Pathogenesis of Portal Hypertension

The portal system drains the capillaries of the intestinal mesentery and the spleen, ending in the hepatic sinusoids ( Figure 76-1 ). The portal vein constitutes about 75% of total hepatic blood flow and supplies partially oxygenated blood rich in nutrients absorbed from the gut. The remaining 25% of flow is provided by the hepatic artery, which supplies highly oxygenated blood distributed to the portal triads, liver capsule, and the walls of larger vessels. The liver is a high compliance, low-resistance system that can accommodate a large blood volume. Blood flow to the liver is autoregulated between the hepatic artery and portal vein, such that any disturbance to flow in one of these vessels can be offset by increased flow through the other vessel, a phenomenon known as the hepatic arterial buffer response. Blood from both the portal venous system and the hepatic arterial system combines within the sinusoids.

Diagram of portal circulation. The normal vascular anatomy and most common sites for the development of portal systemic collaterals are shown. (A) Esophageal submucosal veins, which are supplied by the left gastric vein and drain into the superior vena cava via the azygous vein. (B) Paraumbilical veins, which are supplied by the umbilical portion of the left portal vein and drain into the abdominal wall veins near the umbilicus. These veins may form a caput medusae. (C) Rectal submucosal veins, which are supplied by the inferior mesenteric vein through the superior rectal vein and drain into the internal iliac veins through the middle rectal veins. (D) Splenorenal shunts, which are created spontaneously or surgically.

(From Feldman et al., 2002, with permission.)

Portal hypertension occurs as a result of increased portal resistance, increased portal blood flow, or both ( Figure 76-2 ). Pressure within the portal system is proportional to blood flow and resistance to that flow, demonstrated by Ohm’s Law: P = q × R, where q is blood flow and r is resistance. Resistance is inversely related to the radius of the lumen of the blood vessel, such that small changes in vasculature radius can create large increases in resistance. Portal hypertension is caused by a combination of an increase in resistance, primarily within the hepatic sinusoids, and hemodynamic changes leading to an increase in flow. The portal venous system has a low baseline pressure of 7 to 10 mm Hg, and the hepatic venous pressure gradient (HVPG) ranges from 1 to 4 mm Hg. Portal hypertension is defined as a portal pressure greater than 10 mm Hg or a gradient greater than 5 mm Hg. Pressure gradients of greater than 10 mm Hg have been associated with esophageal varices, and those greater than 12 mm Hg are associated with ascites and variceal bleeding in adult patients. To obtain a measurement of the portal pressure gradient, a catheter can be wedged into the hepatic vein and a wedged hepatic venous pressure (WHVP) measurement can be obtained. The catheter is then retracted into a free-flowing hepatic vein and free hepatic venous pressure (FHVP) is measured. The HVPG is the difference between the WHVP and the FHVP. Causes of portal hypertension can be suggested by the HVPG. In pre-sinusoidal obstruction, the HVPG is normal but the WHVP is slightly raised, whereas in cirrhosis both the WHVP and the HVPG are increased ( Table 76-1 ).

Sites of obstruction to portal venous flow and measurement of portal pressure, illustrating the major locations of extrahepatic (prehepatic and posthepatic) and intrahepatic (presinusoidal, sinusoidal, and postsinusoidal) obstruction. A catheter tip is also shown wedged into a small hepatic vein (HV) for the measurement of the wedged hepatic venous pressure (WHVP). When the catheter tip is withdrawn into the hepatic vein, the free hepatic vein pressure (FHVP) is obtained. Hepatic venous pressure gradient (HVPG) = WHPV − FHVP. Direct measurement of the portal venous pressure (PVP) is accomplished during surgery by catheterization of either the umbilical vein or the portal vein via the transjugular or transhepatic approach. IVC , Inferior vena cava.

(From Feldman et al., 2002, with permission.)

Hepatocyte function is typically well preserved in early portal hypertension, and manifestations of portal hypertension may result prior to appearance of hepatocellular dysfunction. Vasoactive substances play a role in regulating intrahepatic resistance. In liver disease, the ability of the hepatic sinusoidal endothelial cells to secrete and respond to vasodilators such as nitric oxide (NO) are impaired, whereas expression of vasoconstrictors such as endothelin 1 are elevated. Other vascular mediators implicated can include carbon monoxide (CO), norepinephrine, angiotensin, prostaglandins, thromboxane, leukotrienes, and hydrogen sulfide. In addition to regenerative nodules and fibrotic bands, other mechanical factors include capillarization of the sinusoids and swelling of cells.

Hyperdynamic circulation can contribute significantly to the development of portal hypertension. Cirrhosis in both adults and children is associated with hyper­dynamic circulatory state, characterized by increased cardiac output, decreased splanchnic tone, and decreased splanchnic vasoconstrictor responsiveness. Because of the decrease in systemic vascular resistance, there is both an increase in blood return to the heart and diminished afterload. This vasodilation leads to both increased sodium retention and vascular volume as a result of the renal response to vasodilation. There is thus increased portal flow (above baseline) with elevated portal pressures. This leads to further portosystemic shunting (to various collateral connections) and further exacerbation of the hyperdynamic state. Thus, the portal pressure slowly climbs. Later, as a result of shunting, blood flow moves through the various collaterals to form varices. Starling forces within the intestines force fluid into the peritoneum forming ascites.

Clinically, portal hypertension causes splenomegaly and the formation of collateral circulation. Collaterals develop in response to elevation of the portal pressure, and they form in the cardia of the stomach, the anus, the falciform ligament through remnants of the fetal umbilical circulation, and the retroperitoneum. In prehepatic obstruction, collaterals form in order to bypass the blockage and enter directly into the liver at the porta hepatis (cavernous transformation).