Historical perspective

Gilbert and Villaret first coined the term portal hypertension in 1906, recognizing the association of ascites and cirrhosis (1). Banti had postulated that splenomegaly was the antecedent event leading to gastrointestinal bleeding, anemia, hepatomegaly, cirrhosis and ascites (2), but McIndoe (3) and McMichael (4) showed that splenomegaly was the result of portal hypertension. Hemodynamic studies in the 1930s and 1940s, continued through to the present time (5–20), led to a better understanding of the pathophysiology of portal hypertension, to definition of the critical pressure of 12 mmHg, and to guidelines for necessary pressure reduction to prevent bleeding.

Surgical management has evolved over the last century. The first portacaval shunt was performed by Eck in 1877 (21) and in 1893 Pavlov demonstrated that total portal diversion leads to liver failure and encephalopathy (22). Banti popularized splenectomy (23), while Morison (24) and Talma (25) tried omentopexy. Vidal performed the first portocaval shunt in man (26), and portal systemic shunts were reintroduced by Whipple in 1945 (27). While bleeding control was good, liver failure was accelerated. In the 1960s selective shunts were introduced (28), and in the 1980s the ultimate surgical management of portal hypertension became a clinical reality with liver transplantation (29).

Less invasive methods of treating portal hypertension were sclerotherapy, first introduced by Crafoord and Frenckner in 1939 (30), refined in the 1970s with of flexible endoscopy (31) (32), and modified in the 1990s by band ligation of varices (33). Pharmacotherapies were introduced in the 1980s to reduce portal hypertension (34). Finally, in the last decade radiologically placed intrahepatic portacaval shunts are being used to decompress portal hypertension (35).

Anatomy and physiology

The portal vein is formed by the confluence of the superior mesenteric and splenic veins behind the neck of the pancreas and runs for approximately 6 to 8 cm posteriorly up to the porta hepatis where it bifurcates (36). Its main tributaries are variable: the inferior mesenteric vein enters either the splenic or the superior mesenteric vein, and the left gastric vein enters either the splenic or the portal vein behind the pancreas. The middle colic, ileocolic and smaller mesenteric tributaries drain into the superior mesenteric vein, and the umbilical vein drains into the left branch of the portal vein. Normal portal pressures vary from 5 to 8 mmHg, with portal flows greater than one liter per minute. The venous anatomy at the gastroesophageal junction has a consistent pattern with perforating veins and a submucosal channels at the distal 2 cm of the esophagus. (37)

Pathophysiology

Components of both “backward” and “forward” flow theories contribute. The primary factor is the increase of vascular resistance in the portal system leading to back pressure on the splanchnic circulation. Portal systemic collaterals develop to bypass the source of increased resistance. Increased plasma volume and vasodilation contribute to an increase in splanchnic inflow which further aggravates the portal hypertension (38–44).

In portal hypertension, the portal pressure rises as high as 30 mmHg, and gastroesophageal varices develop with this high pressure and increased flow in the left and short gastric veins which run up to the fundus, the gastroesophageal junction and submucosally in the distal esophagus. Other collateral pathways include the umbilical vein that can cause caput medusae, veins in the retroperitoneum and the inferior mesenteric vein that can lead to large hemorrhoids.

Variceal bleeding occurs when the expanding force exceeds that of the venous wall tension as explained by Laplace’s law, where the tension is proportional to the pressure exerted and radius of the vessel and inversely related to the wall thickness and surrounding support tissues (39, 42, 45, 46). There are several factors associated with initial variceal bleeding (table I) (46–49).

Table I

Factors leading to an initial variceal bleeding episode.

The natural history of varices and variceal bleeding has been well examined. Up to onethird of compensated cirrhotic patients will have varices compared to 60% to 80% in decompensated cirrhotic patients (49). The rate of development of varices is approximately 8% to 10% per year in patients with cirrhosis (50, 51). Acute variceal bleeding carries a mortality rate of approximately 30%, and even in some studies as high as 50% (52–54). Most of the deaths are in patients who have poorer or deteriorating liver function (i.e. Child’s C) (52–54). Rebleeding within the first 7 to 10 days occurs in 20% to 50% of the patients and carries a poor prognosis. After 6 weeks the risk drops nearly to that prior to the bleed (54). Rebleeding rates within the first 6 to 24 months vary from 70% to 80% (53, 54). Understanding these risks and the status of the underlying liver disease help the clinician form a logical treatment plan.

Etiology of portal hypertension: This may be presinusoidal, sinusoidal, or post sinusoidal. Cirrhosis causes a sinusoidal block and is the most common cause.

In presinusoidal portal hypertension the obstruction can occur in the extrahepatic or intrahepatic portal system. Extrahepatic thrombosis of the portal vein occurs either in the neonatal group secondary to umbilical sepsis, or in the older age group secondary to a hypercoagulable state such as polycythemia vera, a myeloproliferative disorder or a specific factor deficiency (such as antithrombin III protein C or S) (55–58). Finally, the mass effect or direct invasion of a malignancy can obstruct the portal venous system leading to portal hypertension. Intrahepatic presinusoidal portal hypertension can be caused by congenital hepatic fibrosis (59), early primary biliary cirrhosis (60) and schistosomiasis which causes fibrosis of the terminal portal venules (61). An important common feature to all these causes of presinusoidal obstruction is that liver function is normal.

Cirrhosis is the major cause of sinusoidal portal hypertension and the most common causes are viral hepatitis and alcohol (62, 63). Other less common causes include hemochromatosis, Wilson’s disease, sclerosing cholangitis and primary biliary cirrhosis. Pathophysiologically, there are both portal hypertension and hepatocellular damage and necrosis leading to lobule collapse, fibrosis and disorganized regeneration.

Postsinusoidal portal hypertension is rare and is usually caused by a hepatic venous outflow obstruction. This may be venoocclusive disease which is usually microscopic, major hepatic vein thrombosis, inferior vena caval webs or some tumor obstructing a major hepatic vein outflow. Rarely rightsided heart failure may lead to a functional hepatic out flow obstruction without actual occlusion.

Diagnostic regimens in portal hypertension evaluate the liver disease, varices, and the portal vessels.

Endoscopy is the mainstay of diagnosis and initial treatment of bleeding varices.

Three endoscopic pathologic changes can be seen in a patient with portal hypertension which may occur alone or in combination. Most common are esophageal varices which are usually most prominent in the distal esophagus. Gastric varices usually are seen in the gastric fundus either in continuity with esophageal varices or as isolated gastric varices (64). Finally, portal hypertensive gastropathy occurs when there is increased mucosal flow within the stomach which in combination with high pressure causes congestion (65). The specific signs seen at endoscopy which may portend a higher bleeding risk are large varices (Laplace’s law) and red color signs (65).

Vascular imaging depends on radiologic evaluation with either ultrasonography with duplex and/or angiography with pressure measurements (19, 20).

Ultrasound evaluation is a noninvasive method to assess the main vessels of the portal system, the liver morphology including focal lesions, and to detect ascites. Duplex ultrasonography allows the clinician to assess flow in the portal vein and its tributaries. Factors examined are patency, flow direction and velocities. Collateral vessels may also be seen indicating the severity of the portal hypertension.

Angiography remains the gold standard for defining portal venous anatomy and pressure measurements (18). Standard imaging uses splenic and superior mesenteric arteriography with venous phase imaging enhanced by digital subtraction. Hepatic venous pressure gradient (HVPG), as a measure of portal pressure is the difference between the occluded and free hepatic vein pressures measured at retrograde catheterization. In alcoholic cirrhotic patients HVPG is an accurate measure of portal pressures (18), but is unreliable in patients with presinusoidal portal hypertension (57).

Direct portography, which catheterizes the portal vein, allows direct pressure measurement and imaging. Initially done by splenoportography, then by transhepatic catheterization, this is now done by transjugular transhepatic catheterization of the portal vein.

Liver function assessment is key to management decision making, to prognosis and to outcome.

History focuses on symptoms including fatigue, anorexia, previous bleeding, ascites, edema, problems with infection, and signs of encephalopathy. In addition, a history of exposure to hepatitis is sought. Physical examination looks for evidence of hepatosplenomegaly, ascites, spider angiomata and nutritional wasting. Neurologic examination can help determine the degree of encephalopathy.

Laboratory blood work measures hematologic, biochemical and serologic tests. Hypersplenism results in leukopenia and thrombocytopenia, and liver dysfunction prolongs the prothrombin time. Blood urea nitrogen, creatinine and electrolyte measurements are also important in assessment of fluid balance and renal dysfunction. Serum transaminase, alkaline phosphatase, gamma glutamyl transpeptidase, bilirubin and albumin may indicate acute injury, cholestasis or hepatocellular dysfunction.

Child’s classification (66) and its modification by Pugh (67) gives a clinically useful estimation of risk in patients with liver disease. Based on serum bilirubin, albumin, prothombin time, and degree of ascites and encephalopathy (table II), it classifies good, medium, and poor risk patients with cirrhosis.

Table II

Child’s-Pugh classification.

Quantitative liver function testing falls into three broad categories, but have limitations and are not widely used. First is the clearance of specific drugs such as caffeine and antipyrine (68, 69) that measures the activity of the P₄₅₀ pathways. The second category is the measurement of specific metabolic pathways for example galactose to glucose (70) or indocyanine clearance (68). The final area involved tasks, such as urea or monoethylglycinexylidide synthesis, that the liver performs (71).

Therapies for variceal bleeding can be summarized:

Pharmacotherapy can be used to reduce portal pressure either in the acute or the chronic setting.

In acute bleeding, vasopressin and somatostatin are used (72). Vasopressin infused at 0.2 to 0.4 units/min in conjunction with nitroglycerin to achieve a systolic blood pressure of 90 to 100 mmHg, is effective in up to 80% of patients to control bleeding (73–76). However, when discontinued rebleeding is common. The longer acting analog Glypressin is commonly used in Europe (76). Somatostatin or its longer acting analog octreotide given by infusion at 50 mg/hr is equally effective as the vasopressin/nitroglycerin combination (77–79) and has fewer side effects.

Oral pharmacotherapy is used to reduce both risk of an initial bleed and the occurrence of rebleeding. Lebrec et al. in 1980 introduced noncardioselective beta-adrenergic blockade to reduce splanchnic inflow and showed that portal pressures could be lowered by 20% (34). Studies have shown that a reduction of portal pressures by 20% or HPVG below 12 mmHg significantly reduce the risk of bleeding (80–91). Up to onefifth of the patients have severe enough side-effects that therapy must be stopped. Other medications have been studied and the nitrates have been shown to be as effective as beta-blockers (92–94).

Endoscopic therapy is with sclerotherapy, banding ligation or a combination of both.

Endoscopic treatment of varices gained acceptance in the 1970s with the advent of flexible endoscopy (95–102). The 1980s was the decade of sclerotherapy to control acute bleeding, and it was documented that the risk of rebleeding was significantly reduced to 50% at two years. In the 1990s endoscopic banding was introduced and has largely replaced sclerotherapy (33). Obliteration of varices with either technique requires several sessions, but studies suggest that banding requires less sessions, has a lower complication rate and that the rebleeding rate at two years is 30% to 35% and is significantly lower with banding (33). Mortality is not significantly different between sclerotherapy and banding.

Decompression of varices is by surgical or radiologic shunt, and may be total, partial or selective.

Radiologic shunt is by a transjugular intrahepatic portal systemic shunt (TIPS) and has become a popular method to treat variceal bleeding in the 1990s, especially in the acute setting. The technique evolved from the initial studies in 1969 by Rosch (103), through balloon dilation by Gutierrez and Burgener in 1979 (104), to humans by Colapinto et al. (105). Finally, Richter et al. introduced the use of an expandable metal stent (Palmaz) to create the intraheptic shunt (106).

TIPS are introduced through the right internal jugular vein, catheterization of a main hepatic vein, transparenchymal catheterization of the portal vein, and serial dilation of the track until large enough to insert a stent. Once placed the stent is dilated sufficiently to reduce the portal systemic gradient below 12 mmHg. Technical success rate is 92–99% (107, 108). Absolute contraindications to placement are rightsided heart failure, severe liver failure and polycystic liver disease. Relative contraindications such as hepatic tumors, encephalopathy and hepatic or portal vein thrombosis are judged individually. Complications of TIPS include acute stent thrombosis, hemobilia, stent migration and others related to angiography in general (108–111). Mortality is usually related to the underlying disease.

The major issues with TIPS are the risk of stenosis/occlusion and the occurrences of encephalopathy. Because of these risks careful post procedure follow up is indicated.

Stenosis is monitored by repeated doppler/ultrasound: visible stenosis or velocity changes lead to recatheterization, pressure measurement, and if the gradient is > 12 mmHg to redilation. The incidence of rebleeding after TIPS is 20% in the randomized trials comparing TIPS to sclerotherapy (127–130). This rebleeding rate can probably be lowered by careful follow up and by maintaining the portal/atrial pressure gradient < 12 mmHg (128–130).

Encephalopathy after TIPS is increased 20–30% over baseline (127–130). This is usually easily controlled with lactulose and protein restriction.

Surgical decompression can be achieved with total or partial portal systemic shunts or by selection variceal decompression.

All types of surgical shunts provide greater than 90% control of variceal bleeding. Their difference lies in the degree of portal flow diversion. Total shunts divert all the portal flow to the systemic circulation. Partial shunts maintain some portal flow to the liver. Selective shunts only decompress gastroesophageal varices and maintain portal hypertension and flow to the liver.

Total portal systemic shunts may be an end-to-side shunt where the portal vein is divided at its bifurcation and the proximal end anastomosed to the inferior vena cava, or a side-to-side anastomosis between the portal vein or a tributary greater than 10 mm in diameter and the inferior vena cava. All divert portal flow, and side-to-side shunts also decompress the liver sinusoids. Surgical methods in creating these shunts depend on proper exposure of the vessels involved and attention to details in fashioning the anastamosis. Bleeding control is excellent, but portal flow is diverted which may cause hepatocellular dysfunction.

Partial portal systemic shunt is achieved with a portacaval graft of 8 mm in diameter. This reduces portal pressure to 12 mmHg while maintaining forward portal flow in 83% of patients (112). The operative exposure is similar to that of total portal systemic shunts. In order to optimize flow the ends of the 8 mm graft should be beveled at right angles to each other and be about twice the caliber of the graft. Shortcomings of this technique are graft occlusion and greater chance of technical difficulties.

Selective shunt can achieved with a distal splenorenal shunt (28). This shunt decompresses esophageal and gastric varices by connecting the splenic vein into the left renal vein. With portal azygous disconnection by ligation of the left and right gastric veins, and interruption of the gastroepiploic arcade, portal hypertension is preserved. Key elements in this procedure are mobilization of the splenic flexure of the colon, mobilization of the pancreas from the superior mesenteric vessels to the hilum of the spleen, adequate dissection of the splenic vein to prevent distortion when it is brought down for anastomosis to the left renal vein.

Devascularization procedures are indicated when surgical shunting is not possible secondary to thrombosed portal venous system or inappropriate anatomy for shunts. This procedure consists of splenectomy, gastric and esophageal devascularization, and variably esophageal transection. The goal of this procedure is to interrupt the inflow into the gastroesophageal varices. The success of devascularization in preventing rebleeding depends on an adequate operation: the distal 7 cm of esophagus must be freed, and all the vessels of the upper 2/3rds of the lesser and all the greater curvature of the stomach ligated. The advantage of this operation is that portal hypertension and prograde flow are preserved. The major limitation is a higher risk of rebleeding than surgical shunt procedures. The rebleeding rate in Japan is 6% (113), however, in the rest of the world where there is less experience in performing this procedure, the risk of rebleeding is 20–40% (114). Whether or not the esophagus should be transected remains unclear as there has usually been extensive sclerotherapy which may increase the technical difficulty and risk of transection.

Liver transplantation has changed the management of portal hypertension in the 1990s (115–119). The occurrence of ascites and encephalopathy with variceal bleeding may indicate advanced liver disease and if the patient has no contraindications, liver transplantation may be indicated. However, if the patient has adequate liver function, treatment should be directed at the variceal bleeding: liver transplantation is reserved for patients with end stage liver disease. Shortage of donor organs dictates that recipients may wait for transplantation for an extended period of time. During this period, patients with portal hypertension and variceal bleeding may need treatment that bridges them to transplantation such as endoscopic therapy or TIPS.

Management of variceal bleeding at specific phases can be summarized:

Prevention of rebleeding

First line treatment consists of endoscopic and pharmacologic interventions. The highest risk of rebleeding is in the first 6 weeks and the goal of first line treatment is to reduce the risk from 75% to ≤ 30%. Endoscopic therapy aims to obliterate varices with banding, and/or sclerotherapy (124). Pharmacologic B-blockade or nitrate are effective in reducing the risk of rebleeding. When these two modalities are combined the risk is further lowered (124).

Second line treatment should be used when first line treatment fails. Decompression is the primary choice in this situation. TIPS has become popular with various studies reporting success rate between 93% and 100% for initial placement (127–130). Manageable encephalopathy can occur in up to 25% of these patients with survival determined by severity of their liver disease. Rebleeding is reported in about 20% of these patients secondary to stent occlusion or stenosis which occurs in 75% of patients after TIPS. With good surveillance and redilation of stenosis, patency rates of 95% to 100% can be achieved (128–130).

Surgical shunts control bleeding in > 90% of patients. While selective and partial shunts have a lower rate of encephalopathy than total shunts, survival is not significantly different for any type of surgical shunt and is determined by the underlying liver disease. Studies comparing the various surgical shunt techniques to each other lead to the conclusions summarized in table III (131–142). In the long term, morbidity and mortality is related to the patient’s underlying liver disease. Total portal systemic shunts are rarely used due to the higher risk of encephalopathy and liver failure. Partial shunt procedures carry a 10% to 20% stenosis rate that are usually managed by intervention techniques (112, 143, 144). Selective shunts such as the distal splenorenal shunt do not alter the natural history of the underlying liver disease (145).

Table III

Conclusions of surgical shunts.

The role of TIPS versus surgical decompression is still debated and randomized trials are ongoing.

When surgical decompression or TIPS is not an option devascularization procedure can be done if there is adequate liver function. If there is endstage liver disease the patients should be evaluated for liver transplantation.

Extrahepatic portal vein thrombosis alters treatment recommendations compared to patients with intrinsic liver disease. Because liver function is usually preserved, the primary aim of treatment is to control bleeding. An etiology of the thrombosis should be evaluated (57). Management of initial bleeding should be endoscopic therapy (57, 146), however, there should be a low threshold to provide surgical decompression if the anatomy favors this. If no shuntable vessels are present devascularization may need to be done.

Ascites

Ascites as a complication of portal hypertension is an indictor of poor liver function. Spontaneous bacterial peritonitis and hepatorenal syndrome are more common owing to the endstage liver disease. The pathogenesis of ascites involves portal hypertension, altered sodium and water handling and hypoalbuminemia (147). Treatment is primarily medical (148), with sodium intake restricted to 2 gm/day, and spironolactone and furosemide as the diuretics of choice. If these measures fail large volume paracentesis can be used or more recently TIPS has been shown to alleviate refractory ascites (149, 150). Peritoneovenous shunts have fallen out of favor because of the risk of volume overexpansion, infection and shunt occlusion. Refractory ascites is a sign of liver decompensation, and is an indication for liver transplant.

Budd-Chiari syndrome

This syndrome was first described by Budd (151) in 1845 and Chiari (152) later documented the clinical syndrome in 1899. There are many causes of hepatic venous outflow obstruction such as trauma, tumors, hematologic disorders, rightsided heart failure and structural abnormalities. Whatever the cause, outflow obstruction leads to sinusoidal congestion and if severe enough centrilobular necrosis and liver failure or cirrhosis. Diagnosis of liver damage can only be made with liver biopsy, as laboratory studies are usually misleading. When necrosis is seen decompression of the sinusoids by total portalsystemic shunting is necessary (153, 154). When fibrosis or cirrhosis is seen liver transplantation is usually needed (155–157). Nevertheless determining the etiology of the obstruction is essential. More than 50% of the time a hematologic disorder is found and needs to be treated (153, 158).

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