Management a/Variceal Hemorrhage
0039-6109/90 $0.00
+ .20
Pathophysiology of Portal Hypertension and Variceal Bleeding
Thomas C. Mahl, MD,* and Roberto]. Groszmann, MDt
Portal hypertension is one of the most serious complications of chronic liver disease. It manifests clinically as ascites, portosystemic encephalopathy, and variceal hemorrhage, and often leads to death. To control or prevent these complications, an understanding of the mechanisms involved in the development and maintenance of portal hypertension is important but difficult. Previously held theories are in a state of flux as new information is obtained about the changes that take place in the development and maintenance of portal hypertension in animals and man .. Portal pressure, like pressure in all living or nonliving systems, results from an interaction of flow and resistance. As flow or resistance changes, so does portal pressure. This relationship is conveniently expressed mathematically by Ohm's law: a P = Q x R, where a P is the change in pressure along a vessel, Q the flow in the vessel, and Ii the resistance to that flow. Thus, it follows that increases in flow or resistance are translated into increases in pressure and changes in both have a multiplicative effect. Resistance itself depends on several other factors as expressed by Poiseuille's law: R = 8nU'lTr\ in which n is the coeffecient of viscosity, L the length of the vessel, and r its radius. Because the length of the vessel generally does not change and the viscosity of blood is for the most part constant at the observed hematocrits, changes in resistance are mainly a result of changing the radius of the vessel. 18. 27 Because the radius is taken to the fourth power, small changes in the diameter of the vessel have dramatic effects on resistance in that vessel. These formulae are, of course, simplifications of the pressure, flow, and resistance interactions that occur in the normal and pathologic portal system, but they do serve to organize the variables involved and allow for stepwise examination of each. The contri*Fellow, Division of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut tProfessor of Medicine, Yale University School of Medicine, New Haven; Chief, Digestive Diseases, VA Medical Center, West Haven, Connecticut
Surgical Clinics of North America-Vol. 70, No.2, April 1990
251
252
THOMAS
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MAHL AND ROBERTO
J.
GROSZMANN
butions of blood flow and vascular resistance to the development and maintenance of portal hypertension are discussed separately. VASCULAR RESISTANCE
Under normal conditions, the liver is the main source of resistance to portal blood flow. Resistance in the normal liver is very low, and large increases in splanchnic blood flow can be accommodated with minimal changes in portal pressure. The liver itself has no control over the portal blood it receives; rather, it passively accepts the venous drainage of the gut and spleen, which, for the most part, make up the portal blood flow. Control over portal blood flow is determined by the resistance vessels of those splanchnic organs that drain into the portal vein. 24 The sites of resistance within the normal humi,Ul liver remain poorly understood. Proposed locations include small portal veins, 58, 69 hepatic sinusoids, and terminal hepatic venules;27, 58 nevertheless, resistance normally remains very low. Much of this information has been obtained using animal models, which makes extrapolation to humans difficult. Recently, a large vascular sphincter-like structure in the hepatic veins of cats has been described,36 but studies in man have yet to locate a similar structure. Cirrhosis disrupts the normal architecture of the liver, and changes in intrahepatic resistance should be expected. 44 Like resistance sites in the normal liver, however, the actual locations of the sites of increased resistance are not exactly known. Early views of portal hypertension suggested that the growth of regenerating nodules was responsible for increased intrahepatic resistance secondary to compression of the hepatic venules. 3O More recently, others have questioned this theory and have proposed other mechanisms responsible for changes in resistance. 7 The detection of fibrous tissue deposited around the terminal hepatic venule and adjacent sinusoids in alcoholic liver disease suggest that collagenation of this area may increase resistance and lead to portal hypertension. 45 Inflammatory and occlusive changes of the hepatic venous tree of alcoholics with and without cirrhosis may also playa role. Reportedly, these changes correlate with the degree of portal hypertension. 23 The normal fenestrated permeable endothelial lining of the sinusoids may become occluded after injury. This progresses to the formation of a basement membrane in the space of Disse, which leads to eventual capillarization of the sinusoids 12 and increased resistance to blood flow. The possibility that some part of intrahepatic resistance is reversible is attractive. If so, an opportunity for therapeutic intervention may exist. Sympathetic venous tone may modulate portal pressure. 71 Clonidine, an inhibitor of sympathetic nervous activity, decreases portal venous pressure independent of changes in systemic hemodynamics. Isoproterenol, a beta2 agonist, causes relaxation of vascular endothelial cells. 43 These cells seem to be the primary local modulators of sinusoidal perfusion, at least under normal conditions. 51 Isoproterenol decreases perfusion resistance in cirrhotic rat livers in an isolated perfused system. 42 Other vasodilators have similar effects but require very high concentration for action. 42
PATHOPHYSIOLOGY OF PORTAL HYPERTENSION AND VARICEAL BLEEDING
253
Myofibroblasts are contractile cells that are intermediate in structure between fibroblasts and smooth muscle cells. 54 They proliferate around the sinusoids and terminal hepatic venules in cirrhotic livers,6 and the density of myofibroblasts correlates with vascular resistance,6 It has been suggested that by maintaining an enhanced contractile state, myofibroblasts may increase resistance and contribute to portal hypertension. 5 The pharmacologic sensitivity of these cells has been investigated, and changes' in perfusion resistance in isolated organs have been documented. 5 Hepatocyte enlargement is the end result of several metabolic, infectious, or toxic insults to the liver. The possibility that hepatocyte enlargement, by compresion of sinusoids, may result in increased intrahepatic resistance and portal hypertension has been reported. 7 This theory helps to explain precirrhotic portal hypertension (for example, in alcoholic hepatitis) and its resolution with abstinence and hepatocyte shrinkage. The methods used to record intrahepatic pressure have been questioned, however.16 From the preceding discussion, it is clear that the mechanisms that increase resistance in the cirrhotic liver, like liver disease itself, are diverse. It is possible that several sites or mechanisms of resistance develop following hepatic injury and contribute to portal hypertension. Further studies, especially in models that accurately reflect the changes seen in man, are needed before firm conclusions can be made.
"BACKWARD" AND "FORWARD" FLOW THEORIES The theory that increases in intrahepatic resistance are responsible for portal hypertension has been termed the "backward flow" theory.26 Its proponents claim that portal hypertension results (as explained by Ohm's law) when a fixed volume of blood flows through a liver with increased vascular resistance. If resistance increases and flow remains the same, pressure must increase. This theory is consistent with findings of decreased portal blood flow that have been reported. 10, 17,46 Logically, it would seem that, in an effort to maintain a normal or nearly normal portal pressure in the face of increased hepatic resistance, portal blood flow would decrease, thus reducing portal pressure. Unfortunately, the actual events are much less Simplistic. As a consequence of increased portal pressure, minute embryonic channels between the portal and systemic veins dilate and result in portosystemic shunting. 70 This collateral system is often extensive and may divert most of the portal blood flow away from the liver. 28, 67 Despite this extensive system of decompressing veins, portal hypertension persists. 67 These findings are difficult to reconcile with the "backward flow" theory. If blood flow is constant into the portal system and low-resistance collaterals exist to carry away that blood, portal pressure should decrease. Guido Banti, in 1883, described several patients with splenomegaly, anemia, and leukopenia. I His observations led him to postulate that splenomegaly, portal hypertension, and cirrhosis were the result of increased splenic arterial blood flow (that is, the forward flow of blood was
254
THOMAS
C.
MAHL AND ROBERTO
J.
GROSZMANN
responsible for portal hypertension). The pendulum of opinion on the relative contributions of increased blood flow to the development of portal hypertension has swung back and forth often since Banti's time. Recently, however, evidence has accumulated that increases in splanchnic blood flow may not initiate, but indeed contribute to, the maintenance of portal hypertension in chronic liver disease. 14, 67, 72
SPLANCHNIC BLOOD FLOW On physical examination, the patient with chronic liver disease has evidence of a hyperkinetic circulation33, 47; warm extremities, full bounding pulses, and rapid heart rates. These patients have increased cardiac indices and expanded blood volumes. 47 Evidence has accumulated that these findings are not limited to the peripheral circulation; similar changes occur in the splanchnic vascular bed as well. 22, 63 Recently, experimental data have shown that increased splanchnic blood flow occurs in animal models of portal hypertension. 8, 38, 66, 67 Blood flow to the stomach, intestines, and spleen is increased approximately 50%, presumably through a decrease in splanchnic anteriolar resistance. Of course, the blood to these organs for the most part makes up the portal blood flow. These findings are in contrast to the work referred to earlier in which decreased portal blood flow had been observed in portal hypertensive states. The discrepancy stems from the inability of the previous studies to account for the blood carried away from the liver by portosystemic collaterals. Total splanchnic inflow is responsible for portal pressure, not just the flow that escapes the collaterals and reaches the liver. The mechanisms responsible for the hyperdynamic splanchnic and systemic circulation are not known at this time. Originally, it was believed that collaterals themselves led to a hyperdynamic state,14 much in the way that an arteriovenous fistula increases flow, allowing blood to bypass a capillary bed. However, blood in portosystemic collaterals has already passed through one capillary bed in the spleen or abdominal viscera and, in animal models, the degree of shunting does not correlate with changes in flow. 60 Glucagon, a vasodilator, is found in increased concentrations in the blood of animals and humans with cirrhosis. 57 Some experimental data support that it is a potential mediator of up to 40% of the increase in splanchnic blood flow. 2, 4 Others have found no correlation between blood flow and glucagon levels. 61 Bile acids like glucagon are elevated in the serum of many patients with liver diseases. There is a possibility that these compounds mediate the hyperdynamic circulation to some degree; if so, bile-acid-binding resins could potentially reverse the circulatory changes observed. Unfortunately, normalization of the bile acid levels in an experimental model has no effect on portosystemic shunting or the increased splanchnic blood flow of the model. 21 Following portal vein stenosis, the sympathetic vascular tone in the intestinal circulation may be impaired. 31 This may explain, in part, the intestinal hyperemia that is associated with portal hypertension. The cause of this decreased sensitivity seems to be
255
PATHOPHYSIOLOGY OF PORTAL HYPERTENSION AND VARICEAL BLEEDING
related to a postreceptor mechanism that impairs not only the response to catecholamines but to other constrictors as well. Recently, it has been demonstrated that dietary sodium restriction blunts the expression of the hyperdynamic circulation and results in a dramatic reduction in portal pressure in the portal-vein-ligated rat model of portal hypertension. Sodium restriction apparently hinders the formation of the expanded plasma volume that accompanies the development of portal hypertension. 20 Thus, it seems that, at least in this model, plasma volume expansion and portal hypertension are coupled. Identification of the signal that leads to expansion of plasma volume and sodium retention would be a great step forward. In conclusion, portal pressure in portal hypertensive states is determined by an interaction of portal venous inflow and the resistance offered by the intrahepatic vascular tree (Fig. 1). Neither the "forward flow" theory nor the "backward flow" theory by itself can account for the portal hypertensive syndrome. In all probability, portal hypertension is the end result of increases in portal blood flow and increased resistance to that flow.
ESOPHAGEAL VARICES Portal hypertension results in many disturbances of normal function (ascites, renal failure, and portosystemic encephalopathy are examples). The follOwing discussion centers on probably the most dramatic complications of portal hypertension: the development and rupture of esophageal varices. As portal pressure increases, collateral vessels develop in an attempt to decompress the portal system. In humans, communications between the portal and systemic venous systems occur among the coronary and short gastric veins; the intercostal, esophageal, and azygos veins; the hemorrhoidal veins; at the paraumbilical plexus; and occasionally where the abdominal organs lie in contact with the abdominal wall or retroperitoneum. 56 Although all these vessels contribute to shunting, the esophageal collaterals or varices are the most important clinically because of their predilection to bleeding. High-resolution vascular casts have nicely demonstrated the normal and
t
EXTRAHEPATIC ANDIOR INTRAHEPATIC RESISTANCE TO PORTAL BLOOD FLOW
PORTAL VENOUS INFLOW
r
,
PORTAL HYPERTENSION DEVELOPMENT OF PORTAL SYSTEMIC COLLATERALS
Figure 1. Hemodynamic factors involved in the development and maintenance of portal hypertension. (From Groszmann RJ: Pathophysiology of cirrhotic portal hypertension. In Boyer JL, Bianchi L (eds): Liver Cirrhosis. Lancaster, England, Falk Foundation MTP Press; with permission.)
256
THOMAS
C.
MAHL AND ROBERTO
J.
GROSZMANN
abnormal anatomy.32 Intraepitheal channels in the distal esophagus drain into a superficial plexus of veins. This plexus is in turn connected to larger, deep intrinsic veins that themselves connect to adventitial veins through perforating veins that span the muscular layers. Portal hypertension dilates all of these complex, interconnected vascular channels. 32 The deep intrinsic veins, however, seem to bear the brunt of the insult and dilate massively, becoming what we see endoscopically as esophageal varices. These vessels lie in the lamina propria, where they are poorly supported by surrounding tissue, and bulge into the lumen as they enlarge. The development of esophageal collaterals depends upon a threshold portal pressure below which varices do not occur. In patients with alcoholic liver disease, variceal hemorrhage and varices themselves rarely develop unless the portal pressure (as measured by the hepatic vein wedge pressure gradient) is greater than 12 mm Hg (Fig. 2).19 Thus, adequate portal pressure is required to form varices and to allow them to bleed. If pressure were the only factor involved in hemorrhage, the task for the clinician would be to identifY all those patients with the required portal pressure and intervene before a devastating hemorrhage occurs. Of course, the actual situation is more complicated. Portal pressure is necessary for development and rupture of varices, but it is not sufficient in itself. Many patients who have high portal pressures and varices never bleed (Fig. 3).19 Thus, factors other than portal pressure, presumably local factors, must be involved.
LOCAL FACTORS Esophagitis has received considerable attention as a causative factor in initiation of variceal hemorrhage. It has been proposed that injury to the VARICES PRESENT ( n'72) 35
VARICES ABSENT ( n'15)
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Figure 2. Hepatic venous pressure gradient in patients with alcoholic cirrhosis with and without gastroesophageal varices. (From Garcia-Tsao G, Groszmann RJ, Fisher RL, et al: Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 5:419-424, 1985; with permission.)
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PATHOPHYSIOLOGY OF PORTAL HYPERTENSION AND VARICEAL BLEEDING BLEEDERS
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distal esophagus by acid reflux leads to erosion through the mucosa and varix rupture. 39 Autopsy studies have reported an approximately 50% incidence of esophageal inflammation in patients with varices. 13. 68 However, more recent studies using fresh samples of esophageal material obtained during surgical esophageal transection procedures have disclosed little inflammation. 57. 62 This is in agreement with clinical studies that show essentially no differences in esophageal motility or pH studies between controls and patients with varices. 15. 29 A double-blind, controlled investigation of cimetidine versus placebo for the prevention of variceal hemorrhage disclosed no change in the incidence of hemorrhage between the groups.41 Erosion of the esophageal mucosa precipitating variceal hemorrhage seems unlikely. Other local factors such as variceal wall thickness and the thickness of overlying mucosa may playa role. Endoscopically, changes can be seen in the mucosa overlying varices that may be related to vessel wall thickness and the degree of soft tissue support.
PORTAL PRESSURE As mentioned previously, increased portal pressure is required for the development and rupture of varices, and that pressure is approximately 12 mm Hg.19. 64 No correlation between portal pressure above 12 mm Hg and the risk of variceal hemorrhage has been detected. However, some data seem to support a role from increasing pressure as a cause of rupture. Blood-volume expansion in patients with portal hypertension leads to disproportionate rises in portal pressure and can precipitate variceal hemorrhage. 9 Angiography increases portal pressure and may also precipitate hemorrhage. 11 Portal pressure measured soon after variceal hemorrhage has a predictive value. 52. 64 Patients who die within 2 weeks have significantly
258
THOMAS
C.
MAHL AND ROBERTO
J.
GROSZMANN
higher portal pressures than those who survive (Fig. 4).64 Thus, although a linear relationship between the severity of portal hypertension and the risk of variceal hemorrhage has yet to be identified, the degree of portal hypertension does appear to have a permissive role, and increases in any individual may increase risk of bleeding. Portal pressure is not constant; it varies greatly under different physiologic conditions. Significant increases in portal venous pressure occur during inspiration, coughing, and Valsalva maneuver. The gradient between portal venous and esophageal luminal pressure is also affected by these maneuvers. 53 Although anecdotal reports of hemorrhage precipitated under these conditions exist, their true relationship to bleeding is yet to be defined.
SIZE OF VARICES The size of varices may be important. Variceal hemorrhage is more likely to occur with large rather than small varices. One study noted that 82% of patients with large varices bled, whereas 46% with small varices bled (see Fig. 2).19, 37, 65 Variceal size does not correlate with portal pressure, 19, 37 suggesting again that local factors contribute to promotion of variceal development (Fig. 5). This discussion presents a good deal of data that conflict and overlap regarding the contributions of pressure, size, and local influences to the development of variceal hemorrhage. The inability to identify any single predictor of bleeding suggests that the interaction of the factors just
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0039-6109/90 $0.00
+ .20
Pathophysiology of Portal Hypertension and Variceal Bleeding
Thomas C. Mahl, MD,* and Roberto]. Groszmann, MDt
Portal hypertension is one of the most serious complications of chronic liver disease. It manifests clinically as ascites, portosystemic encephalopathy, and variceal hemorrhage, and often leads to death. To control or prevent these complications, an understanding of the mechanisms involved in the development and maintenance of portal hypertension is important but difficult. Previously held theories are in a state of flux as new information is obtained about the changes that take place in the development and maintenance of portal hypertension in animals and man .. Portal pressure, like pressure in all living or nonliving systems, results from an interaction of flow and resistance. As flow or resistance changes, so does portal pressure. This relationship is conveniently expressed mathematically by Ohm's law: a P = Q x R, where a P is the change in pressure along a vessel, Q the flow in the vessel, and Ii the resistance to that flow. Thus, it follows that increases in flow or resistance are translated into increases in pressure and changes in both have a multiplicative effect. Resistance itself depends on several other factors as expressed by Poiseuille's law: R = 8nU'lTr\ in which n is the coeffecient of viscosity, L the length of the vessel, and r its radius. Because the length of the vessel generally does not change and the viscosity of blood is for the most part constant at the observed hematocrits, changes in resistance are mainly a result of changing the radius of the vessel. 18. 27 Because the radius is taken to the fourth power, small changes in the diameter of the vessel have dramatic effects on resistance in that vessel. These formulae are, of course, simplifications of the pressure, flow, and resistance interactions that occur in the normal and pathologic portal system, but they do serve to organize the variables involved and allow for stepwise examination of each. The contri*Fellow, Division of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut tProfessor of Medicine, Yale University School of Medicine, New Haven; Chief, Digestive Diseases, VA Medical Center, West Haven, Connecticut
Surgical Clinics of North America-Vol. 70, No.2, April 1990
251
252
THOMAS
C.
MAHL AND ROBERTO
J.
GROSZMANN
butions of blood flow and vascular resistance to the development and maintenance of portal hypertension are discussed separately. VASCULAR RESISTANCE
Under normal conditions, the liver is the main source of resistance to portal blood flow. Resistance in the normal liver is very low, and large increases in splanchnic blood flow can be accommodated with minimal changes in portal pressure. The liver itself has no control over the portal blood it receives; rather, it passively accepts the venous drainage of the gut and spleen, which, for the most part, make up the portal blood flow. Control over portal blood flow is determined by the resistance vessels of those splanchnic organs that drain into the portal vein. 24 The sites of resistance within the normal humi,Ul liver remain poorly understood. Proposed locations include small portal veins, 58, 69 hepatic sinusoids, and terminal hepatic venules;27, 58 nevertheless, resistance normally remains very low. Much of this information has been obtained using animal models, which makes extrapolation to humans difficult. Recently, a large vascular sphincter-like structure in the hepatic veins of cats has been described,36 but studies in man have yet to locate a similar structure. Cirrhosis disrupts the normal architecture of the liver, and changes in intrahepatic resistance should be expected. 44 Like resistance sites in the normal liver, however, the actual locations of the sites of increased resistance are not exactly known. Early views of portal hypertension suggested that the growth of regenerating nodules was responsible for increased intrahepatic resistance secondary to compression of the hepatic venules. 3O More recently, others have questioned this theory and have proposed other mechanisms responsible for changes in resistance. 7 The detection of fibrous tissue deposited around the terminal hepatic venule and adjacent sinusoids in alcoholic liver disease suggest that collagenation of this area may increase resistance and lead to portal hypertension. 45 Inflammatory and occlusive changes of the hepatic venous tree of alcoholics with and without cirrhosis may also playa role. Reportedly, these changes correlate with the degree of portal hypertension. 23 The normal fenestrated permeable endothelial lining of the sinusoids may become occluded after injury. This progresses to the formation of a basement membrane in the space of Disse, which leads to eventual capillarization of the sinusoids 12 and increased resistance to blood flow. The possibility that some part of intrahepatic resistance is reversible is attractive. If so, an opportunity for therapeutic intervention may exist. Sympathetic venous tone may modulate portal pressure. 71 Clonidine, an inhibitor of sympathetic nervous activity, decreases portal venous pressure independent of changes in systemic hemodynamics. Isoproterenol, a beta2 agonist, causes relaxation of vascular endothelial cells. 43 These cells seem to be the primary local modulators of sinusoidal perfusion, at least under normal conditions. 51 Isoproterenol decreases perfusion resistance in cirrhotic rat livers in an isolated perfused system. 42 Other vasodilators have similar effects but require very high concentration for action. 42
PATHOPHYSIOLOGY OF PORTAL HYPERTENSION AND VARICEAL BLEEDING
253
Myofibroblasts are contractile cells that are intermediate in structure between fibroblasts and smooth muscle cells. 54 They proliferate around the sinusoids and terminal hepatic venules in cirrhotic livers,6 and the density of myofibroblasts correlates with vascular resistance,6 It has been suggested that by maintaining an enhanced contractile state, myofibroblasts may increase resistance and contribute to portal hypertension. 5 The pharmacologic sensitivity of these cells has been investigated, and changes' in perfusion resistance in isolated organs have been documented. 5 Hepatocyte enlargement is the end result of several metabolic, infectious, or toxic insults to the liver. The possibility that hepatocyte enlargement, by compresion of sinusoids, may result in increased intrahepatic resistance and portal hypertension has been reported. 7 This theory helps to explain precirrhotic portal hypertension (for example, in alcoholic hepatitis) and its resolution with abstinence and hepatocyte shrinkage. The methods used to record intrahepatic pressure have been questioned, however.16 From the preceding discussion, it is clear that the mechanisms that increase resistance in the cirrhotic liver, like liver disease itself, are diverse. It is possible that several sites or mechanisms of resistance develop following hepatic injury and contribute to portal hypertension. Further studies, especially in models that accurately reflect the changes seen in man, are needed before firm conclusions can be made.
"BACKWARD" AND "FORWARD" FLOW THEORIES The theory that increases in intrahepatic resistance are responsible for portal hypertension has been termed the "backward flow" theory.26 Its proponents claim that portal hypertension results (as explained by Ohm's law) when a fixed volume of blood flows through a liver with increased vascular resistance. If resistance increases and flow remains the same, pressure must increase. This theory is consistent with findings of decreased portal blood flow that have been reported. 10, 17,46 Logically, it would seem that, in an effort to maintain a normal or nearly normal portal pressure in the face of increased hepatic resistance, portal blood flow would decrease, thus reducing portal pressure. Unfortunately, the actual events are much less Simplistic. As a consequence of increased portal pressure, minute embryonic channels between the portal and systemic veins dilate and result in portosystemic shunting. 70 This collateral system is often extensive and may divert most of the portal blood flow away from the liver. 28, 67 Despite this extensive system of decompressing veins, portal hypertension persists. 67 These findings are difficult to reconcile with the "backward flow" theory. If blood flow is constant into the portal system and low-resistance collaterals exist to carry away that blood, portal pressure should decrease. Guido Banti, in 1883, described several patients with splenomegaly, anemia, and leukopenia. I His observations led him to postulate that splenomegaly, portal hypertension, and cirrhosis were the result of increased splenic arterial blood flow (that is, the forward flow of blood was
254
THOMAS
C.
MAHL AND ROBERTO
J.
GROSZMANN
responsible for portal hypertension). The pendulum of opinion on the relative contributions of increased blood flow to the development of portal hypertension has swung back and forth often since Banti's time. Recently, however, evidence has accumulated that increases in splanchnic blood flow may not initiate, but indeed contribute to, the maintenance of portal hypertension in chronic liver disease. 14, 67, 72
SPLANCHNIC BLOOD FLOW On physical examination, the patient with chronic liver disease has evidence of a hyperkinetic circulation33, 47; warm extremities, full bounding pulses, and rapid heart rates. These patients have increased cardiac indices and expanded blood volumes. 47 Evidence has accumulated that these findings are not limited to the peripheral circulation; similar changes occur in the splanchnic vascular bed as well. 22, 63 Recently, experimental data have shown that increased splanchnic blood flow occurs in animal models of portal hypertension. 8, 38, 66, 67 Blood flow to the stomach, intestines, and spleen is increased approximately 50%, presumably through a decrease in splanchnic anteriolar resistance. Of course, the blood to these organs for the most part makes up the portal blood flow. These findings are in contrast to the work referred to earlier in which decreased portal blood flow had been observed in portal hypertensive states. The discrepancy stems from the inability of the previous studies to account for the blood carried away from the liver by portosystemic collaterals. Total splanchnic inflow is responsible for portal pressure, not just the flow that escapes the collaterals and reaches the liver. The mechanisms responsible for the hyperdynamic splanchnic and systemic circulation are not known at this time. Originally, it was believed that collaterals themselves led to a hyperdynamic state,14 much in the way that an arteriovenous fistula increases flow, allowing blood to bypass a capillary bed. However, blood in portosystemic collaterals has already passed through one capillary bed in the spleen or abdominal viscera and, in animal models, the degree of shunting does not correlate with changes in flow. 60 Glucagon, a vasodilator, is found in increased concentrations in the blood of animals and humans with cirrhosis. 57 Some experimental data support that it is a potential mediator of up to 40% of the increase in splanchnic blood flow. 2, 4 Others have found no correlation between blood flow and glucagon levels. 61 Bile acids like glucagon are elevated in the serum of many patients with liver diseases. There is a possibility that these compounds mediate the hyperdynamic circulation to some degree; if so, bile-acid-binding resins could potentially reverse the circulatory changes observed. Unfortunately, normalization of the bile acid levels in an experimental model has no effect on portosystemic shunting or the increased splanchnic blood flow of the model. 21 Following portal vein stenosis, the sympathetic vascular tone in the intestinal circulation may be impaired. 31 This may explain, in part, the intestinal hyperemia that is associated with portal hypertension. The cause of this decreased sensitivity seems to be
255
PATHOPHYSIOLOGY OF PORTAL HYPERTENSION AND VARICEAL BLEEDING
related to a postreceptor mechanism that impairs not only the response to catecholamines but to other constrictors as well. Recently, it has been demonstrated that dietary sodium restriction blunts the expression of the hyperdynamic circulation and results in a dramatic reduction in portal pressure in the portal-vein-ligated rat model of portal hypertension. Sodium restriction apparently hinders the formation of the expanded plasma volume that accompanies the development of portal hypertension. 20 Thus, it seems that, at least in this model, plasma volume expansion and portal hypertension are coupled. Identification of the signal that leads to expansion of plasma volume and sodium retention would be a great step forward. In conclusion, portal pressure in portal hypertensive states is determined by an interaction of portal venous inflow and the resistance offered by the intrahepatic vascular tree (Fig. 1). Neither the "forward flow" theory nor the "backward flow" theory by itself can account for the portal hypertensive syndrome. In all probability, portal hypertension is the end result of increases in portal blood flow and increased resistance to that flow.
ESOPHAGEAL VARICES Portal hypertension results in many disturbances of normal function (ascites, renal failure, and portosystemic encephalopathy are examples). The follOwing discussion centers on probably the most dramatic complications of portal hypertension: the development and rupture of esophageal varices. As portal pressure increases, collateral vessels develop in an attempt to decompress the portal system. In humans, communications between the portal and systemic venous systems occur among the coronary and short gastric veins; the intercostal, esophageal, and azygos veins; the hemorrhoidal veins; at the paraumbilical plexus; and occasionally where the abdominal organs lie in contact with the abdominal wall or retroperitoneum. 56 Although all these vessels contribute to shunting, the esophageal collaterals or varices are the most important clinically because of their predilection to bleeding. High-resolution vascular casts have nicely demonstrated the normal and
t
EXTRAHEPATIC ANDIOR INTRAHEPATIC RESISTANCE TO PORTAL BLOOD FLOW
PORTAL VENOUS INFLOW
r
,
PORTAL HYPERTENSION DEVELOPMENT OF PORTAL SYSTEMIC COLLATERALS
Figure 1. Hemodynamic factors involved in the development and maintenance of portal hypertension. (From Groszmann RJ: Pathophysiology of cirrhotic portal hypertension. In Boyer JL, Bianchi L (eds): Liver Cirrhosis. Lancaster, England, Falk Foundation MTP Press; with permission.)
256
THOMAS
C.
MAHL AND ROBERTO
J.
GROSZMANN
abnormal anatomy.32 Intraepitheal channels in the distal esophagus drain into a superficial plexus of veins. This plexus is in turn connected to larger, deep intrinsic veins that themselves connect to adventitial veins through perforating veins that span the muscular layers. Portal hypertension dilates all of these complex, interconnected vascular channels. 32 The deep intrinsic veins, however, seem to bear the brunt of the insult and dilate massively, becoming what we see endoscopically as esophageal varices. These vessels lie in the lamina propria, where they are poorly supported by surrounding tissue, and bulge into the lumen as they enlarge. The development of esophageal collaterals depends upon a threshold portal pressure below which varices do not occur. In patients with alcoholic liver disease, variceal hemorrhage and varices themselves rarely develop unless the portal pressure (as measured by the hepatic vein wedge pressure gradient) is greater than 12 mm Hg (Fig. 2).19 Thus, adequate portal pressure is required to form varices and to allow them to bleed. If pressure were the only factor involved in hemorrhage, the task for the clinician would be to identifY all those patients with the required portal pressure and intervene before a devastating hemorrhage occurs. Of course, the actual situation is more complicated. Portal pressure is necessary for development and rupture of varices, but it is not sufficient in itself. Many patients who have high portal pressures and varices never bleed (Fig. 3).19 Thus, factors other than portal pressure, presumably local factors, must be involved.
LOCAL FACTORS Esophagitis has received considerable attention as a causative factor in initiation of variceal hemorrhage. It has been proposed that injury to the VARICES PRESENT ( n'72) 35
VARICES ABSENT ( n'15)
:f E
.s
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Figure 2. Hepatic venous pressure gradient in patients with alcoholic cirrhosis with and without gastroesophageal varices. (From Garcia-Tsao G, Groszmann RJ, Fisher RL, et al: Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 5:419-424, 1985; with permission.)
257
PATHOPHYSIOLOGY OF PORTAL HYPERTENSION AND VARICEAL BLEEDING BLEEDERS
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l!l .., Figure 3. Hepatic venous pressure gradient in patients with alcoholic cirrhosis with and without variceal bleeding. (From GarciaTsao G, Groszmann RJ, Fisher RL, et al: Portal pressure, presence of gastroesophogeal varices and variceal bleeding. Hepatology 5:419424, 1985; with permission.)
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distal esophagus by acid reflux leads to erosion through the mucosa and varix rupture. 39 Autopsy studies have reported an approximately 50% incidence of esophageal inflammation in patients with varices. 13. 68 However, more recent studies using fresh samples of esophageal material obtained during surgical esophageal transection procedures have disclosed little inflammation. 57. 62 This is in agreement with clinical studies that show essentially no differences in esophageal motility or pH studies between controls and patients with varices. 15. 29 A double-blind, controlled investigation of cimetidine versus placebo for the prevention of variceal hemorrhage disclosed no change in the incidence of hemorrhage between the groups.41 Erosion of the esophageal mucosa precipitating variceal hemorrhage seems unlikely. Other local factors such as variceal wall thickness and the thickness of overlying mucosa may playa role. Endoscopically, changes can be seen in the mucosa overlying varices that may be related to vessel wall thickness and the degree of soft tissue support.
PORTAL PRESSURE As mentioned previously, increased portal pressure is required for the development and rupture of varices, and that pressure is approximately 12 mm Hg.19. 64 No correlation between portal pressure above 12 mm Hg and the risk of variceal hemorrhage has been detected. However, some data seem to support a role from increasing pressure as a cause of rupture. Blood-volume expansion in patients with portal hypertension leads to disproportionate rises in portal pressure and can precipitate variceal hemorrhage. 9 Angiography increases portal pressure and may also precipitate hemorrhage. 11 Portal pressure measured soon after variceal hemorrhage has a predictive value. 52. 64 Patients who die within 2 weeks have significantly
258
THOMAS
C.
MAHL AND ROBERTO
J.
GROSZMANN
higher portal pressures than those who survive (Fig. 4).64 Thus, although a linear relationship between the severity of portal hypertension and the risk of variceal hemorrhage has yet to be identified, the degree of portal hypertension does appear to have a permissive role, and increases in any individual may increase risk of bleeding. Portal pressure is not constant; it varies greatly under different physiologic conditions. Significant increases in portal venous pressure occur during inspiration, coughing, and Valsalva maneuver. The gradient between portal venous and esophageal luminal pressure is also affected by these maneuvers. 53 Although anecdotal reports of hemorrhage precipitated under these conditions exist, their true relationship to bleeding is yet to be defined.
SIZE OF VARICES The size of varices may be important. Variceal hemorrhage is more likely to occur with large rather than small varices. One study noted that 82% of patients with large varices bled, whereas 46% with small varices bled (see Fig. 2).19, 37, 65 Variceal size does not correlate with portal pressure, 19, 37 suggesting again that local factors contribute to promotion of variceal development (Fig. 5). This discussion presents a good deal of data that conflict and overlap regarding the contributions of pressure, size, and local influences to the development of variceal hemorrhage. The inability to identify any single predictor of bleeding suggests that the interaction of the factors just
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