persists, then demeclocycline (an antibiotic with the side effect of inhibiting ADH) can be used. SIADH can also be treated with specific antagonists of the ADH receptors, such as conivaptan or tolvaptan.

High Volume

There is retention of water.

Placing the patient on water restriction can also help in these cases.

Severe hyponatremia may result from a few hours of heavy exercise in high temperature conditions, such as hiking in desert areas, or from endurance athletic events when electrolytes are not supplied. (Such an incident notably happened to long-distance athlete Craig Barrett in 1998).

Common Causes

Causes by Organ System

Cardiovascular Congestive heart failure
Chemical / poisoning No underlying causes
Dermatologic Burns
Drug Side Effect ACE inhibitors, Ajuga nipponensis makino , Asenapine maleate, Cefpodoxime, Chlorpropamide, Cyclophosphamide, Desmopressin, Diuretics, Duloxetine, Felbamate, Fluvoxamine, Interferon gamma, Ixabepilone, Losartan and Hydrochlorothiazide, Nilotinib, Nivolumab, Nonsteriodal anti-inflammatory drugs , Oxcarbazepine, Pramipexole, Rifaximin, Tiagabine, Zonisamide, Tolbutamide, Vortioxetine
Ear Nose Throat No underlying causes
Endocrine Addison's disease, Corticosterone methyloxidase type I deficiency , Diabetes mellitus, Diabetic coma, Glucocorticoid deficiency, Familial hyperreninemic hypoaldosteronism type 2, Hypothyroidism, Mineralocorticoid deficiency, Myxedema coma , Syndrome of inappropriate antidiuretic hormone , Thyrotropin deficiency, 18-Hydroxylase deficiency , Familial hypoaldosteronism
Environmental No underlying causes
Gastroenterologic Acute liver failure , Cirrhosis, Congenital chloride diarrhea , Diarrhea, Gastrointestinal fistula, Ileus, Necrotizing enterocolitis , Pancreatitis, Peritonitis, Vomiting, Cystic fibrosis
Genetic 18-Hydroxylase deficiency , Bartter Syndrome type 4 , Cystic fibrosis, Familial hypoaldosteronism , Corticosterone methyloxidase type I deficiency , Familial hyperreninemic hypoaldosteronism type 2, Congenital chloride diarrhea
Hematologic No underlying causes
Iatrogenic After pituitary surgery, After surgery, Ascitic tap, Gastric drainage, Hypotonic infusions, Pleuracentesis
Infectious Disease Malignant boutonneuse fever , Neonatal bacterial meningitis , Peritonitis
Musculoskeletal / Ortho No underlying causes
Neurologic Intracranial hemorrhage, Subarachnoid hemorrhage, Pituitary cancer
Nutritional / Metabolic Hyperlipidemia, Hyperproteinemia, Hypoalbuminemia, Low sodium diet, Metabolic acidosis, Diabetic coma
Obstetric/Gynecologic Pregnancy
Oncologic Pituitary cancer
Opthalmologic No underlying causes
Overdose / Toxicity Water intoxication
Psychiatric Psychogenic polydipsia, Psychosis, Self-induced water intoxication and schizophrenic disorders syndrome
Pulmonary Cystic fibrosis
Renal / Electrolyte Acute kidney disease, Chronic kidney disease, Diuresis, Glucosuria, Ketonuria, Nephrotic syndrome, Renal Tubular Acidosis, Tubulointerstitial kidney disease, Bartter Syndrome type 4 , Corticosterone methyloxidase type I deficiency , Renal failure
Rheum / Immune / Allergy Addison's disease, Nephrotic syndrome
Sexual Cystic fibrosis
Trauma Burns
Urologic No underlying causes
Dental No underlying causes
Miscellaneous Beer potomania, Ecstasy abuse , Factitious hyponatremia, Hydration, Massive edema, Pseudohyponatremia, Water Intoxication , Hyperlipidemia, Hyperproteinemia, Hypoalbuminemia, Exercise associated hyponatremia

Causes in Alphabetical Order


References

  1. Almond CS et al. (2005) Hyponatremia among runners in the Boston Marathon. N Engl J Med, 352(15):1550-6. PMID 15829535
  2. Siegel AJ et al. (2007) Am J Med, 120(5):461.e11-7. PMID 17466660
  3. Weisberg LS. (1989) Pseudohyponatremia: a reappraisal. Am J Med, 86(3):315-8. PMID 2645773
  4. Nguyen MK et al. (2007) A new method for determining plasma water content: application in pseudohyponatremia. Am J Phys - Renal, 292(5):F1652-6. PMID 17299138