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Managing Hyponatremia in Cirrhosis

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Managing Hyponatremia in Cirrhosis REVIEW Managing Hyponatremia in Cirrhosis Elizabeth Ross, MD Division of Gastroenterology, Department of Medicine, New York University School of Medicine, New York, Samuel H. Sigal, MD New York. Disclosure: S.H. Sigal received an honorarium funded by an unrestricted educational grant from Otsuka America Pharmaceuticals, Inc., for time and expertise spent in the composition of this article. No editorial assistance was provided. He also discloses a speaker’s bureau relationship with Otsuka America Pharmaceuticals, Inc. E. Ross discloses no conflicts of interest. The development of hyponatremia represents an ominous event in the progression of cirrhosis to end-stage liver disease. It usually develops in those with refractory ascites and is a manifestation of the non-osmotic release of arginine vasopressin (AVP). In the hospitalized cirrhotic patient, hyponatremia is associated with increased disease severity and mortality. In this article, we review the pathophysiology of hyponatremia, its clinical implications, evaluation, and treatment. Journal of Hospital Medicine 2010;5:S8–S17. VC 2010 Society of Hospital Medicine. KEYWORDS: hyponatremia, common electrolyte disorder, cirrhosis, portal hypertension, cirrhosis, liver failure. The serum sodium (Na) level is the major determinant of the extremes of age, and those receiving selected medica- serum osmolality. In normal physiologic states is tightly tions, including several that are commonly administered to regulated between 135 mEq/L to 145 mEq/L despite variable cirrhotic patients (diuretics, selective serotonin reuptake intake of water and solute through the interaction of osmor- inhibitors, opiates, proton-pump inhibitors).7,8 Hyponatre- eceptors in the hypothalamus where arginine vasopressin mia is associated with increased total costs per hospital (AVP) is synthesized and then released by the posterior pitu- admission.5,9 In an analysis of the effect of hyponatremia on itary and the binding of AVP with V2 AVP receptors on the length of stay in a retrospective cohort study of hospitalized basolateral surface of the principal cells within the collect- patients derived from a large administrative database of ing duct of the kidney. Binding of AVP to the V2 receptors 198,281 discharges from 39 US hospitals, mean length of promotes the translocation and fusion of cytoplasmic stay was significantly greater among patients with hypona- vesicles which carry the water channel protein aquaporin 2 tremia than those with normal Na levels (8.6 6 8.0 vs. 7.2 6 (AQP2) to the apical membrane of the cell and, in this man- 8.2 days). After adjusting for confounders that may be asso- ner, increases water permeability and absorption.1,2,3 ciated with more severe disease and hyponatremia (age, Patients with hyponatremia, defined by a serum Na level gender, race, geographic region, teaching status of the hos- <135 mEq/L, can be broadly classified by their volume sta- pital, admission source, principal payer, comorbidity index tus into those who are euvolemic, hypervolemic, and hypo- score and primary diagnosis), the presence of hyponatremia volemic (Table 1). In patients with euvolemic hyponatremia contributed an increase in length of stay of 1.0 day. Patients such as those with Syndrome of Inappropriate Antidiuretic with hyponatremia are more frequently admitted to the in- Hormone (SIADH), total body Na is nearly normal, but total tensive care unit (ICU) and require mechanical ventilation. body water is increased. In patients with hypervolemic hy- In patients with CHF, the presence of hyponatremia at dis- ponatremia, both total body Na and water are increased, charge is associated with increased risk for early mortality but water to a much greater degree. These patients typically and rehospitalization.10 have increased extracellular fluid such as edema and/or as- Although frequently asymptomatic, hyponatremia may cites. The most common conditions associated with this be associated with a range of findings, from subtle and non- condition are cirrhosis, congestive heart failure (CHF), and specific complaints, including headache, fatigue, confusion, renal failure. In contrast, hypovolemic hyponatremia is asso- malaise, to severe and life-threatening manifestations with ciated with a reduction in both total body Na and water, but lethargy, seizures, brainstem herniation, respiratory arrest Na to a greater degree. This condition is encountered in and death.11 The most important complications are neuro- patients with excessive fluid losses such as those with over- logic consequences related to cerebral edema. However, diuresis, excessive gastrointestinal losses, burns, and there is increased morbidity even in hyponatremic patients pancreatitis.4 considered to be asymptomatic. Patients with low serum so- Hyponatremia is the most common electrolyte abnormal- dium have attention deficients, and falls are common. In a ity seen in general hospital patients.5 In a database of over study of 122 patients who were considered to have chronic 120,000 patients, a serum sodium level of <136mEq/L was ‘‘asymptomatic hyponatremia,’’ the incidence of falls was observed in 28.2%.6 Hyponatremia is associated with significantly higher at 21.3% compared to only 5.3% in a selected medical conditions (especially cirrhosis and CHF), control population.12 2010 Society of Hospital Medicine DOI 10.1002/jhm.784 Published online in Wiley OnlineLibrary (wileyonlinelibrary.com). S8 Journal of Hospital Medicine Vol 5 No 6 Supplement 3 July/August 2010 TABLE 1. Classification of Hyponatremia: Sodium and Water Changes in the 3 Different Types of Hyponatremia Dilutional Hyponatremia Euvolumic Hypervolumic Depletional Hyponatreima Total body water :::; Total body Na normal :;; Common etiologies SIADH cirrhosis/CHF vomiting, diarrhea In hyponatremia, water enters into the cells to attain osmotic balance, resulting in cellular swelling.4 To avoid cerebral edema, the brain is capable of adapting to hypona- tremia by regulating its volume to avoid swelling, especially when hyponatremia is chronic. In acute hyponatremia, astrocytes and neurons adapt through osmoregulatory mechanisms by extruding intracellular electrolytes such as potassium.13 Chronically, adaption occurs through the loss FIGURE 1. Proposed mechanism of hypersecretion and of low-molecular weight organic compounds termed organic renal and systemic effects of vasopressin in cirrhosis with osmolytes including myoinsoitol, glutamine, choline and ascites. Gines P, Guevara M. Hyponatremia in cirrhosis: taurine. As a result, both the severity and the rate of its de- pathogenesis, clinical significance, and management. Hepatology. velopment are critical factors in determining the neurologic 2008;48:1002–1010. Copyright 2008 John Wiley & Sons, Inc. manifestation of hyponatremia in a given patient.14 Reprinted with permission of John Wiley & Sons, Inc. trations, findings consistent with the presence of a Dilutional Hyponatremia and Cirrhosis decreased effective plasma volume.16 Arterial underfilling is Patients with hyponatremia who are either euvolemic or sensed by baroreceptors located in the left ventricle, aortic hypervolemic are considered to have dilutional hyponatre- arch, carotid sinus and renal afferent arterioles. Decreased mia (DH). Management of these patients is distinct from activation leads to neurohumoral compensatory responses those who are hypovolemic in whom appropriate therapy which include non-osmotic release of vasopressin from the consists of the administration of normal saline. The remain- neurohypophysis and increased levels. Impaired catabolism der of this article addresses the pathogenesis, management of AVP that has been correlated with the severity of liver and treatment of cirrhotic patients with DH. dysfunction may further contribute to increased levels.17 Ini- tially, the increased AVP maintains arterial circulatory integ- rity by inducing splanchnic, peripheral and renal arterial va- Pathogenesis soconstriction through its action on the V1a receptors and The development of hyponatremia in cirrhosis is intimately expansion of blood volume through renal water retention by related to the pathophysiology of portal hypertension and its action on the V2 receptors located on the collecting ducts. the non-osmotic release of AVP3,15 (Figure 1). In the early The initial adaptive response which leads to increased phases of cirrhosis, portal hypertension is the result of an central blood volume can chronically result in detrimental increase in intrahepatic resistance. With the development of effects, including the development of fluid overload with porto-systemic collaterals, a hyperdynamic splanchnic cir- ascites, edema, and hyponatremia.16,18 Additional factors culation develops as a result of splanchnic arterial vasodila- that contribute to hyponatremia include decreased glomeru- tation and increased vascular capacity. Nitric oxide, an en- lar filtration rate (GFR) and/or increased proximal reabsorp- dothelial derived relaxing factor, is the critical mediator of tion of sodium (that reduce the distal delivery of filtrate and this process, and upregulation of its expression is pivotal in the potential for water reabsorption) and decreased cardiac the pathogenesis of portal hypertension. function that further impairs effective central blood vol- Multiple factors are related to the development of DH in ume.19 In addition, urinary levels of AQP2 are increased in cirrhosis. A reduction of effective central blood volume due cirrhotic patients, especially those with decompensated
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