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Pathophysiology of Ascites and Dilutional Hyponatremia: Contemporary Use of Aquaretic Agents

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Pathophysiology of Ascites and Dilutional Hyponatremia: Contemporary Use of Aquaretic Agents medigraphic Artemisaen línea 214 Annals of AnnalsHepatology of Hepatology 2007; 6(4): 6(4) October-December: 2007: 214-221 214-221 Concise Review Annals of Hepatology Pathophysiology of ascites and dilutional hyponatremia: Contemporary use of aquaretic agents Jorge García Leiva;1 Julio Martínez Salgado;1 Jose Estradas;1 Aldo Torre;1 Misael Uribe1 Abstract been used. These agents are called aquaretics and can be useful in the treatment of ascites unresponsive to Ascites, the most common complication of cirrhosis, is conventional therapy. associated with a poor quality of life, an increased risk of infection, and renal failure. Twenty percent of cir- Key words: Ascites, dilutional hyponatremia patho- rhotic patients have ascites at the time of diagnosis, physiology, aquaretics. while 30% and 50% will develop ascites by 5 and 10 years, respectively. There are several factors that con- Introduction tribute to ascites formation in cirrhotic patients, these include splanchnic vasodilatation, arterial hypoten- Cirrhosis is an expanding problem and has multiple sion, high cardiac output, and decreased vascular re- etiologies. Most of the morbidity and mortality of chron- sistance. These factors lead to ineffective intravascular ic liver diseases is due to its progression to cirrhosis and volume (hyperdynamic state), impairment of renal complications of cirrhosis. Ascites is the most common function, and subsequent water and sodium retention, major complication of cirrhosis; other complications in- all of which lead to dilutional hyponatremia (serum so- clude hepatic encephalopathy and variceal hemorrhage. dium <130 mEq/L), one of the most important prognos- Ascites is associated with poor quality of life, increased tic factors in these patients. In conclusion, the thera- risk of infection, and renal failure. Twenty percent of pa- peutic objective is to improve sodium balance and cir- tients with cirrhosis have ascites at the time of the diag- culatory function through non-pharmacological nosis. While 30% and 50% of patients with compensated measures, such as dietary sodium and water restriction cirrhosis will develop ascites in 5 and 10 years of follow- as well as bed rest. Spironolactone (100-400 mg/day) is up, respectively. Ascites, which is a sign of poor progno- the initial drug of choice, while loop diuretics (like fu- sis, characteristically develops during late stages of the rosemide, 40-60 mg/day) are frequently used as adju- disease. Patients with cirrhosis and ascites have 50% vants. Recently, agents that interfere with the renal ef- mortality at two years.1,2 fects of vasopressin by inhibiting water reabsorption in Dilutional hyponatremia is defined as serum sodium < collecting ducts and producing free water diuresis have 130 mEq/l secondary to excess total body water in pa- tients without sodium deficit or diuretic therapy. The inci- dence of dilutional hyponatremia in cirrhotic patients be- ing treated for an episode of ascites is 35%, and it is one of 1 Department of Gastroenterology, Instituto Nacional de Ciencias the most important prognostic factors in these patients.3 Medicas y Nutrición Salvador Zubirán. Abbreviations: Pathophysiology of ascites in cirrhosis RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system; ADH: antidiuretic hormone; ANP: atrial There are several factors involved in the development natriuretic peptide: CGRP: calcitonin gene related peptide; AQP: of ascites in cirrhotic patients. The principal pathophysi- aquaporine; cAMP: cyclic adenosine monophosphate;medigraphic.com EABV: effective arterial blood volume. ological factors are severe sinusoidal portal hypertension and liver failure. Address for correspondence: These factors lead to circulatory dysfunction, charac- Dr. Aldo Torre Departament of Gastroenterology terized by splanchnic arterial vasodilation, arterial hy- Instituto Nacional de Ciencias Médicas y Nutrición potension, increased cardiac output, and decreased vas- “Salvador Zubirán” cular resistance. All these factors lead to ineffective intra- Vasco de Quiroga 15, Section XVI, Tlalpan vascular volume and impairment of renal function that Zip code 14000 Mexico DF. 4 E-mail: [email protected] cause subsequent water and sodium retention. The most important theories of ascites formation in cir- Manuscript received and accepted: 7 August and 10 September 2007 rhotic patients are described in the subsequent paragraphs. J García Leiva et al. Pathophysiology of ascites and dilutional hyponatremia 215 Underfilling hypothesis dynamic circulation (high plasma volume and high car- diac output). With disease progression, compensatory ar- This theory suggests that transudation of water and so- terial splanchnic vasodilation increases, yet it is insuffi- dium into the abdominal cavity, due to hepatic venous cient to maintain circulatory homeostasis and arterial hy- obstruction and portal hypertension, produces hypov- potension develops. Afterwards, several mechanisms are olemia and secondary retention of sodium and water. activated to try to maintain normal arterial pressure. The The forces that regulate the movement of fluid in the principal blood pressure regulatory mechanisms are the extracellular compartment are called Starling forces. rennin-angiotensin-aldosterone system (RAAS), the sym- These forces include the hydrostatic pressure of the vas- pathetic nervous system (SNS), and the antidiuretic hor- cular system, the oncotic pressure of interstitial fluid, the mone (ADH).5,6 The mechanism by which portal hyper- oncotic pressure of plasma proteins, and the hydrostatic tension is associated to arterial splanchnic vasodilatation pressure of interstitial fluid (tissue tension). The first two and the resistance that splanchnic arterioles have to vaso- forces facilitate the movement of fluid from the vascular constrictors are not totally understood. Some studies sug- space to the extravascular space and the last two favor gest that it could be related to increased levels of circu- the movement of fluid towards the intravascular space. lating vasodilators (glucagon, prostaglandins, atrial Portal hypertension (increased hydrostatic pressure of natriuretic peptide (ANP), calcitonin gene-related pep- the vascular system) and hypoalbuminemia (decreased tide (CGRP)). oncotic pressure of plasma) disrupt the Starling equilib- Nevertheless, other authors argue that excess synthe- rium in the splanchnic microcirculation. This imbalance sis or release of local vasodilators (nitric oxide) into the could result in increased production of splanchnic vascular splanchnic compartment is a predominant fac- lymph. tor. No explanation is known for the increased local ac- When portal hypertension is mild to moderate, in- tivity of vasodilators in portal hypertension.4,8-10 creased lymphatic drainage through the thoracic duct Therefore, in compensated cirrhosis (without ascites), compensates excess fluid formation in the abdominal peripheral arterial vasodilatation (underfilling) is the cavity. However, when portal hypertension is severe, first event leading to decreased intravascular blood vol- lymph overflow causes the movement of fluid from the ume. This vasodilation, related to the «underfilling» of interstitial space of splanchnic organs to the abdominal arterial circulation, is associated to compensatory mecha- cavity, which secondarily produces impairment of circu- nisms previously mentioned. latory function and ascites. Increased plasma volume and In order to increase intravascular volume, cardiac out- cardiac output as well as decreased peripheral vascular re- put increases and the kidney retains water and sodium. In sistance in cirrhotic patients are arguments in favor of this stage of cirrhosis there is increased total blood vol- this theory5,6 ume, cardiac output, and peripheral vasodilation. These «compensated cirrhotics» (without diuretic therapy) do Overflow hypothesis not form ascites if a low dietary ingestion of salt is main- tained. At this stage, the plasma levels of renin, aldoster- This theory, proposed by Liberman et al, is based on one, vasopressin, or norepinephrine are not elevated. the fact that cirrhotic patients with ascites have increased This hypothesis proposes a transient elevation of the total blood volume. The overflow hypothesis suggests aforementioned hormones during compensatory reten- that ascites formation is not related to decreased intravas- tion of sodium and water by the kidney. This elevation cular volume and rather is a secondary phenomenon due leads to volume expansion and return to normal hormone to «primary» retention of sodium and water. It proposes levels. On the other hand, decompensated cirrhosis is de- that the cause of this «primary» retention is a «hepatore- fined by ascites formation. It represents an advanced nal reflex» that predominates over the normal volume stage in the arterial vasodilation hypothesis. At this regulation mechanism.7 stage, increased blood volume secondary to transitory re- nal retention of water and sodium is not enough to main- Peripheral arterial vasodilation hypothesismedigraphic.comtain circulatory homeostasis. In addition, decreased plas- ma oncotic pressure could be an additional factor con- This theory includes characteristics of both theories tributing to decreased effective arterial blood volume. and considers that splanchnic arteriolar vasodilation sec- Therefore, when arteriolar baroreceptors detect dimin- ondary to portal hypertension is the initial event. Cardi- ished filling of the arterial tree, vasopressin
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