Portal Hypertension and Varices

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Chapter 359 Portal Hypertension and Varices

Frederick J. Suchy

Portal hypertension, defined as an elevation of portal pressure >10-12 mm Hg, is a major cause of morbidity and mortality in children with liver disease. The normal portal venous pressure is ∼7 mm Hg. The clinical features of the various forms of portal hypertension may be similar, but the associated complications, management, and prognosis can vary significantly and depend on whether the process is complicated by hepatic insufficiency.

Etiology

Portal hypertension can result from obstruction to portal blood flow anywhere along the course of the portal venous system. The various disorders associated with portal hypertension are outlined in Table 359-1. Portal hypertension can occur as a result of prehepatic, intrahepatic, or posthepatic obstruction to the flow of portal blood.

Table 359-1 CAUSES OF PORTAL HYPERTENSION

EXTRAHEPATIC PORTAL HYPERTENSION

Portal vein agenesis, atresia, stenosis
Portal vein thrombosis or cavernous transformation
Splenic vein thrombosis
Increased portal flow
Arteriovenous fistula

INTRAHEPATIC PORTAL HYPERTENSION

Hepatocellular disease

Acute and chronic viral hepatitis
Cirrhosis
Congenital hepatic fibrosis
Wilson disease
α1-Antitrypsin deficiency
Glycogen storage disease type IV
Hepatotoxicity

Methotrexate
Parenteral nutrition

Biliary tract disease

Extrahepatic biliary atresia
Cystic fibrosis
Choledochal cyst
Sclerosing cholangitis
Intrahepatic bile duct paucity

Idiopathic portal hypertension
Postsinusoidal obstruction

Budd-Chiari syndrome
Veno-occlusive disease

Extrahepatic portal vein obstruction is an important cause of portal hypertension in childhood. The obstruction can occur at any level of the portal vein. Umbilical infection (omphalitis) with or without a history of catheterization of the umbilical vein may be causal in neonates. The infection can potentially spread from the umbilical vein to the left branch of the portal vein and eventually to the main portal venous channel. Intra-abdominal infections, including acute appendicitis and primary peritonitis, can be causal in older children. Portal vein thrombosis has also been associated with neonatal dehydration and systemic infection. In older children, inflammatory bowel disease can be associated with a hypercoagulable state and portal venous obstruction. Thrombosis of the portal vein has also occurred in association with biliary tract infections and primary sclerosing cholangitis. Portal vein thrombosis is associated with hypercoagulable states such as deficiencies of factor V Leiden, protein C, or protein S. The portal vein can be replaced by a fibrous remnant or contain an organized thrombus. Rare developmental anomalies producing extrahepatic portal hypertension include agenesis, atresia, or stenosis of the portal vein. Obstruction by a web or diaphragm can also occur. At least half of reported cases have no defined cause.

Uncommonly, presinusoidal hypertension can be caused by increased flow through the portal system as a result of a congenital or acquired arteriovenous fistula.

The intrahepatic causes of portal hypertension are numerous. Obstruction to flow can occur on the basis of a presinusoidal process, including acute and chronic hepatitis, congenital hepatic fibrosis, and schistosomiasis. Portal infiltration with malignant cells or granulomas can also contribute. An idiopathic form of portal hypertension characterized by splenomegaly, hypersplenism, and portal hypertension without occlusion of portal or splenic veins and with no obvious disease in the liver has been described. In some patients, noncirrhotic portal fibrosis has been observed.

Cirrhosis is the predominant cause of portal hypertension and is related to obstruction of blood flow through the portal vein. The numerous causes of cirrhosis include recognized disorders such as biliary atresia, autoimmune hepatitis, chronic viral hepatitis, and metabolic liver disease such as α1-antitrypsin deficiency, Wilson disease, glycogen storage disease type IV, hereditary fructose intolerance, and cystic fibrosis.

Postsinusoidal causes of portal hypertension are also observed in childhood. The Budd-Chiari syndrome occurs with obstruction to hepatic veins anywhere between the efferent hepatic veins and the entry of the inferior vena cava into the right atrium. In most cases, no specific cause can be found, but thrombosis can occur from inherited and acquired hypercoagulable states (antithrombin III deficiency, protein C or S deficiency, factor V Leiden or prothrombin mutations, paroxysmal nocturnal hemoglobinemia, pregnancy, oral contraceptives) and can complicate hepatic or metastatic neoplasms, collagen vascular disease, infection, and trauma. Additional causes of the Budd-Chiari syndrome include Behçet syndrome, inflammatory bowel disease, aspergillosis, dacarbazine therapy, and inferior vena cava webs. Sinusoidal obstruction syndrome (veno-occlusive disease) is the most common cause of hepatic vein obstruction in children. In this disorder, occlusion of the centrilobular venules or sublobular hepatic veins occurs. The disorder occurs after total body irradiation with or without cytotoxic drug therapy that is commonly used before bone marrow transplantation. The disease has also occurred after ingestion of herbal remedies containing the pyrrolizidine alkaloids, which are sometimes taken as medicinal teas.

Pathophysiology

The primary hemodynamic abnormality in portal hypertension is increased resistance to portal blood flow. This is the case whether the resistance to portal flow has an intrahepatic cause such as cirrhosis or is due to portal vein obstruction. Portosystemic shunting should decompress the portal system and thus significantly lower portal pressures. Despite the development of significant collaterals deviating portal blood into systemic veins, portal hypertension is maintained by an overall increase in portal venous flow and thus maintenance of portal hypertension. A hyperdynamic circulation is achieved by tachycardia, an increase in cardiac output, and decreased systemic vascular resistance. Splanchnic dilatation also occurs. Overall, the increase in portal flow likely contributes to an increase in variceal transmural pressure. The increase in portal blood flow is related to the contribution of hepatic and collateral flow; the actual portal blood flow reaching the liver is reduced. It is also likely that hepatocellular dysfunction and portosystemic shunting lead to the generation of various humoral factors that cause vasodilatation and an increase in plasma volume.

Many of the portal hypertension complications can be accounted for by the development of a remarkable collateral circulation. Collateral vessels can form prominently in areas in which absorptive epithelium joins stratified epithelium, particularly in the esophagus or anorectal region. The superficial submucosal collaterals, especially those in the esophagus and stomach and, to a lesser extent, those in the duodenum, colon, or rectum, are prone to rupture and bleeding under increased pressure. In portal hypertension, the vascularity of the stomach is also abnormal and demonstrates prominent submucosal arteriovenous communications between the muscularis mucosa and dilated precapillaries and veins. The resulting lesion, a vascular ectasia, has been called congestive gastropathy and contributes to a significant risk of bleeding from the stomach.

Clinical Manifestations

Bleeding from esophageal varices is the most common presentation. Less commonly, patients bleed from varices around a stoma or from anorectal varices. In patients with underlying hepatic disease, physical examination might show jaundice and stigmata of cirrhosis such as palmar erythema and vascular telangiectasias. Growth retardation can occur in patients with cirrhosis and, to a lesser extent, in children with isolated extrahepatic portal vein obstruction. Ascites may be present in patients with intrahepatic causes of portal hypertension and can transiently occur with portal vein obstruction. Dilated cutaneous collateral vessels carrying blood from the portal to systemic circulation may be apparent in the periumbilical region.

In the absence of clinical or biochemical features of liver disease and with a liver of normal size, portal vein obstruction is most likely. Well-compensated cirrhosis cannot be completely ruled out under these conditions. Cholestasis and liver dysfunction with elevated serum bilirubin and aminotransferases occur uncommonly in portal vein obstruction as a result of external compression of bile ducts by cavernous transformation of the portal vein. An enlarged, hard liver with minimal disturbance of hepatic function suggests the possibility of congenital hepatic fibrosis.

Hemorrhage, particularly in children with portal vein obstruction, can be precipitated by minor febrile, intercurrent illness. The mechanism is often unclear; aspirin or other nonsteroidal anti-inflammatory drugs may be a contributing factor by damaging the integrity of a congested gastric mucosa or interfering with platelet function. Coughing during a respiratory illness can also increase intravariceal pressure. The bleeding may become apparent with hematemesis or with melena. Gastrointestinal (GI) hemorrhage can also originate from portal hypertensive gastropathy or from gastric, duodenal, peristomal, or rectal varices.

Splenomegaly, sometimes with hypersplenism, is the next most common presenting feature in portal vein obstruction and may be discovered 1st on routine physical examination. Because more than half of patients in many series with portal vein obstruction do not experience bleeding until after age 6 yr, the diagnosis should be suggested in a child without hepatocellular disease who had a complicated neonatal course and in whom asymptomatic splenomegaly later developed. Long-term follow-up of patients with portal vein obstruction has revealed a variety of complications including variceal hemorrhage, hypersplenism, biliary obtruction, growth and development retardation, and neuropsychiatric dysfunction.

Children with portal hypertension, regardless of the underlying cause, may have recurrent bouts of life-threatening hemorrhage. In patients with portal vein obstruction and normal hepatic function, the bleeding usually stops spontaneously. In patients with intrahepatic disease, the combination of portal hypertension and poor liver synthetic ability (coagulopathy) can make bleeding much more difficult to control. Moreover, esophageal hemorrhage and cirrhosis can have injurious effects on the liver, further impairing hepatic function and sometimes precipitating jaundice, ascites, and encephalopathy. Blood in the intestinal lumen can promote bacterial translocation, leading to peritonitis.

Another serious complication of portal hypertension is the hepatopulmonary syndrome, which develops in ≥10% of patients with cirrhosis. It is defined as an arterial oxygenation defect induced by intrapulmonary microvascular dilatation, resulting from release of mediators such as nitric oxide into the venous circulation.

Diagnosis

In patients with established chronic liver disease or in those in whom portal vein obstruction is suspected, an experienced ultrasonographer should be able to demonstrate the patency of the portal vein, and Doppler flow ultrasonography can demonstrate the direction of flow within the portal system. The pattern of flow correlates with the severity of cirrhosis and encephalopathy. Reversal of portal vein blood flow (hepatofugal flow) is more likely to be associated with variceal bleeding. Ultrasonography is also effective in detecting the presence of esophageal varices. Another important feature of extrahepatic portal vein obstruction is cavernous transformation of the portal vein, in which an extensive complex of small collateral vessels form in the paracholedochal and epicholedochal venous system to bypass the obstruction. Other imaging techniques also contribute to further definition of the portal vein anatomy but are required less often; contrast-enhanced CT and magnetic resonance angiography provide information similar to ultrasonography. Selective arteriography of the celiac axis, superior mesenteric artery, and splenic vein may be useful in precise mapping of the extrahepatic vascular anatomy. This is not required to establish a diagnosis but can prove valuable in planning surgical decompression of portal hypertension.

In a patient with hypoxia (hepatopulmonary syndrome), intrapulmonary microvascular dilatation is demonstrated with contrast-enhanced echocardiography that shows delayed appearance in the left heart of microbubbles from a saline bolus injected into a peripheral vein.

Endoscopy is the most reliable method for detecting esophageal varices and for identifying the source of GI bleeding. Although bleeding from esophageal or gastric varices is most common in children with portal hypertension, up to one third of patients, particularly those with cirrhosis, have bleeding from some other source such as portal hypertensive gastropathy or gastric or duodenal ulcerations. There is a strong correlation between variceal size as assessed endoscopically and the probability of hemorrhage. Red spots apparent over varices at the time of endoscopy are a strong predictor of imminent hemorrhage.

Treatment

The therapy of portal hypertension can be divided into emergency treatment of potentially life-threatening hemorrhage and prophylaxis directed at prevention of initial or subsequent bleeding. It must be emphasized that the use of many therapies is based on experience in adults with portal hypertension.

Treatment of patients with variceal hemorrhage must focus on fluid resuscitation, initially in the form of crystalloid infusion, followed by the replacement of red blood cells. Correction of coagulopathy by administration of vitamin K and/or infusion of platelets or fresh frozen plasma may be required. A nasogastric tube should be placed to document the presence of blood within the stomach and to monitor for ongoing bleeding. An H2 receptor blocker or proton pump inhibitor should be given intravenously to reduce the risk of bleeding from gastric erosions. In most patients, particularly those with extrahepatic portal hypertension and with normal hepatic synthetic function, bleeding usually stops spontaneously. Care should be taken in fluid resuscitation of children after bleeding to avoid producing an excessively high venous pressure and increasing risk for further bleeding.

Pharmacologic therapy to decrease portal pressure may be considered in patients with continued bleeding. Vasopressin or one of its analogs has been commonly used and is thought to act by increasing splanchnic vascular tone and thus decreasing portal blood flow. Vasopressin is administered initially with a bolus of 0.33 U/kg over 20 min, followed by a continued infusion of the same dose on an hourly basis or a continuous infusion of 0.2 U/1.73 m2/min. The drug has a half-life of ∼30 min. Its use may be limited by the side effects of vasoconstriction, which can impair cardiac function and perfusion to the heart, bowel, and kidneys and can also, as a result, exacerbate fluid retention. Nitroglycerin, usually given as a portion of a skin patch, has also been used to decrease portal pressure and, when used in conjunction with vasopressin, can ameliorate some of its untoward effects. The somatostatin analog octreotide is more commonly used, and it decreases splanchnic blood flow with fewer side effects. It may be administered by continuous intravenous infusion of 1.0-5.0 µg/kg/hr. However, the use of octreotide in adults with variceal hemorrhage has not been associated with a reduction in rates of rebleeding or mortality. Its use and efficacy in children have not been rigorously evaluated.

After an episode of variceal hemorrhage or in patients in whom bleeding cannot be controlled, endoscopic sclerosis or elastic band ligation of esophageal varices are important options. In endoscopic sclerosis, sclerosants are injected either intravariceally or paravariceally until bleeding has stopped. Although bleeding can be controlled acutely in most cases, further sessions of sclerotherapy are required to achieve temporary obliteration of the varices. Treatments may be associated with further bleeding, bacteremia, esophageal ulceration, and stricture formation. Most centers do not perform endoscopic sclerotherapy of varices prophylactically but use the procedure as a bridge to the time of liver transplantation or until collateral circulation develops in extrahepatic portal vein obstruction. Endoscopic elastic band ligation of varices has been shown in adult and pediatric studies to be more effective and associated with fewer complications than is sclerotherapy.

In patients who continue to bleed despite pharmacologic and endoscopic methods to control hemorrhage, a Sengstaken-Blakemore tube may be placed to stop hemorrhage by mechanically compressing esophageal and gastric varices. The device is rarely used now, but it may be the only option to control life-threatening hemorrhage. It carries a significant rate of complications and a high rate of bleeding when the device is removed, and it poses a particularly high risk for pulmonary aspiration. The tube is not well tolerated in children without significant sedation.

Various surgical procedures have been devised to divert portal blood flow and to decrease portal pressure. A portacaval shunt diverts nearly all of the portal blood flow into the subhepatic inferior right vena cava. Although portal pressure is significantly reduced, because of the significant diversion of blood from the liver, patients with parenchymal liver disease have a marked risk for hepatic encephalopathy. More selective shunting procedures, such as mesocaval or distal splenorenal shunt, can effectively decompress the portal system while allowing a greater amount of portal blood flow to the liver. The small size of the vessels makes these operations technically challenging in infants and small children, and there is a significant risk of failure as a result of shunt thrombosis. A shunt may be good option in a child with relatively well-preserved liver function, as sometimes occurs in patients with biliary atresia or cystic fibrosis. Portal vein thrombosis has been managed with the Rex shunt (mesenterico-left portal vein bypass), which restores physiologic portal blood flow and inflow of hepatotrophic factors. Growth and cognitive function improve after this procedure.

A transjugular intrahepatic portosystemic shunt (TIPS), in which a stent is placed by an interventional radiologist between the right hepatic vein and the right or left branch of the portal vein, can aid in the management of portal hypertension in children, especially in those needing temporary relief before liver transplantation. The TIPS procedure can precipitate hepatic encephalopathy and is prone to thrombosis.

Orthotopic liver transplantation represents a much better therapy for portal hypertension resulting from intrahepatic disease and cirrhosis. A prior portosystemic shunting operation does not preclude a successful liver transplantation but makes the operation technically more difficult.

Long-term treatment with nonspecific β-blockers such as propranolol has been used extensively in adults with portal hypertension. These agents might act by lowering cardiac output and portal perfusion. Evidence in adult patients shows that β-blockers can reduce the incidence of variceal hemorrhage and improve long-term survival. A therapeutic effect is thought to result when the pulse rate is reduced by ≥25%. There is limited published experience with the use of this therapy in children.

Prognosis

Portal hypertension secondary to intrahepatic disease has a poor prognosis. Portal hypertension is usually progressive in these patients and is often associated with deteriorating liver function. Efforts should be directed toward prompt treatment of acute bleeding and prevention of recurrent hemorrhage with available methods. Patients with progressive liver disease and significant esophageal varices ultimately require orthotopic liver transplantation. Liver transplantation is the only effective therapy for hepatopulmonary syndrome and should also be considered for patients with portal hypertension secondary to hepatic vein obstruction or resulting from severe veno-occlusive disease.

In patients with portal vein obstruction, episodes of bleeding can become less frequent and severe with age as a collateral circulation develops, >50% experience bleeding during adolescence. Neurocognitive defects diagnosed by careful psychologic testing indicate portosystemic encephalopathy caused by naturally occurring portosystemic shunts. Progressive liver disease can occur later as a consequence of bile duct compression from dilated collateral venous channels (portal biliopathy). These complications can be treated or prevented by the Rex shunt.

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