Journal of Clinical Gastroenterology:
Hyponatremia in Cirrhosis Answers and Questions
Heuman, Douglas M. MD
Department of Medicine, Virginia Commonwealth University, Richmond, VA
Conflict of Interest and Funding: The author has no conflict of interest to declare related to the findings or treatments discussed in this paper. In the preceding 2 years, the author has conducted corporate sponsored research for the pharmaceutical industry including Bayer, Novartis, Bristol Myers Squibb, Scynexis, Wyeth, MannKind, Ocera, Salix, GlobeImmune, Hoffman LaRoche, SciClone, UCB, Celgene, Centocor, Millenium and Osiris, and has served as a consultant to Genzyme.
Reprints: Douglas M. Heuman, MD, GI Section (111–N), Hunter Holmes McGuire Department of Veterans Affairs Medical Center, 1201 Broad Rock Boulevard, Richmond, VA 23249 (e-mail: DMHeuman@VCU.edu).
Serum sodium concentration is an indicator of osmolality. Normally, osmolality of body fluids is regulated within a narrow range by the hypothalamus, which releases antidiuretic hormone (ADH; also known as vasopressin) when osmolality increases above the physiological set point. ADH binds to vasopressin type 2 (V2) receptors in the renal collecting duct, leading to activation of aquaporin channels and reabsorption of water. Conversely, when osmolality drops, ADH secretion decreases; without ADH, renal aquaporin channels close and free water is retained in the ductal lumen, resulting in excretion of dilute urine.1
Under pathologic conditions of decreased effective arterial volume and relative arterial hypotension, activation of neural sensors in the left heart and major arteries causes the hypothalamus to override its normal osmoregulatory drive and release ADH. This hypovolemic stimulus to ADH secretion can be regarded as a survival mechanism: in the face of impending vascular collapse, the body sacrifices osmolar homeostasis to preserve circulation. As a consequence, water is retained and body fluids are diluted, resulting in hyponatremia.2
Hyponatremia commonly occurs in conditions associated with hypotension and reduced effective arterial volume. Hyponatremia has consistently been shown to be an indicator of disease severity and an important independent predictor of mortality in infectious diarrhea,3 pneumonia,4,5 myocardial infarction,6 congestive heart failure,7,8 pulmonary hypertension,9 and hepatic cirrhosis.10,11 Among general patient populations surveyed in emergency rooms, hospitals, nursing homes, and intensive care units, the presence and severity of hyponatremia were strongly predictive of duration of hospitalization, cost of care, and mortality.12–16
Cirrhosis is characterized by a progressive hemodynamic derangement whose main features are decreased systemic vascular resistance, high cardiac output, relative systemic hypotension, renal hypoperfusion, and activation of the renin-angiotensin system leading to avid renal sodium retention.17 Hyponatremia typically develops only in relatively advanced cirrhosis. Cirrhotic hyponatremia is associated with jaundice, hepatic encephalopathy, refractory ascites, and hepatorenal syndrome.18 Sodium less than 130 meq/L in cirrhosis is associated with a median transplant-free survival of less than 6 months.11 Hyponatremia predicts short-term mortality in cirrhotic patients awaiting liver transplantation, independently of Model for End-stage Liver Disease score,11 and incorporation of sodium into the Model for End-stage Liver Disease score improves its prognostic accuracy.19 Pretransplant hyponatremia also may be associated with poorer post transplant outcomes including frequency of complications and prolonged length of stay.20–22
The study of Jenq et al23 in this issue adds further support to the importance of hyponatremia as a prognostic indicator in patients with cirrhosis. Among cirrhotic patients in Taiwan requiring admission to an intensive care unit (ICU), these investigators found that serum sodium at the time of ICU admission was less than 135 in 53% and less than 130 in 29%. Low serum sodium was associated with ascites, encephalopathy, sepsis and renal failure, but not with gastrointestinal hemorrhage. Patients with low serum sodium at time of ICU admission had higher in-hospital mortality as well as poorer 6-month survival. The authors conclude that critically ill cirrhotic patients with hyponatremia should receive high priority for liver transplantation.
It has been suggested that correction of hyponatremia may represent a promising strategy for improving outcomes in cirrhosis and liver transplantation. Hyponatremia per se can produce a variety of neurological disturbances including muscle weakness, seizures, cognitive impairment, and coma,24 and may contribute to hepatic encephalopathy through osmolar changes in brain astrocytes and neurons.25,26 Hyponatremia can be corrected at least transiently via measures such as water restriction, diuretic withdrawal, administration of pressors, and volume expansion. Newly developed selective V2 receptor antagonist drugs such as tolvaptan, lixivaptan, and sativaptan produce a rapid free water diuresis and may provide more durable correction of hyponatremia.27,28
However, available evidence suggests that dilutional hyponatremia is primarily an indicator of circulatory failure, and correction of hyponatremia per se is likely to be of only limited benefit unless the underlying circulatory derangement is also corrected. In patients with heart failure, improvement of hyponatremia produced by tolvaptan therapy had no effect on short-term mortality.29 In cirrhotic patients referred to us for consideration of liver transplantation, a history of prior hyponatremia in the preceding 30 to 180 days was associated with high short-term mortality, even if the hyponatremia had subsequently resolved (unpublished data). Similarly, among cirrhotic patients with normal serum sodium undergoing liver transplantation, those with a history of hyponatremia in the preceding 6 months had poorer outcomes.20 Thus, correction of serum sodium may not eliminate the associated mortality risk. Further prospective studies are needed in cirrhotic patients to determine whether sustained correction of hyponatremia through pharmacologic interventions can alter the natural history of this challenging disorder.
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