The Overflow Hypothesis

The underfill hypothesis has been challenged on several fronts. Lieberman, Levy, their co-workers, and others have advanced clinical and experimental data which challenge the early sequence shown in Fig. 1 [15,16]. Careful studies of dogs with experimental cirrhosis and patients with early hepatic cirrhosis demonstrate that renal salt and water retention can develop prior to the formation of ascites or edema. The classic underfill hypothesis requires that ascites and/or edema develop first, to reduce the EABV and thereby activate neurohormonal cascades which increase renal salt and water retention. (The modified underfill hypothesis which begins with vasodilation and shunting was discussed above. The data are consistent with that modification.)

In contrast, the overflow hypothesis begins with hepatic abnormalities which in some way cause the kidneys to retain salt and water. This salt retention precedes detectable ascites or edema. This sequence leads to ECF expansion and ascites and edema then follow (Fig. 2). Proponents of the overflow theory believe that cirrhosis and hepatic sinusoidal hypertension activate sensors in the liver which directly, or indirectly, stimulate the kidney to retain salt and water. The retained salt and water are preferentially sequestered in the peritoneal space as a result of hypoalbuminemia and the high hepatic sinusoidal and splanchnic capillary pressures.

The earliest signals for salt retention remain unknown, but they can be blocked or blunted by the creation of a portocaval shunt which prevents the development of portal hypertension [30]. The kidneys of successfully shunted animals with early cirrhosis do not retain salt and water. Closure of the porta-systemic shunt promptly increases portal and intrahepatic pressures and quickly leads to salt and water retention and then ascites formation.

Several clinical observations have been used as support of the overflow hypothesis. Spontaneous diuresis and natriuresis occur in some cirrhotic patients in the absence of any measurable change in vascular volume. In these patients, a low vascular volume (?EABV) may not be the proximate cause of salt and water retention [13]. Some cirrhotic patients will diurese in response to intra-

Cirrhosis Edema

figure 2. Renal salt and water retention and the development of ascites and edema in patients with cirrhosis: The Overflow Hypothesis. Factor X refers to signals from hepatic volume and pressure sensors which are transmitted to the kidney via a neural and/or hormonal mechanism. See text for explanation.

figure 2. Renal salt and water retention and the development of ascites and edema in patients with cirrhosis: The Overflow Hypothesis. Factor X refers to signals from hepatic volume and pressure sensors which are transmitted to the kidney via a neural and/or hormonal mechanism. See text for explanation.

vascular volume expansion, produced either by the infusion of intravenous fluids or head-out water immersion, but many others do not respond to such maneuvers [4, 29]. The absence of a diuretic response indicates that the underfill hypothesis may not be operative in these patients. However, an alternative explanation is that the degree of volume expansion achieved in these individuals may not have adequately expanded the EABV.

It is possible that the overflow hypothesis operates during the earliest phases of cirrhosis, whereas underfill dynamics develop later when hepatic decompensation progresses. The clinical findings in almost all patients with advanced liver disease are most consistent with an underfilled state.

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