Portal Hypertension

Extrahepatic Presinusoidal Obstruction

Presinusoidal extrahepatic obstruction is most commonly caused by thrombosis of the portal vein. Portal vein thrombosis occurs in both children and adults. In children, the most common cause is infectious, such as appendicitis or omphalitis. In adults, there are multiple causes, including hypercoagulable states, inflammatory diseases, complications of medical interventions, malignancy, and most commonly cirrhosis. Portal vein thrombosis occurs with an incidence of 0.6% to 22% in adult patients with these conditions.

Intrahepatic Presinusoidal Obstruction

Intrahepatic presinusoidal obstruction occurs from fibrosis and compression of portal venules, which subsequently restrict portal flow. This can be seen with hepatic fibrosis, sarcoidosis, chronic arsenic exposure, Wilson disease, hepatoportal sclerosis, primary biliary cirrhosis, schistosomiasis, and myeloproliferative disorders. Wilson disease is a hereditary disorder of copper metabolism, in which copper accumulates in hepatocytes due to an inability to excrete copper into the biliary system.

Schistosomiasis is the most common cause of PHT in third world countries. It occurs from ova deposition in portal vein walls, resulting in a granulomatous inflammatory reaction that causes fibrosis and restriction of portal blood flow. The mechanism of action in myeloproliferative disorders involves deposition of cellular material into the portal zones. In sarcoidosis the deposition of sarcoid granulomas within the portal vein leads to its obstruction and increase in portal blood flow. ^,

Intrahepatic Sinusoidal and Postsinusoidal Portal Hypertension

Sinusoidal hypertension results from alcoholic, viral, and toxic hepatitis. Postsinusoidal obstruction is caused by alcoholic liver disease, postnecrotic cirrhosis, and hemochromatosis. Together, sinusoidal and postsinusoidal hypertension resulting in cirrhosis are the most common causes of PHT in the Western world. The mechanism of action is mechanical obstruction of portal blood flow by regenerating hepatic nodules and cirrhotic bands in the liver. In addition to the effects on the hepatic sinusoids, these phenomena can also damage presinusoidal and postsinusoidal structures. The normal architecture becomes distorted.

Cirrhosis also results in increases in hepatic blood flow. The liver generates multiple arteriovenous shunts and collaterals, which lead to nearly 33% of blood flow bypassing functional hepatocytes. This causes an increase in cardiac output and diminished systemic resistance, therefore elevating hepatic wedge pressure and portal liver pressure. Moreover, since a third of portal blood is shunted away from functioning hepatocytes, the cirrhotic patient develops impaired hepatic function.

Extrahepatic Postsinusoidal Obstruction

Extrahepatic postsinusoidal obstruction results from hepatic vein thrombosis and cardiac disease. Precipitating factors for hepatic vein thrombosis include malignancies, trauma, pregnancy, and oral contraceptives. Hepatic vein occlusion also occurs in Budd–Chiari syndrome, which in turn is associated with myeloproliferative disorders and hypercoagulable states.

Arteriovenous Fistulae

Arteriovenous fistulae cause PHT by increasing flow in the portal circulation. As the disease progresses to fibrosis and obstruction of the presinusoidal spaces, PHT is exacerbated. Arteriovenous fistulae can be caused by percutaneous transhepatic manipulation or penetrating trauma. They can also be associated with splenic fistulae from splenic artery aneurysms, sarcoidosis, Gauche disease, and myeloid metaplasia.

Variceal Formation and Hemorrhage

The formation of portal–systemic collaterals is seen when portal pressures reach 10 to 12 mm Hg above systemic venous pressures. Due to elevated portal pressures and increased splanchnic blood flow diverted from the portal to the systemic system, the vascular resistance of the collateral beds increases. Although it is lower than the obstructed portal system, it is still higher than normal portal pressure. This phenomenon explains why the formation of portal–systemic collaterals does not normalize the elevated portal pressures.

Varices are mainly the result of dilation and dysfunction of the preexisting embryonic connections between the portal and systemic venous systems, but formation of new blood vessels via neoangiogenesis also occurs. These new vessels are abnormal, with marked hyperplasia and hypertrophy of their walls. The left gastric vein arising from the portal vein and the short gastric veins arising from the splenic vein are the vessels most often affected.

Esophageal varices form when the left gastric vein becomes dilated, and both esophageal and gastric varices form as a result of dysfunction and dilation of the short gastric veins. These vessels divert portal blood flow into the azygos venous system via the venous plexus of the lamina propria and submucosa of the esophagus and stomach. Esophageal varices form from the distal to proximal esophagus and can be divided into four zones: the gastric, palisade, transitional, and truncal zones. The transitional zone is defined as the 2 cm above the gastroesophageal junction and extends superiorly for another 2 cm; it is the zone most susceptible to bleeding. Gastric varices can be divided into type I and type II, where type I are gastric varices that extend above the cardia as esophageal varices and type II are isolated to the stomach, most commonly on the fundus.

Varices can also be seen on the abdominal wall from collateralization between the left portal vein and the systemic system via periumbilical veins in the falciform ligament. The physical exam finding associated with this is known as caput medusae.

Esophageal and gastric varices are present in roughly 50% of cirrhotic patients at the time of diagnosis, and the incidence increases to 90% of patients with long-term follow-up. Rupture with bleeding occurs from small varices (<5 mm) in 7% of patients over a 2-year period, and in 30% of patients with large varices over the same period. The mortality rate after the first bleed reaches 35%, and 60% of patients rebleed within the first year. Each additional bleed carries a mortality rate of 20%. ^,

The most widely accepted explanation as to why varices bleed is the explosion hypothesis. It suggests that when the hydrostatic pressure inside varices increases to above 10 mm Hg, variceal dilation, and a decrease in wall thickness occurs. Ruptures occur when the tension in the expanding wall can no longer be countered by wall tension (Law of LaPlace). The critical hepatic venous pressure gradient is 12 mm Hg. In the presence of varices, pressures above 12 mm Hg are associated with a significant risk of variceal bleeding; however, the magnitude above this value does not necessarily correlate with risk of hemorrhage. Medical therapy and interventions are aimed at keeping the hepatic venous pressure gradient below 12 mm Hg; pressures below this level are associated with minimal risk of bleeding.

Ascites

Ascites occur in up to 80% of patients with PHT. With the increase in portal pressure, Starling forces drive fluid out of vessels and into the interstitial space, causing ascites. Low oncotic pressure resulting from the hypoalbuminemia manifested by cirrhotic patients also occurs, exacerbating the problem. In addition, the lymphatic system typically becomes overwhelmed.

The accumulation of ascites places patients at risk for spontaneous bacterial peritonitis (SBP). In the past, approximately 75% of these infections were attributed to Gram-negative aerobic bacteria, suggesting the gastrointestinal tract as the source. However, more recent data show that up to one-third of cases are associated with Gram-positive bacteria. ^, Approximately 30% of patients with ascites require hospital admission at some point for antimicrobial treatment of SBP. Its presence is associated with increased mortality in cirrhotics.

Encephalopathy

Hepatic encephalopathy refers to any neuropsychiatric dysfunction caused by liver disease. The symptoms are broad, ranging from subclinical to coma or death. Due to malfunctioning hepatocytes and portosystemic shunting, increased levels of ammonia and glutamine derived from ammonia occur in the arterial system. These cause dysfunction of astrocytes in the brain as well as mitochondrial dysfunction, ultimately resulting in alterations of cerebral function, cerebral edema, and potentially cerebral herniation. These changes are graded by the Wes Haven Criteria. Grades I and II include mild symptoms such as changes in cognition, altered sleep patterns, mood changes (anxiety or euphoria), mild disorientation, asterixis, and increasing apathy and drowsiness. Grades III and IV consist of somnolence or coma. ^,

Encephalopathy occurs in 30% to 40% of patients with decompensated liver failure and is associated with an increase in mortality. It is thought that obstruction of blood flow in the liver together with the development of collaterals result in the shunting of neuroactive peptides into the systemic circulation. It is considered a reversible disorder; early recognition can prevent progression.

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) occurs when renal function is decreased in the presence of cirrhosis and ascites. It is considered a “diagnosis of exclusion”; therefore, other causes of renal dysfunction must be ruled out to confirm its presence. Clinically it presents as oliguria, hyponatremia, and low urinary sodium output. It can occur rapidly (deterioration of renal function within 2 weeks) or as a more chronic disorder. Rapid deterioration is associated with a poor prognosis; only 10% of patients survive hospitalization.