Updated: 03/13/08 01:44 PM
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Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
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S. Ascites, Edema and Renal Failure in Liver Disease

Renal sodium and water retention occurs even before ascites formation   Sodium and water retention occur in virtually all cases of cirrhosis, even before fluid accumulation is detectable clinically within the peritoneal space (ascites) and (less often) peripheral tissues (edema). In this pre-ascitic phase, the major factor is increased renal release of renin, activating angiotensin II, causing increased proximal tubular reabsorption of sodium. The unknown stimulus for this increased renin release originates in the liver. As cirrhosis progresses, multiple other factors, whose relative importance varies among patients, determine whether fluid retention develops and where it accumulates.

1. Factors promoting renal sodium and water retention
(Figure 22)

Primary event is splanchnic vaso-dilatation   a. Splanchnic vasodilation lleads to pooling of blood in splanchnic vessels, with diversion of blood volume from peripheral circulation. Systemic (including renal) circulation is underfilled, pressure falls.

Release of renin and catecholamines   b. Decrease in renal arterial and glomerular pressure and flow causes release of renin; decreased peripheral arterial pressure causes release of catecholamines. The catecholamines cause an increase in cardiac rate and output, aspects of the hyperdynamic circulation.

Increased release of angiotensin and aldosterone   c. Renin activates angiotensin II, which causes increased adrenal formation and release of aldosterone. Aldosterone mediates increased distal tubular reabsorption of sodium in exchange for potassium.

Decreased glomerular blood flow and filtration   d. Vasoconstriction of preglomerular arterioles occurs, with shunting of blood from the glomeruli (renal cortex) to the tubules (renal medulla), with further decrease in glomerular blood flow.

Increased Na+ reabsorption in distal tubules   e. Glomerular filtration of sodium decreases, with decreased delivery of Na+ to the distal tubules. Distal tubules continue to avidly reabsorb Na+ in exchange for K+.



Figure 22
Pathogenesis of Na+ Retention and Renal Complications of Cirrhosis

Flow diagram of the sequence of changes in renal and neurohumoral function that lead to the major clinical complications of cirrhosis. These complications are highlighted by the shaded boxes.

The renal sodium and water retention and late renal failure are primarily secondary complications of the activation of the renin-angiotensin-aldosterone system and sympathetic nervous system in response to the systemic hypotension generated by the shift of fluid from the systemic to splanchnic vascular beds (“splanchnic steal”).

Conversion of the reversible early hepatorenal syndrome to the usually fatal late hepatorenal syndrome is usually due to superimposed cardiocirculatory failure, often triggered by infection (such as spontaneous bacterial peritonitis) and the resultant release of cytokines. In some cases, the late hepatorenal syndrome is triggered by inhibition of renal synthesis of vasodilating prostaglandins resulting from treatment with aspirin and non-steroidal anti-inflammatory drugs (not shown).

Not shown also is the very early increase in renal sodium and water retention, before there is increased portal pressure, triggered by yet unidentified neuro-humoral stimuli that increase intrarenal release of renin.

2. Renal Failure in Cirrhosis -
The Hepatorenal Syndrome (Fig. 22)

Hypovolemia causes release of vasoconstrictors







Two stages of hepatorenal syndrome









Late syndrome often precipitated by NSAID Rx. 		 
  1. Central hypovolemia secondary to splanchnic pooling of blood leads to activation of the renin-angiotensin II-aldosterone system and increased release of catecholamines and antidiuretic hormone (ADH).


  2. Early hepato-renal syndrome rresults from the consequent intense renal arteriolar vasoconstriction, with decreased glomerular filtration and increased Na+ and H2O retention.


  3. Late hepato-renal syndrome ensues when more extreme renal vasoconstriction, often combined with cardiac failure, leads to a rapidly progressive decrease in glomerular perfusion. This may be triggered by ischemic activation of other intrarenal vasoconstrictors (endothelin, adenosine) and/or by failure of the compensatory intrarenal synthesis of the vasodilators, NO and prostaglandins. This often irreversible syndrome is frequently precipitated by treatment with prostaglandin synthesis inhibitors (aspirin, NSAIDs), as well as by sepsis or hemorrhage.
3. Factors Determining the Degree and
Site of Fluid Accumulation

  a. Decreased plasma oncotic pressure

Low plasma albumin decreases plasma oncotic pressure   This results from a combination of reduced hepatic albumin synthesis and dilution of albumin by the body's expanded fluid pools. The decreased oncotic pressure increases filtration of fluid across all capillary beds, including the hepatic sinusoids. This is the principal mechanism of the peripheral edema often seen in cirrhosis.

b. Portal hypertension

Increased portal and sinusoidal pressure   This is considered an essential element to the formation of ascites in cirrhosis. As the pressure in the portal venous system and sinusoids increases, the tendency to form ascites increases also.

c. Increased formation of hepatic lymph

Increased lymph flow and leakage from liver surface   The increased intrasinusoidal pressure, combined with decreased oncotic pressure, causes up to a 20-fold increase in formation of hepatic lymph. This exceeds the flow capacity within the thoracic and right hepatic lymphatic ducts, and lymph leaks from the surface of the liver into the peritoneal space, producing ascites.

d. Resorption of fluid and protein across the peritoneal membrane

Limited capacity of peritoneum to reabsorb fluid   i. Peritoneal permeability

Normally, the poorly permeable peritoneal membrane can absorb no more than 1 liter per day of fluid leaked into the peritoneal space. If there is inflammation and/or infection of the peritoneum, as in spontaneous bacterial peritonitis, capillary permeability increases and fluid, protein and leukocytes leak into the peritoneal cavity.

Variations in intra-peritoneal pressure   ii. Intraperitoneal Pressure

As the peritoneal cavity fills with fluid, the ascites becomes tense, and intra-abdominal pressure rises, promoting reabsorption of fluid. When ascites is removed therapeutically by abdominal puncture (paracentesis), the acute drop in intra-abdominal pressure may favor rapid reaccumulation of the ascites.

4. Treatment of Ascites, Edema & Hepatorenal Syndrome

  a. Ascites and edema:

Decrease portal pressure and plasma volume  
  1. Improve hepatic function by treating underlying liver disease
  2. Pharmacologically decrease portal pressure (see section R.3).
  3. Directly remove fluid from peritoneal cavity (paracentesis)
  4. Decrease plasma volume (low Na+ intake, diuretics, aldactone)
  5. Increase plasma oncotic pressure (infuse albumin or polymers)
  6. Mechanically decrease portal pressure (see section R.3).
b. Hepatorenal syndrome:

Expand plasma volume and give splanchnic vasoconstrictor   Early hepatorenal syndrome often responds to correction of precipitating factors, plus plasma volume expansion with albumin to normalize central venous pressure. Addition of terlipressin or norepinephrine, to selectively constrict dilated splanchnic vessels, reportedly reverses the majority of cases of late hepatorenal syndrome. The others respond to successful liver transplantation.

Renal failure is more serious than ascites   Note: Since treatments of ascites and hepatorenal syndrome may be contradictory, and the hepatorenal syndrome is much more serious, always treat renal failure rather than ascites.

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