The Use of Diuretics in the Treatment of Ascites and Edema in Hepatic Cirrhosis

Michael Emmett and Donald W. Seldin*

Department oj Internal Medicine, Baylor University Medical Center, Dallas, Texas 75246; and *University oj Texas Health Sciences Center, Dallas, Texas 75235


Cirrhosis of the liver is a major cause of salt and water retention. The tendency for accumulating fluid to localize in the peritoneal cavity is typical of cirrhosis and is far more pronounced than in congestive heart failure or the nephrotic syndrome. Although peripheral edema does occur with cirrhosis, it is generally of lesser magnitude and rarely dominates the clinical picture. In the late stages of cirrhosis, malnutrition and severe hypoalbuminemia may contribute to the development of massive edema.

The pathogenesis of the renal salt and water retention in patients with hepatic cirrhosis remains obscure. Two major fluid-retaining hypotheses have been advanced: (i) the underfill theory and (ii) the overflow theory. In this chapter we review the evidence in support of these two theories, discuss the indications for dietary salt restriction and diuretic therapy, the specific diuretic options which are available, common complications of diuretic therapy, complications specific to the cirrhotic population, and briefly review other therapeutic modalities.


The Classic Underfill Hypothesis

A great deal of clinical and experimental evidence is consistent with the classic underfill hypothesis which is outlined in Fig. 1. Hepatic pathology produces scarring, fibrosis, and nodular hypertrophy of the liver. These anatomic alterations restrict the flow of blood out of hepatic sinusoids producing post-sinusoidal venous blockade. Hydrostatic pressure within the sinusoids increases and the higher pressures are transmitted into the splanchnic veins and mesenteric capillary beds. These elevated hydrostatic pressures accelerate the filtration of fluid into the hepatic interstitium (spaces of Disse). The epithelium lining hepatic sinusoids is very permeable to albumin (it has a low albumin reflection coefficient), so that the fluid which accumulates in the hepatic inter-

Salt Poor Albumin For Ascites
figure 1. Renal salt and water retention and the development of ascites and edema in patients with cirrhosis: the underfill hypothesis. See text for explanation.

stitial spaces has a high albumin concentration. Fluid also accumulates on the surface of the liver and weeps into the peritoneal space. High venous and capillary pressures in other intraabdominal organs produces edema in these locations and some of this fluid also collects in the peritoneal space. Peritoneal fluid derived from these nonhepatic sources has a lower albumin concentration. The ascitic fluid originating from the liver mixes with fluid from other intraabdominal organs and results in ascites with a relatively high albumin concentration. However, in virtually all (—98%) patients with ascites due to portal hypertension, the gradient between the serum and the ascitic albumin concentrations exceeds 1.1 g%, i.e., a serum-ascitic albumin gradient (SAAG) > 1.1 g% [22],

The accumulation of interstitial fluid and ascites markedly increases lymph flow. Lymphatic flow through the thoracic duct can increase 20-fold. During the early phases of cirrhosis, this compensatory response prevents the accumulation of a large quantity of ascites. However, the high rate of fluid filtration eventually overwhelms this compensatory response, resulting in intraabdominal organ edema and progressive ascites. As liver function deteriorates, the albumin synthetic rate falls and combines with malnutrition to produce hypoalbuminemia. The resulting low colloid oncotic pressure increases the transudation of fluid into the abdominal cavity and the peripheral interstitial spaces.

The fluid shift from the vascular to the interstitial and peritoneal spaces reduces the effective arterial blood volume (EABV) (see Chapter VA1), activating multiple counterregulatory responses. The responding mediators include the renin-angiotensin system, aldosterone, antidiuretic hormone, sympathetic nerves, catecholamines, thromboxane, neuropeptide Y, and endothelin. This neurohormonal cascade increases renal salt and water retention and constricts renal blood vessels. However, despite the elevated levels of multiple vasoconstrictors, systemic vasoconstriction does not develop in most cirrhotic patients. In fact, these patients are usually vasodilated and arteriovenous shunting develops in the skin and pulmonary circulations. Cardiac output increases and blood pressure falls. Thus, the circulatory status of cirrhotic patients is "hyperdynamic." The pathogenesis of the vasodilated, shunted circulation of cirrhosis remains unknown.

Under normal circumstances, whenever vasoconstricting and salt retaining cascades are elicited by some stimulus such as hemorrhage, a simultaneous series of counterbalancing modulating systems is also activated. These modulating factors prevent unrestrained systemic vasoconstriction and renal salt retention which would be deleterious. The moderating mediators include vaso-dilatory prostanoids, atrial and other natriuretic peptides, kinins, nitric oxide, and a number of other less well-defined vasodilating and natriuretic substances including substance P, /3-endorphins, and adrenomedulin. In patients with congestive heart failure or the nephrotic syndrome, vasoconstricting and vaso-

dilating forces also develop simultaneously. However, with hemorrhage, heart failure, and nephrotic syndrome the balance generally favors systemic vasoconstriction. In contrast, vasodilation is usually dominant in the systemic circulation of most cirrhotic patients. Recent studies have focused on the potential role played by nitric oxide, a locally generated systemic vasodilator. Cirrhotic patients may develop low grade intermittent endotoxemia which can trigger nitric oxide generation. Excess nitric oxide generation may be one of the features which distinguishes cirrhosis from the other salt-retention disorders [2],

The kidneys of patients with advanced cirrhosis are an exception to this rule—renal vessels usually constrict. The EABV falls as a result of systemic vascular shunting, systemic vasodilation and translocation of fluid into the in-terstitium and peritoneum. The low EABV increases neurohormonal mediators which produce renal vasoconstriction. Contraction of the glomerular efferent arterioles is more intense than the glomerular afferent arterioles. This pattern of arterial constriction stabilizes glomerular filtration despite the low EABV and/or blood pressure. Renal plasma flow falls to a greater extent than the glomerular filtrate rate and this increases the filtration fraction (FF = GFR/RPF). A high filtration fraction stimulates proximal tubule sodium and fluid reabsorption (see Chapter VA1).

Many of the neurohormonal vasoconstricting responses listed above, including angiotensin II (which stimulates aldosterone), catecholamines, ADH, and activation of adrenergic nerves also increase renal salt and water reabsorption. The fall in EABV may be partially corrected, but a large fraction of the retained fluid accumulates in the peritoneal cavity. This occurs because of the Starling block which exists across the liver due to the restriction to blood flow out of the hepatic sinusoids.

In summary, the underfill hypothesis requires (1). Fluid shifts out of the vascular compartment (as a result of hypoalbuminemia and the restricted blood flow out of hepatic sinusoids) and (2). This stimulates the kidneys to retain salt and water. The retained salt and water is transferred into the peritoneal cavity and this prevents ECF expansion from normalizing the EABV. A-V shunts and generalized vasodilation also contribute to the low EABV and stimulate renal salt retention. Vascular shunting and peritoneal sequestration of fluid may result in unrelenting renal salt and water retention.

The underfill model receives support from studies of cirrhotic patients subjected to head-out water immersion [4]. This maneuver redistributes blood volume from peripheral capacitance vessels to the central circulation and expands EABV. The antinatriuretic and antidiuretic forces described above are often ameliorated and a diuresis frequently ensues. These results are consistent with the inference that cirrhosis is a disorder which produces a low EABV, as a result of peripheral vasodilation and A-V shunting, despite a high cardiac output and an expanded extracellular fluid (ECF). To the extent that the EABV can be normalized the antinatriuretic and antidiuretic stimuli are reduced or eliminated.

The classic underfill hypothesis described above and shown in Fig. 1 requires that ascites and edema develop before the EABV contracts and before renal salt retention occurs. However, it is possible that primary expansion of vascular capacity (i.e., A-V shunts) develops first and that this is the proximal cause of the reduced EABV and renal salt and water retention. If this occurred, then renal salt and water retention could precede development of overt ascites or edema [25]. This modification of the underfill hypothesis has been strongly advanced by Schrier [25, 39], Ascites and edema formation may then follow rather than precede renal salt retention.

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