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Ascites in Liver Disease: Pathogenesis and Treatment
Ascites in Liver Disease Pathogenesis and TreatJnent
GEORGE E. WANTZ, M.D.*
ASCITES, a dramatic finding in hepatic disease, most commonly occurs as a complication of portal cirrhosis and sometimes in other types of cirrhosis and hepatic disease. It implies portal hypertension and usually hepatocellular failure. Portacaval shunts are now widely performed to relieve patients with portal hypertension who frequently have ascites or may quickly develop it after a hemorrhage. Because several operations including portacaval shunt have been proposed for the treatment of ascites, surgeons are now frequently called upon to treat this condition. The pathogenesis of ascites was once considered simple. However, it is now known to be the sequel of a complex interplay of several pathologic and homeostatic processes, and it is often impossible to recognize which process is dominant. To achieve the greatest success in treating ascites its causes must be understood. Therefore, this paper will discuss the pathogenesis and treatment of ascites in liver disease. GENERAL PRINCIPLES OF FLUID INTERCHANGE
Starling first proposed that the hydrostatic pressure and the osmotic pressure of the blood plasma and interstitial fluid were the main physical forces which govern the interchange of fluid. The hydrostatic pressure in the arterial end of the capillaries forces fluid across the semipermeable membrane of the capillary wall into the interstitial space. At the venous end of the capillaries, hydrostatic pressure is dissipated and plasma proteins concentrated. Fluid returns then to the circulation because osmotic pressure exceeds hydrostatic pressure of the plasma. This fluid interchange is a continuous, dynamic process and huge amounts of fluid are exchanged daily between the blood stream and the tissue spaces (about 75 per cent of plasma water per minute). The capillary membranes are freely permeable to inorganic ions, From the Department of Surgery, The New York Hospital-Cornell Medical Center, New York, N. Y.
* Assistant Professor of Clinical Surgery, Cornell University Medical College; Assistant Attending Surgeon, The New York Hospital.
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whereas they are for the most part impermeable to the plasma proteins. However, as a result of hydrostatic pressure, protein does leak into the interstitial fluid through pores in the capillary walls (about 5 to 6 per cent of plasma albumin hourly). This protein oncotically opposes the return of fluid to the circulation, and with the tissue tension (hydrostatic pressure) maintains the normal, small quantity of interstitial fluid. The ionic concentrations in the plasma and the interstitial fluid are nearly identical and differ only as required by the Donnan effect of the nondiffusible protein. The small lymphatics supplement the venous system since they are permeable to all the components of the interstitial fluid. One of their principal functions is to return about 90 per cent of the protein, and consequently some fluid, which passes into the interstitial spaces. The quantity and flow of lymph are related to the physical forces of fluid interchange and body activity. Thus, the exchange of fluid between the blood and tissue spaces is due to the net filtration pressure, and the interstitial fluid is in fact an ultrafiltrate. However, exchange between the interstitial fluid and the cells is controlled by the osmotic force exerted by sodium, the predominant ion in extracellular fluid. It is apparent then that large shifts of water into or out of the extracellular space may occur without upsetting Starling's theory. Oral ingestion of water and renal function largely control osmolarity and total body water. All these processes controlling fluid interchange are necessary to promote normal metabolism and to maintain homeostasis. Edema is the state in which there is an increase of interstitial fluid. It occurs whenever the net filtration of plasma constituents through the capillaries exceeds the drainage capacity of the lymphatics. The application of Starling's law leads to the conclusion that the factors promoting the formation of edema are: (1) an increase in capillary hydrostatic pressure; (2) reduced plasma proteins, especially albumin; (3) obliteration or obstruction of the lymphatics; (4) an increase in capillary permeability; and (5) a reduced tissue tension. Edema. should be self-limiting because the dynamic relationships between the blood and the interstitial fluid should establish a new equilibrium. However, if the primary cause is intense or prolonged, blood volume is reduced by excessive loss of the intravascular fluid into the tissue space. Then other mechanisms to control blood volume and osmolarity are stimulated, and extracellular fluid is increased until a new equilibrium is obtained. The exact nature of these homeostatic processes is not clear and many mechanisms are involved. In edema, those that control sodium and water retention are significant. In response to reduced blood volume, the adrenal cortex secretes aldosterone which acts on the distal convoluted tubules to ret~ sodium and a proportional quantity of water.
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Adrenal stimulation may be mediated by hypothetical volumoreceptors in the hypothalamus l or chest. 2 Though these seem to be necessary, their existence is still uncertain. Intimately linked to this mechanism of volume control is the regulation of osmolarity. The hypothalamus contains osmoreceptors3 which respond to increases of osmolarity by stimulating thirst and by instigating the posterior pituitary to secrete the antidiuretic hormone which acts on the renal tubules to retain water independently of sodium. These processes maintain correct proportions of salt and water and preserve plasma volume. PATHOGENESIS
Hydrostatic Forces
1. Extrahepatic Portal Hypertension. In hepatic disease a factor that may contribute to localization of ascites to the peritoneal cavity is an elevated hydrostatic pressure within the capillaries draining into the portal vein. Portal hypertension of some degree is always present in patients with cirrhosis and ascites, and consequently fluid may transude from the splanchnic capillaries. Yet, by itself, portal hypertension infrequently causes ascites. Most patients with transient or sustained extrahepatic portal hypertension do not exhibit ascites. Similarly, ascites does not occur in experimental extrahepatic portal hypertension. In both instances, however, if hypoproteinemia is superimposed, clinical ascites develops. Nevertheless, transudation from the splanchnic system is regularly seen at operation in patients with intrahepatic or extrahepatic portal hypertension and ascites. Even in such patients with normal plasma proteins, the mesentery is usually edematous and remains moist throughout the operation despite exposure, and the mesenteric lymphatics are dilated and tense. Moreover, ascites regularly diminishes in patients with cirrhosis and ascites who have undergone portacaval shunt to relieve portal hypertension. Indeed, in most patients it disappears completely and permanently. It is likely that the reduction in the extrahepatic portal hypertension contributes toward the disappearance of ascites. 2. Hepatic Vein Hypertension. The relation of ascites to hepatic venous hypertension is well established. Examples are congestive cardiac failure, constrictive pericarditis, and thrombophlebitis of the hepatic veins (Budd-Chiari syndrome). With the exception of the Budd-Chiari syndrome, portal pressure is rarely elevated sufficiently to produce extensive collateral circulation or esophageal varices. The only sure method of producing severe experimental canine ascites is to constrict the thoracic inferior vena cava. 4 • 5 When this is done, only transient portal hypertension occurs, yet the ascites persists unchanged. In all these instances the liver is the chief source of the ascitic fluid, hepatic function is usually good, and serum proteins nearly normal. These observations
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and the facts that ascites does not always subside in cirrhosis after portacaval shunt and that in cirrhosis it can occur with only minimal elevation of portal pressure have focused attention on hepatic venous congestion or increased sinusoidal pressure as a major factor producing ascites. Hepatic venous obstruction ultimately develops in cirrhosis, and is demonstrated by the gradient between wedged hepatic venous pressures and free hepatic venous pressures. Typically, wedged hepatic venous pressures are elevated, correlate with portal pressure, are augmented by hepatocellular failure, and are significantly higher when ascites is present. 6, 7 Free hepatic venous pressures, however, remain nearly normal. Such large pressure differences cannot occur without postsinusoidal obstruction and increased sinusoidal resistance. Casts of the vascular system in the cirrhotic liver show that this obstruction results chiefly from nodular regenerated hepatic tissue which distorts and constricts the hepatic veins, and also displaces the central veins peripherally where they are incorporated in scar tissue. 8 However, presinusoidal obstruction is also present because of fibrosis in the portal areas, a principal pathologic alteration in cirrhosis. Thus, the pressure in the sinusoids depends on the relationship of presinusoidal to postsinusoidal obstruction, because sinusoidal pressure is determined by the mean of the pressures at opposite ends of the sinusoids. The continually changing chaotic architecture of cirrhosis suggests that all degrees of obstruction are likely to occur on either side of the sinusoids, in different stages of the disease as well as in various areas of the liver. Thus fluid may transude from the liver in cirrhosis. Presinusoidal obstruction appears to prevail in cirrhosis and therefore sinusoidal pressure may be normal. This is suggested by higher wedged hepatic venous pressures in cirrhosis without ascites, and lower wedged hepatic venous pressures in congestive cardiac failure with ascites. In addition, sinusoids and central veins are not dilated as they should be were they subjected to elevated pressure. If an extreme degree of postsinusoidal obstruction should develop, sinusoidal pressure certainly will be increased and retrograde flow of blood might occur. Yet this is uncommon and only rarely have we encountered an increase in intrahepatic portal pressure after occluding the portal vein during portacaval shunt in patients with Laennec's cirrhosis. In these patients, the hepatic lymphatics have always been enormous and ascites severe. Until more is known of the hemodynamics of cirrhosis, the role of hepatic venous hypertension as a major factor producing ascites in most patients with this diEease will remain speculative. For the present, the only conclusion possible is that presinusoidal and postsinusoidal obstruction occur in established cirrhosis, and in either instance portal hypertension develops. Consequently, ascitic fluid may originate from
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the liver or splanchnic capillaries, independently or in various combinations. 3. Intra-abdominal Pressure. Just as an elastic stocking opposes the edema of thrombophlebitis, an increase in intra-abdominal pressure may resist the outpouring of ascites and quicken lymphatic absorption. The astonishing rapidity with which ascites sometimes recurs after paracentesis may so reduce the plasma volume that shock ensues. Moreover, as the ascites returns, its rate diminishes with increasing abdominal distention. Intra-abdominal pressure represents the hydrostatic force opposing the portal pressure, and therefore the effective portal pressure depends on the degree of portal hypertension. In addition, intra-abdominal pressure increases lymphatic absorption and flow. However, only the extremes of intra-abdominal tension influence ascites. Furthermore, intra-abdominal tension is limited since the abdominal wall continues to stretch, and a tense full abdomen is discomforting and not tolerated by the patient. Colloidal Osmotic Forces 1. Plasma Proteins. The liver synthesizes albumin. Thus, hypoalbuminemia commonly occurs in patients with hepatic disease. Levels of albumin as low as 2 to 2.5 grams per 100 ml. are not uncommon. Hypoalbuminemia influences ascites because the rates of transudation of fluid depend on the differences between hydrostatic and oncotic pressures. Krook 6 has demonstrated this inverse relation between the degree of elevated wedged hepatic vein pressures (portal hypertension) and the degree of hypoalbuminemia in patients with ascites due to cirrhosis. Largely because of the hydrostatic forces, there is no constant relation between ascites and serum albumin levels or oncotic pressures. N evertheless, ascites is more apt to develop if the serum albumin is less than 3 grams per 100 ml. or serum osmotic pressures are less than 250 mm. H 20. Once the tendency to form ascites becomes more severe, the serum level of albumin or serum osmotic pressure may have virtually no effect on the formation of ascites, presumably because of the increased hydrostatic forces at play. Hypoalbuminemia then is an essential factor in the production of ascites, provided the hydrostatic forces in the liver or distal portal capillaries are only mildly elevated. 2. The Ascitic Fluid. The protein content of ascitic fluid in cirrhosis is proportional to the plasma protein and usually varies between 1 and 2 grams per 100 ml. All the plasma proteins are present in the ascitic fluid which also regularly contains red blood cells, often in significant quantities. Rarely, however, is it bloody or cheilous. Ascitic fluid, like normal interstitial fluid, is continuously interchanged with the plasma. Since they are freely diffusible, water and electrolyte turnover is rapid and enormous. Moreover, protein enters and leaves the ascitic pool at essentially the same rate, provided the ascites
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is maintained at a steady volume spontaneously or as a result of salt restriction. 9 Presumably due to the high hydrostatic pressures that are active in causing ascites to form in cirrhosis, there is a larger difference between the ascitic and plasma osmotic pressures than in ascites of other causes, such as peritoneal carcinoma. 1o This osmotic equilibrium must always be considered when administering albumin intravenously, because the albumin diffuses proportionally between the plasma and the extracellular space. Albumin sufficient to raise the colloidal osmotic pressure of the plasma one degree also raises the ascitic colloidal osmotic pressure one degree. LYInphatics
Though fluid transuding from the liver appears in experimental ascites, 5 it is rarely seen in cirrhosis. We have seen fluid dripping from a cirrhotic liver only once, and in this instance the hemodynamics were those of the Budd-Chiari syndrome. Nevertheless, increased hepatic lymph flow occurs in cirrhosis, as well as in those rare patients with portal hypertension due solely to congenital or acquired obliteration of the intrahepatic portal radicals. In these situations the hepatic lymphatics may be more easily overloaded. Augmented hepatic lymph flow is evidenced by the dilated tense lymphatics beneath Glisson's capsule and emerging from the porta hepatis. These occur despite the probable obliteration of the capillary lymphatics in the fibrous portal areas. The fact that hepatic edema in cirrhosis is uncommon indicates that the unexpandable scar-encased cirrhotic liver probably assists lymphatic function. However, this tissue tension is insufficient to counteract the . vascular hydrostatic forces. The enlarged hepatic lymphatics usually do not overshadow those buried in the mesentery. Nevertheless, sometimes they are immense even though they may not be associated with ascites and this may indicate marked postsinusoidal obstruction. The hepatic lymphatics are particularly noticeable to surgeons during portacaval shunts. Indeed, lymph may swamp the operative field if a prominent hepatic lymphatic is unintentionally cut. Although temporary ascites commonly develops in the postoperative period of portacaval shunts, a troubleseome variety may occasionally occur when these lymphatics are greatly enlarged. This may be due to lymphorrhea from unligated lymphatics, and in such cases the ascitic fluid contains extremely large quantities of protein. The mesenteric lymphatics have been mentioned. No evidence indicates that the lymphatics draining either end of the portal system are enlarged because their trunks are obstructed. Furthermore, there are many alterate lymphatic routes to the thoracic duct, and although it has not been measured, undoubtedly thoracic duct lymph flow in ascites due to cirrhosis is greatly increased as it is in experimental ascites. The lymphatics draining the ascitic fluid reside chiefly in the dia-
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phragm, since constant motion promotes lymphatic flow. The parietal peritoneal lymphatics also absorb ascitic fluid, but to a lesser degree. The serositis, adhesions, and diminished respirations commonly present in chronic ascites due to cirrhosis may reduce the efficiency of these lymphatics in picking up the ascitic protein, thereby prolonging and enhancing the ascites. In most instances, however, their function is quite satisfactory. Endothelial PerIlleability
There is no evidence to indicate a general alteration of capillary or endothelial permeability as a contributing cause of ascites. Generalized edema never occurs and studies with l l3l-tagged albumin show nearly normal diffusion rates from the blood into extracellular space in malnourished patients with advanced cirrhosis. l l A local increase in capillary or peritoneal permeability has been postulated but has not been demonstrated. SodiuIll and Water Retention
The typical patient with advanced cirrhosis and refractory ascites tenaciously retains salt. The daily urine often contains less than 1 mEq. of sodium, and subnormal amounts of sodium are present in the saliva, sweat and feces. Likewise, water retention occurs, and the daily quantities of urine are small and concentrated in nature. Paradoxically, however, the serum sodium is usually about 130 mEq., and the plasma volume expanded. Diminished renal function may contribute to sodium retention. Reduced glomerular filtration rates have been demonstrated in patients with ascitic cirrhosis.l 2 This may result from altered renal vein pressures produced by the tense ascitic abdomen or from reduced renal plasma flow. However, some patients with ascites may have normal glomerular filtration rates. l3 The retention of sodium appears to be largely due to the salt-retaining hormones of the adrenal cortex. Aldosterone has been demonstrated in the urine of patients with ascites, indicating an increase since the quantity of aldosterone in normal urine is too small to measure. l4 The damaged liver may fail to detoxify these hormones. However, fluctuations of the urinary salt-retaining hormone vary with the quantity of salt intake and the tendency to form ascites. This suggests an actual increased output of these hormones. The importance of the adrenal cortical salt-retaining hormones in ascites has been demonstrated experimentally. In dogs rendered ascitic, the ascites completely disappears after bilateral adrenalectomy, but returns if dexoxycorticosterone is· administered in excess of daily requirements. l5 Nevertheless, ascites may continue to form in the absence of the salt-retaining hormones. Bilateral adrenalectomy has been per-
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formed in a patient with cirrhosis and refractory ascites. 16 The ascites did not disappear, yet urinary sodium increased. Another hormone possibly contributing to salt retention is estrogen. 11 Excessive quantities of estrogens, which are weakly salt-retaining, have been demonstrated in the blood of patients with cirrhosis, presumably due to failure of the cirrhotic liver to inactivate them. Water retention usually varies directly and precisely with the degree of retained sodium. With more severe ascites, a disproportional volume of water may be retained. This water retention may be caused by accelerated production of the antidiuretic hormone (ADH).18 Increased urinary quantities of ADH have been demonstrated in patients with chronic ascites due to cirrhosis, and delayed diuresis after water loading is typical.1 9 The liver detoxifies ADH. However, the response to pitressin is usually normal,20 suggesting that hepatic inactivation of ADH may not be delayed as has been postulated, and that an actual increase of ADH occurs. Vasodepressor material (VDM) produced by the diseased liver has antidiuretic properties. VDM may contribute to water retention, but probably only in preterminal states. The disproportional water retention is reflected in hyponatremia. III most instances this hyponatremia is actually a kind of salt-depletion and dehydration, although it appears as a "dilution hyponatremia" due to the expansions of plasma volume and extracellular fluid. 21 . 22 The expanded plasma volume, typically present in advanced cirrhosis, is misleading because it usually depicts splanchnic congestion and increased portal capacity. Plasma volumes are nearly normal after portacaval shunt or in the absence of esophageal varices. Thus, while the effective plasma volume may be normal, it may be diminished in severe ascites. For instance, if the forces producing it are extreme, ascites may continue to develop, demanding salt and water from the plasma in quantities insufficiently satisfied by maximal salt retention, and consequently plasma volume shrinks. ADH is then secreted and extra water is retained in an attempt to preserve effective plasma volume. Therefore, the concentration of sodium in the body fluids falls due to the disproportionate retention of wat.er in the abdomen, and the degree of deviation from the normal may roughly parallel the degree of elevation of local hydrostatic forces. Salt restriction, paracentesis and diuresis may also enhance the hyponatremia. This hyponatremia is strangely asymptomatic and cannot be corrected by the administration of salt without increasing the ascites, since salt administration just causes more water retention. However, serum sodium levels gradually rise as the ascites begins to abate, indicating that the hyponatremia is not permanent. The chronic disease state may contribute to the hyponatremia. 2. 23 In such instances, intracellular potassium is lost owing to cellular disintegration, and sodium and hydrogen enter the cells. This leads to
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intracellular hypotonicity and consequently hyponatremia of extracellular fluid. Prolonged or excessive aldosterone secretion may also contribute to potassium depletion. 24 The salt and water retentions are secondary homeostatic mechanisms attempting to maintain effective plasma volume, but also greatly increasing the ascites. Most patients with cirrhosis correctly secrete water and sodium before the onset of ascites, unless hypoalbuminemia is present. Furthermore, the degree of salt and water retention varies with the severity of the ascites and ceases upon complete subsidence of the ascites, either spontaneously or after portacaval shunt. 25 Should hypoproteinemia develop following portacaval shunt, salt retention recurs but edema instead of ascites develops. Finally, the production of the antiduretic factors and the salt-retaining factors are just sufficient to feed the accumulation of ascites, since in advanced cirrhosis with ascites edema does not occur. TREATMENT
The ascites of nearly all patients with cirrhosis can be improved. The treatment should be individualized to the patient. It consists mainly of saIt restriction and diuretics. In a small select group of patients, portal decompression is indicated. Above all, however, measures to improve hepatic function are paramount. The therapeutic measures to combat hepatocellular failure and improve hepatic function apply whether or not ascites is present. They include rest, a diet high in protein and carbohydrate, large quantities of vitamins, and complete abstinence from alcohol. Merely arresting hepatocellular failure often checks the ascites without employing specific therapy directed at the ascites. Only the specific treatment of ascites will be discussed. Salt Restriction
The restriction of salt is the most effective specific treatment of ascites. It checks ascites by creating dehydration. Water restriction is not necessary. The degree of saIt restriction varies with each patient. Mere avoidance of saIt in cooking and at the dinner table is occasionally all that is necessary to control ascites. Generally, it is advisable to prescribe a 2 to 3 gram salt diet. If the patient is retaining salt avidly, his total excretion of sodium chloride by all routes may be less than 1 gram daily, and every gram of sodium chloride taken in excess of this will increase the ascites by approximately 100 ml. Therefore, a diet containing less than 1 gram of sodium chloride daily may be necessary. Careful adherence to well prepared diet lists is necessary to avoid many hidden sources of dietary salt. The common dietary sources of protein such as meat, eggs, milk and cheese have a high salt content. Howeve~, salt-free milk, bread and protein supplements are available, and the diet need not be deficient in protein. In most instances, ascites is promptly
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controlled, paracenteses are avoided, and the steady increase in ascites is prevented. Whether the residual ascites eventually completely reabsorbs depends on the ultimate course of the underlying hepatic disease. Should the ascites disappear, salt restriction may be relaxed. Despite the common occurrence of hyponatremia, patients tolerate salt restriction surprisingly well, and only rarely exhibit the low-salt syndrome. By itself, hyponatremia must not be mistaken for the lowsalt syndrome, and if it does develop, no attempt should be made to correct it. Finally, protein intake occasionally must be sharply curtained in spite of its essentiality, since a few patients may exhibit meat intoxication. Diuretics
The mercurial compounds are the most effective diuretics. They act by preventing sodium and chloride reabsorption by the renal tubules. Mercurial compounds do not always produce diuresis in ascites, but if diuresis occurs, they should be continued. Two milliliters of mercuhydrin administered intramuscularly twice a week generally suffice. Increasing serum chloride potentiates mercurial diuresis. Most patients with cirrhosis tolerate 3 to 4 grams of ammonium chloride daily without exhibiting mental changes. Calcium chloride is a good substitute if the ammonium chloride produces any neurolgoic signs such as confusion, somnolence or tremor. Carbonic anhydrase inhibitor (Diamox) should be avoided in patients with cirrhosis since it may precipitate the same neurologic complications. Cation Exchange Resins
The cation exchange resins exchange one cation for another, such as sodium. Therefore they could be used to curtail sodium absorption or permit a higher salt intake. However, they are ineffectual in binding sodium. In sufficient quantities to be effective in cirrhosis, they commonly cause nausea, vomiting, constipation, acidosis and neurologic symptoms. The resins of ammonium phase must be avoided. Cation exchange resins are not too effective, are often dangerous, and should not be used in hepatic disease. Intravenous AlbuIllin
The effects of intravenous salt-poor human albumin in ascites have already been mentioned. Albumin diffuses proportionately throughout the extracellular spaces, and enormous quantities, constantly administered, are frequently necessary to correct the hypoalbuminemia in advanced cirrhosis. Even then, diuresis may not occur. Their effect is transient since they are short-lived. Moreover, they increase plasma volume, often in the presence of an already expanded plasma volume, and consequently hazards of inducing pulmonary edema or hemorrhage
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from esophageal varices are always present. Small quantities (25 grams) may improve the patient nutritionally, but since it is expensive, such use is unjustified. If given shortly before a mercurial diuretic, diuresis may be augmented. In general, albumin as well as other plasma expanders have limited use in treating ascites. Paracentesis
Most patients with cirrhosis do not need paracentesis. In general, paracentesis should be avoided because large quantities of albumin will be removed with the ascitic fluid. Since the diseased liver may not be capable of replacing this albumin, hypoalbuminemia is accelerated. Nevertheless, paracentesis is often necessary if a taut abdomen develops which is very uncomfortable and reduces respiratory efficiency and alimentation. Occasionally, an initial paracentesis performed at the onset of salt restriction may save time and facilitate abdominal examination. The fluid should be removed slowly to prevent syncope. The low-salt syndrome may follow paracentesis. This syndrome consists of weakness, apathy, muscle cramps, nausea, vomiting, hypotension, thready pulse, and an elevated blood urea nitrogen, and must not be diagnosed by the serum sodium level alone. It is caused by acute hyponatremia following rapid loss of serum sodium to the reforming ascitic fluid and may develop from a few hours to several days after paracentesis, depending on the rate of ascitic reaccumulation. More commonly, it occurs after prolonged salt restriction, and may not occur if there is peripheral edema which can supply the reforming ascites with salt and water. If ascites develops following an operation in a patient with cirrhosis, this syndrome may develop concomitantly with the onset of the ascites and complicate postoperative care. The best treatment in patients with cirrhosis is intravenous isotonic saline. In addition, albumin, plasma, or blood are usually required to replete the lost plasma proteins and plasma volume. Hypertonic saline, although frequently recommended, is most useful as initial treatment only if the symptoms are especially acute. Occasionally frequent paracentesis becomes necessary. In such instances, the loss of sodium and protein should be countervailed simultaneously with paracentesis by intravenous administration of 25 to 50 grams of albumin mixed with either dextrose and water or isotonic saline as the case requires. Surgical Treatlllent of Ascites
Portal decompression is currently the only operation which may successfully relieve and prevent ascites. Mahy operations have been devised in the past to relieve ascites. The list includes the insertion of buttons or catheters between the abdomen and subcutaneous tissue, saphenoperitoneal anastomosis, renal pelvoperitoneal anastomosis, hepatopexy, omentopexy, splenopexy, splenectomy, and ligation of hepatic and splenic
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arteries. All these operations have been unsatisfactory and none should be performed. Several years ago Crosby and Cooney26 devised a new button, and renewed interest in subcutaneous drainage of ascitic fluid followed. Surgeons are still prevailed upon to implant them in the abdominal wall. Although they function for a month or so, they ultimately fail. A fibrous sac lined by endothelium develops in the subcutaneous tissue and absorption of fluid ceases. Their use is not recommended. Recently Neumann27 has devised an operation to relieve ascites. It consists of isolating a segment of ileum, slitting the lumen, and suturing its edges to parietal peritoneum. The ascitic fluid is absorbed by the ileal mucosa. At present the operation is still in the experimental stages and clinical experience is extremely limited. The results in the few patients in whom it has been performed are unsatisfactory, and sepsis has been a problem. It should not be performed until proven benefits from the operation are demonstrated. Despite some unjust criticism, portal decompression has a definite place in the treatment of refractory ascites due to cirrhosis. It relieves splanchnic congestion and most likely reduces sinusoidal pressure,28 although this is not definitely known, since alterations in hepatic hemodynamics following portacaval shunt have not been fully clarified. Nevertheless, portal decompression regularly relieves ascites due to cirrhosis. Moreover, ascites almost never reappears even though hypoalbuminemia and salt retention may develop and cause edema and anasarca. If technically possible, end-to-side portacaval anastomosis is preferred to splenorenal anastomosis, since there is a greater reduction of portal pressure and the anastomosis stays patent. Furthermore, after end-to-side portacaval shunt, the intrahepatic portal pressures are never as low as the shunted portal pressures, and consequently in side-to-side portacaval or splenorenal shunt portal blood often would not flow through the liver. Also, there is no evidence that end-to-side portacaval shunt is less effective in relieving ascites than other types of shunts. However, if there is retrograde portal blood flow, splenorenal or side-toside portacaval anastomosis is mandatory. The presence of enormous hepatic lymphatics may be a clue to such a situation which is definitely established if portal pressure falls or intrahepatic portal pressure rises upon occluding the portal vein. Most of the experience in the relief of ascites by portal decompression has been gained through follow-up observations in patients with refractory ascites who have undergone portacaval shunt to prevent recurrent hemorrhage from esophageal varices. The experience in the use of portacaval shunt to treat ascites specifically is still somewhat limited, although the earliest portacaval shunts were performed for this purpose. Consequently, a conservative approach is advisable while this problem undergoes reevaluation. Candidates for operation should be carefully evaluated and should meet certain requirements if satisfactory results are to be expected. In
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addition, the benefits of the operation must be weighed against the significantly high mortality in portacaval shunt and the possibility that diverted portal blood may increase the incidence of neurologic symptoms. The ascites should be refractory, which means that there has not been a reasonable response after careful treatment for eight to 12 months. This is not unduly long, since ascites may subside spontaneously even after a year, provided the patients are carefully managed. The serum albumin should exceed 3 grams per 100 ml., since severe hypoalbuminemia may be an essential factor in the formation of the ascites and may represent poor hepatic function. Moreover, patients with critically low levels of serum albumin due to cirrhosis are extraordinarily poor surgical risks. Should such patients recover from the operation, severe dependent edema may supervene and irk the patients more than the ascites. Hyponatremia does not necessarily contraindicate operation, since it develops in all patients with prolonged ascites treated by salt restriction. However, patients with extreme degrees of hyponatremia tolerate operation poorly, and therefore serum sodium should be at least 130 mEq. Naturally, hepatic function as well as the over-all outlook of the cirrhosis itself must be reasonably good. Portal hypertension is prerequisite, although high degrees of portal pressures are not essential to insure successful results. Portal pressure can be evaluated by percutaneous splenic puncture 29 or hepatic vein catheterization. The mere presence of esophageal varices generally indicates a portal pressure exceeding 30 cm. of saline, yet does not mandatorily indicate operation unless hemorrhage has occurred. Patients with chronic constrictive pericarditis may be mistaken for patients with refractory ascites due to cirrhosis, especially those meeting the requirements for portal decompression. Such confusion must be carefully avoided, because constrictive pericarditis is amenable to pericardectomy. Thus portal decompression specifically to relieve ascites is limited to only a small group of patients. Perhaps as experience enlarges and more is learned of the etiology of ascites in cirrhosis and the hemodynamics of cirrhosis before and following portacaval shunt, the indications for operation may be extended. REFERENCES 1. Viar, W. N., Oliver, B. B., Eisenberg, S., Lombardo, T. A., Willis, K. and Harrison, T. R.: Effect of Posture and of Compression of Neck on Excretion of Electrolytes and Glomerular Filtration: Further Studies. Circulation 3: 105, 1951. 2. Sims, E. A. H., Welt, L. G., Orloff, J. and Needham, J. W.: Asymptomatic Hyponatremia in Pulmonary Tuberculosis. J. Clin. Invest. 29: 1545, 1950. 3. Verney, E. B.: Antidiuretic Hormone and Factors Which Determine Its Release. Croonian Lecture, Proc. Roy. Soc., London, s. B 135: 25, 1947. 4. McKee, F. W., Shilling, J. A., Tishkoff, G. H. and Hyatt, R. E.: Experimental Ascites. Effects of Sodium Chloride and Protein Intake on Protein Metabolism of Dogs with Constricted Inferior Vena Cava. Surg., Gynec. & Obst. 89: 529, 1949.
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5. Hyatt, R E. and Smith, J. R: Mechanism of Ascites. Am. J. Med. 31: 434, 1954. 6. Krook, H.: Circulatory Studies in Liver Cirrhosis. Acta med. Scandinav. 156: Supple. 318, 1956. 7. Taylor, W. J. and Negus, J. D.: Occlusive Hepatic venous Catheterization in Study of Normal Liver, Cirrhosis of Liver and Noncirrhotic Portal Hypertension. Circulation 13: 368, 1956. 8. Kelty, R H., Robertson, A. H. and Butt, H. R: Relation of Regenerated Liver Nodule to Vascular Bed in Cirrhosis. Gastroenterostomy 15: 285,1950. 9. Eisenmenger, W. J. and Slater, R. J.: Distribution and Decay of p3l-Tagged Albumin and Gamma Globulin in Patients with Cirrhosis. J. Clin. Invest. 32: 564, 1953. 10. Giges, B. and Kunkel, H. G.: Osmotic Pressure Measurements of Serum and Ascitic Fluid in Patients with Cirrhosis of Liver. J. Clin. Invest. 33: 257, 1954. 11. Eisenmenger, W. J.: Personal communioation. 12. Leslie, S. H., Johnston, B. and Ralli, E. P.: Renal Function as Factor in Fluid retention in patients with Cirrhosis of Liver. J. Clin. Invest. 20: 1200, 1951. 13. Epstein, F. H., Lesser, G. T. and Berger, E. Y.: Renal Function in Decompensated Cirrhosis of Liver. Proc. Soc. Exper. BioI. & Med. 75: 822, 1950. 14. Axelrod, L. R., Cates, J. E., Johnson, B. B. and Luetscher, J. A. Jr.: Aldosterone in Urine of Normal Man and of Patients with Oedema. Brit. M. J. 1: 196, 1955. 15. Davis, J. 0., Howell, D. S. and Southworth, J. L. III: Effect of Adrenalectomy and Subsequent DCA Administration on Ascites Formation. Circulation Research 1: 260, 1953. 16. Marson, F. G. W.: Total Adrenalectomy in Hepatic Cirrhosis with Ascites. Lancet 2: 847, 1954. 17. Preedy, J. R K. and Aitken, E. H.: Effect of Estrogen on Water and Electrolyte Metabolism. II. Hepatic Disease. J. Clin. Invest. 35: 430, 1956. 18. Leaf, A. and Mamby, A. R: An Antidiuretic Mechanism Not Regulated by Extracellular Fluid Tonicity. J. Clin. Invest. 31: 60, 1952. 19. Ralli, E. P., Robson, J. S., Clarke, D. and Hoagland, C. L.: Factors Influencing Ascites in Patients with Cirrhosis of Liver. J. Clin. Invest. 24: 316, 1945. 20. White, A. G., Rubin, G. and Lester, L.: Effect of Pitressin on Renal Excretion of Water and Electrolytes in Patients with and without Liver Disease. J. Clin. Invest. 30: 1287, 1951. 21. Eisenmenger, W. J., B1ondheim, S. H., Bongiovanni, A. M. and Kunkel, H. G.: Electrolyte Studies on Patients with Cirrhosis of Liver. J. Clin. Invest. 29: 1491, 1950. 22. Eisenmenger, W. J.: Role of Sodium in Formation and Control of Ascites in Patients with Cirrhosis. Ann. Int. Med. 37: 261, 1952. 23. Elkington, J. R, Winkler, A. W. and Danowski, T. S.: Inactive Cell Base and Measurement of Changes in Cell Water. Yale J. BioI. & Med. 17: 383,1944. 24. Conn, J. W. and Louis, J. H.: Primary Aldosteronism, a New Clinical Entity. Ann. Int. Med. 44: 1, 1956. 25. Eisenmenger, W. J. and Nickel, W. F.: Relationship of Portal Hypertension to Ascites in Laennec's Cirrhosis. Am. J. Med. 20: 879, 1956. 26. Crosby, R C. and Cooney, E. A.: Surgical Treatment of Ascites. New England J. Med. 235: 581, 1946. 27. Neumann, C. G., Braunwald, N. S. and Hinton, J. W.: Absorption of Ascitic Fluid following Eversion of Segment of Intestinal Mucosa Within Abdomen. Surgical Forum, 1955. Philadelphia, W. B. Saunders Co., 1956, pp. 374-376. 28. Bradley, S. E., Smythe, C. M., Fitzpatrick, H. F. and Blakemore, A. H.: Effect of Portacaval Shunt on Estimated Hepatic Blood Flow and Oxygen Uptake in Cirrhosis. J. Clin. Invest. 32: 526, 1953. 29. Atkinson, M. and Sherlock, S.: Intrasplenic Pressure as Index of Portal Venous Pressure. Lancet 1: 1325, 1954. 445 East 68th Street New York, 21, N. Y.
GEORGE E. WANTZ, M.D.*
ASCITES, a dramatic finding in hepatic disease, most commonly occurs as a complication of portal cirrhosis and sometimes in other types of cirrhosis and hepatic disease. It implies portal hypertension and usually hepatocellular failure. Portacaval shunts are now widely performed to relieve patients with portal hypertension who frequently have ascites or may quickly develop it after a hemorrhage. Because several operations including portacaval shunt have been proposed for the treatment of ascites, surgeons are now frequently called upon to treat this condition. The pathogenesis of ascites was once considered simple. However, it is now known to be the sequel of a complex interplay of several pathologic and homeostatic processes, and it is often impossible to recognize which process is dominant. To achieve the greatest success in treating ascites its causes must be understood. Therefore, this paper will discuss the pathogenesis and treatment of ascites in liver disease. GENERAL PRINCIPLES OF FLUID INTERCHANGE
Starling first proposed that the hydrostatic pressure and the osmotic pressure of the blood plasma and interstitial fluid were the main physical forces which govern the interchange of fluid. The hydrostatic pressure in the arterial end of the capillaries forces fluid across the semipermeable membrane of the capillary wall into the interstitial space. At the venous end of the capillaries, hydrostatic pressure is dissipated and plasma proteins concentrated. Fluid returns then to the circulation because osmotic pressure exceeds hydrostatic pressure of the plasma. This fluid interchange is a continuous, dynamic process and huge amounts of fluid are exchanged daily between the blood stream and the tissue spaces (about 75 per cent of plasma water per minute). The capillary membranes are freely permeable to inorganic ions, From the Department of Surgery, The New York Hospital-Cornell Medical Center, New York, N. Y.
* Assistant Professor of Clinical Surgery, Cornell University Medical College; Assistant Attending Surgeon, The New York Hospital.
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whereas they are for the most part impermeable to the plasma proteins. However, as a result of hydrostatic pressure, protein does leak into the interstitial fluid through pores in the capillary walls (about 5 to 6 per cent of plasma albumin hourly). This protein oncotically opposes the return of fluid to the circulation, and with the tissue tension (hydrostatic pressure) maintains the normal, small quantity of interstitial fluid. The ionic concentrations in the plasma and the interstitial fluid are nearly identical and differ only as required by the Donnan effect of the nondiffusible protein. The small lymphatics supplement the venous system since they are permeable to all the components of the interstitial fluid. One of their principal functions is to return about 90 per cent of the protein, and consequently some fluid, which passes into the interstitial spaces. The quantity and flow of lymph are related to the physical forces of fluid interchange and body activity. Thus, the exchange of fluid between the blood and tissue spaces is due to the net filtration pressure, and the interstitial fluid is in fact an ultrafiltrate. However, exchange between the interstitial fluid and the cells is controlled by the osmotic force exerted by sodium, the predominant ion in extracellular fluid. It is apparent then that large shifts of water into or out of the extracellular space may occur without upsetting Starling's theory. Oral ingestion of water and renal function largely control osmolarity and total body water. All these processes controlling fluid interchange are necessary to promote normal metabolism and to maintain homeostasis. Edema is the state in which there is an increase of interstitial fluid. It occurs whenever the net filtration of plasma constituents through the capillaries exceeds the drainage capacity of the lymphatics. The application of Starling's law leads to the conclusion that the factors promoting the formation of edema are: (1) an increase in capillary hydrostatic pressure; (2) reduced plasma proteins, especially albumin; (3) obliteration or obstruction of the lymphatics; (4) an increase in capillary permeability; and (5) a reduced tissue tension. Edema. should be self-limiting because the dynamic relationships between the blood and the interstitial fluid should establish a new equilibrium. However, if the primary cause is intense or prolonged, blood volume is reduced by excessive loss of the intravascular fluid into the tissue space. Then other mechanisms to control blood volume and osmolarity are stimulated, and extracellular fluid is increased until a new equilibrium is obtained. The exact nature of these homeostatic processes is not clear and many mechanisms are involved. In edema, those that control sodium and water retention are significant. In response to reduced blood volume, the adrenal cortex secretes aldosterone which acts on the distal convoluted tubules to ret~ sodium and a proportional quantity of water.
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Adrenal stimulation may be mediated by hypothetical volumoreceptors in the hypothalamus l or chest. 2 Though these seem to be necessary, their existence is still uncertain. Intimately linked to this mechanism of volume control is the regulation of osmolarity. The hypothalamus contains osmoreceptors3 which respond to increases of osmolarity by stimulating thirst and by instigating the posterior pituitary to secrete the antidiuretic hormone which acts on the renal tubules to retain water independently of sodium. These processes maintain correct proportions of salt and water and preserve plasma volume. PATHOGENESIS
Hydrostatic Forces
1. Extrahepatic Portal Hypertension. In hepatic disease a factor that may contribute to localization of ascites to the peritoneal cavity is an elevated hydrostatic pressure within the capillaries draining into the portal vein. Portal hypertension of some degree is always present in patients with cirrhosis and ascites, and consequently fluid may transude from the splanchnic capillaries. Yet, by itself, portal hypertension infrequently causes ascites. Most patients with transient or sustained extrahepatic portal hypertension do not exhibit ascites. Similarly, ascites does not occur in experimental extrahepatic portal hypertension. In both instances, however, if hypoproteinemia is superimposed, clinical ascites develops. Nevertheless, transudation from the splanchnic system is regularly seen at operation in patients with intrahepatic or extrahepatic portal hypertension and ascites. Even in such patients with normal plasma proteins, the mesentery is usually edematous and remains moist throughout the operation despite exposure, and the mesenteric lymphatics are dilated and tense. Moreover, ascites regularly diminishes in patients with cirrhosis and ascites who have undergone portacaval shunt to relieve portal hypertension. Indeed, in most patients it disappears completely and permanently. It is likely that the reduction in the extrahepatic portal hypertension contributes toward the disappearance of ascites. 2. Hepatic Vein Hypertension. The relation of ascites to hepatic venous hypertension is well established. Examples are congestive cardiac failure, constrictive pericarditis, and thrombophlebitis of the hepatic veins (Budd-Chiari syndrome). With the exception of the Budd-Chiari syndrome, portal pressure is rarely elevated sufficiently to produce extensive collateral circulation or esophageal varices. The only sure method of producing severe experimental canine ascites is to constrict the thoracic inferior vena cava. 4 • 5 When this is done, only transient portal hypertension occurs, yet the ascites persists unchanged. In all these instances the liver is the chief source of the ascitic fluid, hepatic function is usually good, and serum proteins nearly normal. These observations
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and the facts that ascites does not always subside in cirrhosis after portacaval shunt and that in cirrhosis it can occur with only minimal elevation of portal pressure have focused attention on hepatic venous congestion or increased sinusoidal pressure as a major factor producing ascites. Hepatic venous obstruction ultimately develops in cirrhosis, and is demonstrated by the gradient between wedged hepatic venous pressures and free hepatic venous pressures. Typically, wedged hepatic venous pressures are elevated, correlate with portal pressure, are augmented by hepatocellular failure, and are significantly higher when ascites is present. 6, 7 Free hepatic venous pressures, however, remain nearly normal. Such large pressure differences cannot occur without postsinusoidal obstruction and increased sinusoidal resistance. Casts of the vascular system in the cirrhotic liver show that this obstruction results chiefly from nodular regenerated hepatic tissue which distorts and constricts the hepatic veins, and also displaces the central veins peripherally where they are incorporated in scar tissue. 8 However, presinusoidal obstruction is also present because of fibrosis in the portal areas, a principal pathologic alteration in cirrhosis. Thus, the pressure in the sinusoids depends on the relationship of presinusoidal to postsinusoidal obstruction, because sinusoidal pressure is determined by the mean of the pressures at opposite ends of the sinusoids. The continually changing chaotic architecture of cirrhosis suggests that all degrees of obstruction are likely to occur on either side of the sinusoids, in different stages of the disease as well as in various areas of the liver. Thus fluid may transude from the liver in cirrhosis. Presinusoidal obstruction appears to prevail in cirrhosis and therefore sinusoidal pressure may be normal. This is suggested by higher wedged hepatic venous pressures in cirrhosis without ascites, and lower wedged hepatic venous pressures in congestive cardiac failure with ascites. In addition, sinusoids and central veins are not dilated as they should be were they subjected to elevated pressure. If an extreme degree of postsinusoidal obstruction should develop, sinusoidal pressure certainly will be increased and retrograde flow of blood might occur. Yet this is uncommon and only rarely have we encountered an increase in intrahepatic portal pressure after occluding the portal vein during portacaval shunt in patients with Laennec's cirrhosis. In these patients, the hepatic lymphatics have always been enormous and ascites severe. Until more is known of the hemodynamics of cirrhosis, the role of hepatic venous hypertension as a major factor producing ascites in most patients with this diEease will remain speculative. For the present, the only conclusion possible is that presinusoidal and postsinusoidal obstruction occur in established cirrhosis, and in either instance portal hypertension develops. Consequently, ascitic fluid may originate from
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the liver or splanchnic capillaries, independently or in various combinations. 3. Intra-abdominal Pressure. Just as an elastic stocking opposes the edema of thrombophlebitis, an increase in intra-abdominal pressure may resist the outpouring of ascites and quicken lymphatic absorption. The astonishing rapidity with which ascites sometimes recurs after paracentesis may so reduce the plasma volume that shock ensues. Moreover, as the ascites returns, its rate diminishes with increasing abdominal distention. Intra-abdominal pressure represents the hydrostatic force opposing the portal pressure, and therefore the effective portal pressure depends on the degree of portal hypertension. In addition, intra-abdominal pressure increases lymphatic absorption and flow. However, only the extremes of intra-abdominal tension influence ascites. Furthermore, intra-abdominal tension is limited since the abdominal wall continues to stretch, and a tense full abdomen is discomforting and not tolerated by the patient. Colloidal Osmotic Forces 1. Plasma Proteins. The liver synthesizes albumin. Thus, hypoalbuminemia commonly occurs in patients with hepatic disease. Levels of albumin as low as 2 to 2.5 grams per 100 ml. are not uncommon. Hypoalbuminemia influences ascites because the rates of transudation of fluid depend on the differences between hydrostatic and oncotic pressures. Krook 6 has demonstrated this inverse relation between the degree of elevated wedged hepatic vein pressures (portal hypertension) and the degree of hypoalbuminemia in patients with ascites due to cirrhosis. Largely because of the hydrostatic forces, there is no constant relation between ascites and serum albumin levels or oncotic pressures. N evertheless, ascites is more apt to develop if the serum albumin is less than 3 grams per 100 ml. or serum osmotic pressures are less than 250 mm. H 20. Once the tendency to form ascites becomes more severe, the serum level of albumin or serum osmotic pressure may have virtually no effect on the formation of ascites, presumably because of the increased hydrostatic forces at play. Hypoalbuminemia then is an essential factor in the production of ascites, provided the hydrostatic forces in the liver or distal portal capillaries are only mildly elevated. 2. The Ascitic Fluid. The protein content of ascitic fluid in cirrhosis is proportional to the plasma protein and usually varies between 1 and 2 grams per 100 ml. All the plasma proteins are present in the ascitic fluid which also regularly contains red blood cells, often in significant quantities. Rarely, however, is it bloody or cheilous. Ascitic fluid, like normal interstitial fluid, is continuously interchanged with the plasma. Since they are freely diffusible, water and electrolyte turnover is rapid and enormous. Moreover, protein enters and leaves the ascitic pool at essentially the same rate, provided the ascites
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is maintained at a steady volume spontaneously or as a result of salt restriction. 9 Presumably due to the high hydrostatic pressures that are active in causing ascites to form in cirrhosis, there is a larger difference between the ascitic and plasma osmotic pressures than in ascites of other causes, such as peritoneal carcinoma. 1o This osmotic equilibrium must always be considered when administering albumin intravenously, because the albumin diffuses proportionally between the plasma and the extracellular space. Albumin sufficient to raise the colloidal osmotic pressure of the plasma one degree also raises the ascitic colloidal osmotic pressure one degree. LYInphatics
Though fluid transuding from the liver appears in experimental ascites, 5 it is rarely seen in cirrhosis. We have seen fluid dripping from a cirrhotic liver only once, and in this instance the hemodynamics were those of the Budd-Chiari syndrome. Nevertheless, increased hepatic lymph flow occurs in cirrhosis, as well as in those rare patients with portal hypertension due solely to congenital or acquired obliteration of the intrahepatic portal radicals. In these situations the hepatic lymphatics may be more easily overloaded. Augmented hepatic lymph flow is evidenced by the dilated tense lymphatics beneath Glisson's capsule and emerging from the porta hepatis. These occur despite the probable obliteration of the capillary lymphatics in the fibrous portal areas. The fact that hepatic edema in cirrhosis is uncommon indicates that the unexpandable scar-encased cirrhotic liver probably assists lymphatic function. However, this tissue tension is insufficient to counteract the . vascular hydrostatic forces. The enlarged hepatic lymphatics usually do not overshadow those buried in the mesentery. Nevertheless, sometimes they are immense even though they may not be associated with ascites and this may indicate marked postsinusoidal obstruction. The hepatic lymphatics are particularly noticeable to surgeons during portacaval shunts. Indeed, lymph may swamp the operative field if a prominent hepatic lymphatic is unintentionally cut. Although temporary ascites commonly develops in the postoperative period of portacaval shunts, a troubleseome variety may occasionally occur when these lymphatics are greatly enlarged. This may be due to lymphorrhea from unligated lymphatics, and in such cases the ascitic fluid contains extremely large quantities of protein. The mesenteric lymphatics have been mentioned. No evidence indicates that the lymphatics draining either end of the portal system are enlarged because their trunks are obstructed. Furthermore, there are many alterate lymphatic routes to the thoracic duct, and although it has not been measured, undoubtedly thoracic duct lymph flow in ascites due to cirrhosis is greatly increased as it is in experimental ascites. The lymphatics draining the ascitic fluid reside chiefly in the dia-
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phragm, since constant motion promotes lymphatic flow. The parietal peritoneal lymphatics also absorb ascitic fluid, but to a lesser degree. The serositis, adhesions, and diminished respirations commonly present in chronic ascites due to cirrhosis may reduce the efficiency of these lymphatics in picking up the ascitic protein, thereby prolonging and enhancing the ascites. In most instances, however, their function is quite satisfactory. Endothelial PerIlleability
There is no evidence to indicate a general alteration of capillary or endothelial permeability as a contributing cause of ascites. Generalized edema never occurs and studies with l l3l-tagged albumin show nearly normal diffusion rates from the blood into extracellular space in malnourished patients with advanced cirrhosis. l l A local increase in capillary or peritoneal permeability has been postulated but has not been demonstrated. SodiuIll and Water Retention
The typical patient with advanced cirrhosis and refractory ascites tenaciously retains salt. The daily urine often contains less than 1 mEq. of sodium, and subnormal amounts of sodium are present in the saliva, sweat and feces. Likewise, water retention occurs, and the daily quantities of urine are small and concentrated in nature. Paradoxically, however, the serum sodium is usually about 130 mEq., and the plasma volume expanded. Diminished renal function may contribute to sodium retention. Reduced glomerular filtration rates have been demonstrated in patients with ascitic cirrhosis.l 2 This may result from altered renal vein pressures produced by the tense ascitic abdomen or from reduced renal plasma flow. However, some patients with ascites may have normal glomerular filtration rates. l3 The retention of sodium appears to be largely due to the salt-retaining hormones of the adrenal cortex. Aldosterone has been demonstrated in the urine of patients with ascites, indicating an increase since the quantity of aldosterone in normal urine is too small to measure. l4 The damaged liver may fail to detoxify these hormones. However, fluctuations of the urinary salt-retaining hormone vary with the quantity of salt intake and the tendency to form ascites. This suggests an actual increased output of these hormones. The importance of the adrenal cortical salt-retaining hormones in ascites has been demonstrated experimentally. In dogs rendered ascitic, the ascites completely disappears after bilateral adrenalectomy, but returns if dexoxycorticosterone is· administered in excess of daily requirements. l5 Nevertheless, ascites may continue to form in the absence of the salt-retaining hormones. Bilateral adrenalectomy has been per-
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formed in a patient with cirrhosis and refractory ascites. 16 The ascites did not disappear, yet urinary sodium increased. Another hormone possibly contributing to salt retention is estrogen. 11 Excessive quantities of estrogens, which are weakly salt-retaining, have been demonstrated in the blood of patients with cirrhosis, presumably due to failure of the cirrhotic liver to inactivate them. Water retention usually varies directly and precisely with the degree of retained sodium. With more severe ascites, a disproportional volume of water may be retained. This water retention may be caused by accelerated production of the antidiuretic hormone (ADH).18 Increased urinary quantities of ADH have been demonstrated in patients with chronic ascites due to cirrhosis, and delayed diuresis after water loading is typical.1 9 The liver detoxifies ADH. However, the response to pitressin is usually normal,20 suggesting that hepatic inactivation of ADH may not be delayed as has been postulated, and that an actual increase of ADH occurs. Vasodepressor material (VDM) produced by the diseased liver has antidiuretic properties. VDM may contribute to water retention, but probably only in preterminal states. The disproportional water retention is reflected in hyponatremia. III most instances this hyponatremia is actually a kind of salt-depletion and dehydration, although it appears as a "dilution hyponatremia" due to the expansions of plasma volume and extracellular fluid. 21 . 22 The expanded plasma volume, typically present in advanced cirrhosis, is misleading because it usually depicts splanchnic congestion and increased portal capacity. Plasma volumes are nearly normal after portacaval shunt or in the absence of esophageal varices. Thus, while the effective plasma volume may be normal, it may be diminished in severe ascites. For instance, if the forces producing it are extreme, ascites may continue to develop, demanding salt and water from the plasma in quantities insufficiently satisfied by maximal salt retention, and consequently plasma volume shrinks. ADH is then secreted and extra water is retained in an attempt to preserve effective plasma volume. Therefore, the concentration of sodium in the body fluids falls due to the disproportionate retention of wat.er in the abdomen, and the degree of deviation from the normal may roughly parallel the degree of elevation of local hydrostatic forces. Salt restriction, paracentesis and diuresis may also enhance the hyponatremia. This hyponatremia is strangely asymptomatic and cannot be corrected by the administration of salt without increasing the ascites, since salt administration just causes more water retention. However, serum sodium levels gradually rise as the ascites begins to abate, indicating that the hyponatremia is not permanent. The chronic disease state may contribute to the hyponatremia. 2. 23 In such instances, intracellular potassium is lost owing to cellular disintegration, and sodium and hydrogen enter the cells. This leads to
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intracellular hypotonicity and consequently hyponatremia of extracellular fluid. Prolonged or excessive aldosterone secretion may also contribute to potassium depletion. 24 The salt and water retentions are secondary homeostatic mechanisms attempting to maintain effective plasma volume, but also greatly increasing the ascites. Most patients with cirrhosis correctly secrete water and sodium before the onset of ascites, unless hypoalbuminemia is present. Furthermore, the degree of salt and water retention varies with the severity of the ascites and ceases upon complete subsidence of the ascites, either spontaneously or after portacaval shunt. 25 Should hypoproteinemia develop following portacaval shunt, salt retention recurs but edema instead of ascites develops. Finally, the production of the antiduretic factors and the salt-retaining factors are just sufficient to feed the accumulation of ascites, since in advanced cirrhosis with ascites edema does not occur. TREATMENT
The ascites of nearly all patients with cirrhosis can be improved. The treatment should be individualized to the patient. It consists mainly of saIt restriction and diuretics. In a small select group of patients, portal decompression is indicated. Above all, however, measures to improve hepatic function are paramount. The therapeutic measures to combat hepatocellular failure and improve hepatic function apply whether or not ascites is present. They include rest, a diet high in protein and carbohydrate, large quantities of vitamins, and complete abstinence from alcohol. Merely arresting hepatocellular failure often checks the ascites without employing specific therapy directed at the ascites. Only the specific treatment of ascites will be discussed. Salt Restriction
The restriction of salt is the most effective specific treatment of ascites. It checks ascites by creating dehydration. Water restriction is not necessary. The degree of saIt restriction varies with each patient. Mere avoidance of saIt in cooking and at the dinner table is occasionally all that is necessary to control ascites. Generally, it is advisable to prescribe a 2 to 3 gram salt diet. If the patient is retaining salt avidly, his total excretion of sodium chloride by all routes may be less than 1 gram daily, and every gram of sodium chloride taken in excess of this will increase the ascites by approximately 100 ml. Therefore, a diet containing less than 1 gram of sodium chloride daily may be necessary. Careful adherence to well prepared diet lists is necessary to avoid many hidden sources of dietary salt. The common dietary sources of protein such as meat, eggs, milk and cheese have a high salt content. Howeve~, salt-free milk, bread and protein supplements are available, and the diet need not be deficient in protein. In most instances, ascites is promptly
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controlled, paracenteses are avoided, and the steady increase in ascites is prevented. Whether the residual ascites eventually completely reabsorbs depends on the ultimate course of the underlying hepatic disease. Should the ascites disappear, salt restriction may be relaxed. Despite the common occurrence of hyponatremia, patients tolerate salt restriction surprisingly well, and only rarely exhibit the low-salt syndrome. By itself, hyponatremia must not be mistaken for the lowsalt syndrome, and if it does develop, no attempt should be made to correct it. Finally, protein intake occasionally must be sharply curtained in spite of its essentiality, since a few patients may exhibit meat intoxication. Diuretics
The mercurial compounds are the most effective diuretics. They act by preventing sodium and chloride reabsorption by the renal tubules. Mercurial compounds do not always produce diuresis in ascites, but if diuresis occurs, they should be continued. Two milliliters of mercuhydrin administered intramuscularly twice a week generally suffice. Increasing serum chloride potentiates mercurial diuresis. Most patients with cirrhosis tolerate 3 to 4 grams of ammonium chloride daily without exhibiting mental changes. Calcium chloride is a good substitute if the ammonium chloride produces any neurolgoic signs such as confusion, somnolence or tremor. Carbonic anhydrase inhibitor (Diamox) should be avoided in patients with cirrhosis since it may precipitate the same neurologic complications. Cation Exchange Resins
The cation exchange resins exchange one cation for another, such as sodium. Therefore they could be used to curtail sodium absorption or permit a higher salt intake. However, they are ineffectual in binding sodium. In sufficient quantities to be effective in cirrhosis, they commonly cause nausea, vomiting, constipation, acidosis and neurologic symptoms. The resins of ammonium phase must be avoided. Cation exchange resins are not too effective, are often dangerous, and should not be used in hepatic disease. Intravenous AlbuIllin
The effects of intravenous salt-poor human albumin in ascites have already been mentioned. Albumin diffuses proportionately throughout the extracellular spaces, and enormous quantities, constantly administered, are frequently necessary to correct the hypoalbuminemia in advanced cirrhosis. Even then, diuresis may not occur. Their effect is transient since they are short-lived. Moreover, they increase plasma volume, often in the presence of an already expanded plasma volume, and consequently hazards of inducing pulmonary edema or hemorrhage
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from esophageal varices are always present. Small quantities (25 grams) may improve the patient nutritionally, but since it is expensive, such use is unjustified. If given shortly before a mercurial diuretic, diuresis may be augmented. In general, albumin as well as other plasma expanders have limited use in treating ascites. Paracentesis
Most patients with cirrhosis do not need paracentesis. In general, paracentesis should be avoided because large quantities of albumin will be removed with the ascitic fluid. Since the diseased liver may not be capable of replacing this albumin, hypoalbuminemia is accelerated. Nevertheless, paracentesis is often necessary if a taut abdomen develops which is very uncomfortable and reduces respiratory efficiency and alimentation. Occasionally, an initial paracentesis performed at the onset of salt restriction may save time and facilitate abdominal examination. The fluid should be removed slowly to prevent syncope. The low-salt syndrome may follow paracentesis. This syndrome consists of weakness, apathy, muscle cramps, nausea, vomiting, hypotension, thready pulse, and an elevated blood urea nitrogen, and must not be diagnosed by the serum sodium level alone. It is caused by acute hyponatremia following rapid loss of serum sodium to the reforming ascitic fluid and may develop from a few hours to several days after paracentesis, depending on the rate of ascitic reaccumulation. More commonly, it occurs after prolonged salt restriction, and may not occur if there is peripheral edema which can supply the reforming ascites with salt and water. If ascites develops following an operation in a patient with cirrhosis, this syndrome may develop concomitantly with the onset of the ascites and complicate postoperative care. The best treatment in patients with cirrhosis is intravenous isotonic saline. In addition, albumin, plasma, or blood are usually required to replete the lost plasma proteins and plasma volume. Hypertonic saline, although frequently recommended, is most useful as initial treatment only if the symptoms are especially acute. Occasionally frequent paracentesis becomes necessary. In such instances, the loss of sodium and protein should be countervailed simultaneously with paracentesis by intravenous administration of 25 to 50 grams of albumin mixed with either dextrose and water or isotonic saline as the case requires. Surgical Treatlllent of Ascites
Portal decompression is currently the only operation which may successfully relieve and prevent ascites. Mahy operations have been devised in the past to relieve ascites. The list includes the insertion of buttons or catheters between the abdomen and subcutaneous tissue, saphenoperitoneal anastomosis, renal pelvoperitoneal anastomosis, hepatopexy, omentopexy, splenopexy, splenectomy, and ligation of hepatic and splenic
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arteries. All these operations have been unsatisfactory and none should be performed. Several years ago Crosby and Cooney26 devised a new button, and renewed interest in subcutaneous drainage of ascitic fluid followed. Surgeons are still prevailed upon to implant them in the abdominal wall. Although they function for a month or so, they ultimately fail. A fibrous sac lined by endothelium develops in the subcutaneous tissue and absorption of fluid ceases. Their use is not recommended. Recently Neumann27 has devised an operation to relieve ascites. It consists of isolating a segment of ileum, slitting the lumen, and suturing its edges to parietal peritoneum. The ascitic fluid is absorbed by the ileal mucosa. At present the operation is still in the experimental stages and clinical experience is extremely limited. The results in the few patients in whom it has been performed are unsatisfactory, and sepsis has been a problem. It should not be performed until proven benefits from the operation are demonstrated. Despite some unjust criticism, portal decompression has a definite place in the treatment of refractory ascites due to cirrhosis. It relieves splanchnic congestion and most likely reduces sinusoidal pressure,28 although this is not definitely known, since alterations in hepatic hemodynamics following portacaval shunt have not been fully clarified. Nevertheless, portal decompression regularly relieves ascites due to cirrhosis. Moreover, ascites almost never reappears even though hypoalbuminemia and salt retention may develop and cause edema and anasarca. If technically possible, end-to-side portacaval anastomosis is preferred to splenorenal anastomosis, since there is a greater reduction of portal pressure and the anastomosis stays patent. Furthermore, after end-to-side portacaval shunt, the intrahepatic portal pressures are never as low as the shunted portal pressures, and consequently in side-to-side portacaval or splenorenal shunt portal blood often would not flow through the liver. Also, there is no evidence that end-to-side portacaval shunt is less effective in relieving ascites than other types of shunts. However, if there is retrograde portal blood flow, splenorenal or side-toside portacaval anastomosis is mandatory. The presence of enormous hepatic lymphatics may be a clue to such a situation which is definitely established if portal pressure falls or intrahepatic portal pressure rises upon occluding the portal vein. Most of the experience in the relief of ascites by portal decompression has been gained through follow-up observations in patients with refractory ascites who have undergone portacaval shunt to prevent recurrent hemorrhage from esophageal varices. The experience in the use of portacaval shunt to treat ascites specifically is still somewhat limited, although the earliest portacaval shunts were performed for this purpose. Consequently, a conservative approach is advisable while this problem undergoes reevaluation. Candidates for operation should be carefully evaluated and should meet certain requirements if satisfactory results are to be expected. In
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addition, the benefits of the operation must be weighed against the significantly high mortality in portacaval shunt and the possibility that diverted portal blood may increase the incidence of neurologic symptoms. The ascites should be refractory, which means that there has not been a reasonable response after careful treatment for eight to 12 months. This is not unduly long, since ascites may subside spontaneously even after a year, provided the patients are carefully managed. The serum albumin should exceed 3 grams per 100 ml., since severe hypoalbuminemia may be an essential factor in the formation of the ascites and may represent poor hepatic function. Moreover, patients with critically low levels of serum albumin due to cirrhosis are extraordinarily poor surgical risks. Should such patients recover from the operation, severe dependent edema may supervene and irk the patients more than the ascites. Hyponatremia does not necessarily contraindicate operation, since it develops in all patients with prolonged ascites treated by salt restriction. However, patients with extreme degrees of hyponatremia tolerate operation poorly, and therefore serum sodium should be at least 130 mEq. Naturally, hepatic function as well as the over-all outlook of the cirrhosis itself must be reasonably good. Portal hypertension is prerequisite, although high degrees of portal pressures are not essential to insure successful results. Portal pressure can be evaluated by percutaneous splenic puncture 29 or hepatic vein catheterization. The mere presence of esophageal varices generally indicates a portal pressure exceeding 30 cm. of saline, yet does not mandatorily indicate operation unless hemorrhage has occurred. Patients with chronic constrictive pericarditis may be mistaken for patients with refractory ascites due to cirrhosis, especially those meeting the requirements for portal decompression. Such confusion must be carefully avoided, because constrictive pericarditis is amenable to pericardectomy. Thus portal decompression specifically to relieve ascites is limited to only a small group of patients. Perhaps as experience enlarges and more is learned of the etiology of ascites in cirrhosis and the hemodynamics of cirrhosis before and following portacaval shunt, the indications for operation may be extended. REFERENCES 1. Viar, W. N., Oliver, B. B., Eisenberg, S., Lombardo, T. A., Willis, K. and Harrison, T. R.: Effect of Posture and of Compression of Neck on Excretion of Electrolytes and Glomerular Filtration: Further Studies. Circulation 3: 105, 1951. 2. Sims, E. A. H., Welt, L. G., Orloff, J. and Needham, J. W.: Asymptomatic Hyponatremia in Pulmonary Tuberculosis. J. Clin. Invest. 29: 1545, 1950. 3. Verney, E. B.: Antidiuretic Hormone and Factors Which Determine Its Release. Croonian Lecture, Proc. Roy. Soc., London, s. B 135: 25, 1947. 4. McKee, F. W., Shilling, J. A., Tishkoff, G. H. and Hyatt, R. E.: Experimental Ascites. Effects of Sodium Chloride and Protein Intake on Protein Metabolism of Dogs with Constricted Inferior Vena Cava. Surg., Gynec. & Obst. 89: 529, 1949.
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5. Hyatt, R E. and Smith, J. R: Mechanism of Ascites. Am. J. Med. 31: 434, 1954. 6. Krook, H.: Circulatory Studies in Liver Cirrhosis. Acta med. Scandinav. 156: Supple. 318, 1956. 7. Taylor, W. J. and Negus, J. D.: Occlusive Hepatic venous Catheterization in Study of Normal Liver, Cirrhosis of Liver and Noncirrhotic Portal Hypertension. Circulation 13: 368, 1956. 8. Kelty, R H., Robertson, A. H. and Butt, H. R: Relation of Regenerated Liver Nodule to Vascular Bed in Cirrhosis. Gastroenterostomy 15: 285,1950. 9. Eisenmenger, W. J. and Slater, R. J.: Distribution and Decay of p3l-Tagged Albumin and Gamma Globulin in Patients with Cirrhosis. J. Clin. Invest. 32: 564, 1953. 10. Giges, B. and Kunkel, H. G.: Osmotic Pressure Measurements of Serum and Ascitic Fluid in Patients with Cirrhosis of Liver. J. Clin. Invest. 33: 257, 1954. 11. Eisenmenger, W. J.: Personal communioation. 12. Leslie, S. H., Johnston, B. and Ralli, E. P.: Renal Function as Factor in Fluid retention in patients with Cirrhosis of Liver. J. Clin. Invest. 20: 1200, 1951. 13. Epstein, F. H., Lesser, G. T. and Berger, E. Y.: Renal Function in Decompensated Cirrhosis of Liver. Proc. Soc. Exper. BioI. & Med. 75: 822, 1950. 14. Axelrod, L. R., Cates, J. E., Johnson, B. B. and Luetscher, J. A. Jr.: Aldosterone in Urine of Normal Man and of Patients with Oedema. Brit. M. J. 1: 196, 1955. 15. Davis, J. 0., Howell, D. S. and Southworth, J. L. III: Effect of Adrenalectomy and Subsequent DCA Administration on Ascites Formation. Circulation Research 1: 260, 1953. 16. Marson, F. G. W.: Total Adrenalectomy in Hepatic Cirrhosis with Ascites. Lancet 2: 847, 1954. 17. Preedy, J. R K. and Aitken, E. H.: Effect of Estrogen on Water and Electrolyte Metabolism. II. Hepatic Disease. J. Clin. Invest. 35: 430, 1956. 18. Leaf, A. and Mamby, A. R: An Antidiuretic Mechanism Not Regulated by Extracellular Fluid Tonicity. J. Clin. Invest. 31: 60, 1952. 19. Ralli, E. P., Robson, J. S., Clarke, D. and Hoagland, C. L.: Factors Influencing Ascites in Patients with Cirrhosis of Liver. J. Clin. Invest. 24: 316, 1945. 20. White, A. G., Rubin, G. and Lester, L.: Effect of Pitressin on Renal Excretion of Water and Electrolytes in Patients with and without Liver Disease. J. Clin. Invest. 30: 1287, 1951. 21. Eisenmenger, W. J., B1ondheim, S. H., Bongiovanni, A. M. and Kunkel, H. G.: Electrolyte Studies on Patients with Cirrhosis of Liver. J. Clin. Invest. 29: 1491, 1950. 22. Eisenmenger, W. J.: Role of Sodium in Formation and Control of Ascites in Patients with Cirrhosis. Ann. Int. Med. 37: 261, 1952. 23. Elkington, J. R, Winkler, A. W. and Danowski, T. S.: Inactive Cell Base and Measurement of Changes in Cell Water. Yale J. BioI. & Med. 17: 383,1944. 24. Conn, J. W. and Louis, J. H.: Primary Aldosteronism, a New Clinical Entity. Ann. Int. Med. 44: 1, 1956. 25. Eisenmenger, W. J. and Nickel, W. F.: Relationship of Portal Hypertension to Ascites in Laennec's Cirrhosis. Am. J. Med. 20: 879, 1956. 26. Crosby, R C. and Cooney, E. A.: Surgical Treatment of Ascites. New England J. Med. 235: 581, 1946. 27. Neumann, C. G., Braunwald, N. S. and Hinton, J. W.: Absorption of Ascitic Fluid following Eversion of Segment of Intestinal Mucosa Within Abdomen. Surgical Forum, 1955. Philadelphia, W. B. Saunders Co., 1956, pp. 374-376. 28. Bradley, S. E., Smythe, C. M., Fitzpatrick, H. F. and Blakemore, A. H.: Effect of Portacaval Shunt on Estimated Hepatic Blood Flow and Oxygen Uptake in Cirrhosis. J. Clin. Invest. 32: 526, 1953. 29. Atkinson, M. and Sherlock, S.: Intrasplenic Pressure as Index of Portal Venous Pressure. Lancet 1: 1325, 1954. 445 East 68th Street New York, 21, N. Y.