Management of Portal Hypertension

History

In early civilizations, Egyptians, Greeks, and Romans tried to ascribe function to the liver. The Babylonians and Assyrians took note of the fullness of blood in the liver and postulated that this was the “seat of the soul.” Writings from Hippocrates reference liver failure by stating “in cases of jaundice it is a bad sign when the liver becomes hard.” An understanding of splanchnic and hepatic circulation has existed since empiric evidence of transhepatic blood flow was demonstrated by Francis Glisson in the early 17th century. Despite the long fascination with this organ, a conceptual understanding of its function and dysfunction has only developed over the past one to two centuries. It was not until microscopic examination became possible that the liver lobule with its hexagonal appearance, portal venous and hepatic arterial inflow from the periphery, and hepatic venous drainage from the center could be fully understood.

Clinical consequences of portal hypertension ailed ancient societies, with mention of ascites in ancient Egyptian, Mayan, and Greek texts. Gastroesophageal varices were recognized in the mid-19th century; however, the etiology of portal hypertension was elusive for nearly 100 years. In 1883 Italian physician Guido Banti observed that patients with anemia, leukopenia, and splenomegaly had elevated portal pressures and cirrhosis. From these observations, Banti postulated that splenomegaly and portal hypertension resulted primarily from increased blood flow to the spleen, which in turn damaged the liver. The popularity of Banti's “forward-flow” theory of portal hypertension led to the term hepatosplenopathy to describe these patients' disease process. In the 1920s a New Zealand surgeon Archibald McIndoe proposed a “backward-flow” hypothesis which attributes portal hypertension to an obstruction of flow along the portal circulation. Except in rare situations (e.g., arteriovenous fistulas), portal hypertension results from increased resistance and decreased portal flow. The relationship between flow and resistance and their contribution to the development of portal-systemic collaterals remained incompletely understood.

Banti's forward-flow hepatosplenopathies led to numerous therapies focused on prehepatic blood flow with splenectomy and omentopexy and other “preobstructive” operations. As this school of thought gave way to the backward-flow hypothesis, treatment shifted toward decompressive operations. The first end-to-side portacaval shunt was performed on dogs by Nicolai Eck in St. Petersburg in the late 19th century. The “Eck fistula” was later used by Ivan Pavlov (better known for his work in gastric physiology and classical conditioning) to shunt all portal flow away from the liver to demonstrate encephalopathy, progressive muscle wasting, and inanition, which he termed “meat intoxication.” Early use of portacaval shunts in humans were unsuccessful until the pioneering work of Whipple and his colleagues at Columbia University in New York in the 1930s. Although surgical shunts were able to control bleeding and ascites, subsequent acceleration of liver failure nullified any survival advantage to their patients.

Portal hypertension has evolved over the past 60 years because of the multiple randomized controlled trials performed for all treatment modalities introduced. This was one of the earliest fields of medicine to receive such scrutiny and therefore was early to use level 1 evidence since the 1950s. Initial trials compared surgical shunts with medical therapy in patients prior to the first variceal bleed and showed that mortality was increased with such intervention. Subsequent studies comparing medical therapy and surgical shunts in patients following their initial variceal bleed showed no improvement in overall survival, but rather the mode of death shifted from variceal bleeding to liver failure. These observations stimulated the investigators of that time to look for new treatment modalities.

Selective shunts pioneered by Warren et al. and Inokuchi et al., who developed distal splenorenal shunts (DSRSs) and left gastric venous-caval shunts. These shunts could achieve variceal decompression while maintaining adequate portal flow to the liver. Partial shunting via portacaval H-grafts was studied and championed by Sarfeh et al. in the 1980s. Preservation of portal flow resulted in lower rates of encephalopathy and liver failure.

Simultaneously, less invasive methods of treated variceal bleeding related to portal hypertension were developed. Chafoord and Frenckner first described esophagoscopic injection sclerotherapy in the treatment of esophageal varices. American surgeon Gregory Stiegmann and colleagues developed endoscopic variceal ligation as an alternative to sclerotherapy in 1989. Relatively recent technologic advances revolutionized portal venous decompression using the method of transjugular intrahepatic portosystemic shunting (TIPS) first described by Rösch et al. Intrahepatic shunting by means of TIPS is now a mainstay of therapy. The evolution of these interventions were combined with an increasingly sophisticated understanding of portal venous pathophysiology. A recognition that portal hypertension can be exacerbated by splanchnic hyperemia and hyperdynamic systemic circulation led to the introduction of noncardioselective β-blockers in 1980 by Lebrec et al. to ameliorate these changes. Since that time, medical therapy to reduce portal pressure and decrease variceal wall tension has become a mainstay of management.

Finally, the history of portal hypertension must recognize the role of liver transplantation introduced by Starzl and Calne in the 1970s and coming of age in the mid-1980s and 1990s. Their perseverance and pioneering work to resolve many of the technical issues of liver transplantation bore fruit. However, it was really the immunologic advances and the introduction of powerful new immunosuppressants that gave life to liver transplantation. The clinical reality is that most interventions address only the complications of late-stage liver disease, and in many patients survival improved only by liver transplantation. For the surgeon, this brings the management of such patients full circle, where the surgeon's role is now largely in the field of liver transplantation as part of the multidisciplinary team taking care of such patients.

Anatomy

The portal venous system arises from two embryologic sources: (1) the intraembryonic anterior and posterior cardinal venous system, which become the main systemic veins, and (2) the extraembryonic vitelline and umbilical veins, which become the portal venous system. The vitelline veins intercommunicate in the septum transverse where later liver sinusoids develop. The left vitelline vein forms most of the extrahepatic portal venous system draining the primitive intestine and plays a critical role in utero as the ductus venosus, which communicates directly from the rudimentary portovenous system via the vitelloumbilical anastomosis to the hepatic and cardiac channels, bypassing primitive hepatic sinusoids.

The portal vein is formed behind the neck of the pancreas by the joining of the superior mesenteric and splenic veins. It is normally 10 to 20 mm in diameter but in portal hypertension may enlarge. It courses along the free edge of the gastrohepatic ligament to the liver hilus, where it divides into right and left branches ( Fig. 135.1 ). Its feeding tributaries have some variability, with the inferior mesenteric vein entering the splenic vein in approximately two-thirds of persons and superior mesenteric vein in one-third. Similarly the left gastric or coronary vein enters the portal vein in approximately two-thirds and the splenic vein in one-third. The latter may vary considerably in size in portal hypertension and is often one of the major veins feeding into gastroesophageal varices. The umbilical vein is remarkably constant in its communication with the left branch of the portal vein, and in portal hypertension when recanalized this may be quite large. The major changes of clinical significance are around the gastroesophageal junction in portal hypertension. Radiologic studies using corrosion casting and morphometry have clarified the venous pathologic changes at this location in portal hypertension. These are schematically represented in Fig. 135.2 , where the following four zones are recognized:

• 1

  The gastric zone extends 2 to 3 cm below the gastroesophageal junction. These veins run longitudinally in the submucosa and lamina propria to the short gastric and left gastric veins.

• 2

  The palisade zone extends 2 to 3 cm superiorly from the gastric zone in the lower esophagus. These parallel palisades run longitudinally and correspond to the esophageal mucosal folds. There are multiple communications between these veins in the lamina propria, but there are no perforating veins in the palisade zone linking the intrinsic and extrinsic venous plexuses.

• 3

  The perforating zone extends approximately 2 cm higher up the esophagus, just superior to the palisade zone. In this zone the vessels perforate through the esophageal wall linking the internal and external veins.

• 4

  The truncal zone extends 8 to 10 cm up the esophagus and is characterized by four or five longitudinal veins in the lamina propria. In this zone, there are irregular perforating veins from the submucosa to the external esophageal venous plexuses.

Hepatic arterial anatomy is highly variable, with anomalies being of clinical importance to transplant surgeons, particularly during donor hepatectomy. The normal arterial anatomy is a common hepatic artery arising from the celiac axis that gives rise to a right and left artery just above the gastroduodenal artery. In approximately 20% of persons, there is an anomalous right accessory or replaced hepatic artery arising from the superior mesenteric artery. Similarly, there is an approximately 20% incidence for an accessory or replaced left hepatic artery arising from the left gastric artery. These two anomalies may coexist ( Fig. 135.3 ).

Functional anatomy of the liver can be divided based on their vascular supply. The liver is divided into four sections, which in turn consist of two hepatic segments each. The eight segments of the liver possess their own hepatic artery and portal venous inflow and hepatic venous drainage ( Fig. 135.4 ). Division of these planes allows for functional remnant and donor grafts during liver resection and living-donor liver transplantation. The microarchitecture of the liver parenchyma is also divisible into structural units. The primary modular unit of the liver parenchyma are polyhedral structures where the portal venous and hepatic arterial tree terminates. These primary lobules aggregate to form a secondary structure often called the “classical lobule.” Blood flow through these structures transverse septum like inflow fronts to pass through sinusoids and eventually drain into central hepatic veins.

Pathophysiology

The hepatic venous pressure gradient (HVPG) is the pressure difference between the portal vein and the vena cava. Portal hypertension is defined by an elevation in the HVPG greater than 6 mm Hg. This gradient can be caused by increased resistance to blood flow in the presinusoidal, sinusoidal, or postsinusoidal portal circulation. As in all venous systems, portal pressure is equivalent to the portal flow × resistance to portal flow. In rare cases, increases in flow in the portal system without concomitant increase in resistance may lead to clinically significant portal hypertension (i.e., splanchnic arteriovenous fistula).

Portal blood flow is determined by vasoconstriction and dilation of the mesenteric and splanchnic arterioles. In healthy individuals, portal flow is responsible for 75% to 80% of the inflow to the liver, with the remainder coming from the hepatic artery. Total flow ranges from 800 to 1200 mL/min, approximately 25% of total cardiac output. Normal portal pressures are in the range of 6 to 10 mm Hg. Regulation of hepatic artery flow can compensate for changes in portal venous flow by intrinsic regulatory system known as the hepatic arterial buffer response.

The changes in portal hypertension occur on this physiologic background. The steps in the development of the pathophysiology of portal hypertension have been carefully elucidated in the past two decades in animal models. Portal hypertension is present when portal pressure exceeds 8 mm Hg, but variceal bleeding rarely occurs until portal pressure exceeds 12 mm Hg. There is a well-defined sequence of events, as follows, that occurs in the pathophysiology of portal hypertension ( Fig. 135.5 ):

• Obstruction to portal venous flow is usually secondary to an intrahepatic block with cirrhosis. However, the inciting event may be one of the other etiologic causes of portal hypertension.

• Functional increase in resistance occurs secondary to activated hepatic stellate cells and myofibroblasts in the fibrous septa of the sinusoid. These represent a potentially reversible component to intrahepatic resistance.

• There is an imbalanced production of vasoconstrictors, such as endothelin, norepinephrine, and angiotensin, with an insufficient release of hepatic vasodilators, such as nitric oxide and prostaglandins.

• Splanchnic vasodilation occurs with increased splanchnic flow aggravating and contributing to the portal hypertensive syndrome. This is multifactorial, with neurogenic, humoral, and local mediators.

• Portosystemic collaterals develop not only at the gastroesophageal junction but also in the abdominal wall and retroperitoneum.

• There is an increase in plasma volume secondary to the vascular changes.

• A systemic hyperdynamic circulation develops with increased cardiac output, low total systemic vascular resistance, and further aggravation of the splanchnic hyperemia and overall hyperdynamic state.

This sequence of pathophysiologic changes in the hepatic, splanchnic, and finally systemic circulation offers an opportunity for pharmacologic manipulation and management of portal hypertension.

Etiology of Portal Hypertension

Portal hypertension can be attributed to processes that can be classified as (1) prehepatic, (2) intrahepatic obstruction, and (3) posthepatic venous outflow obstruction. Etiologies found under each category are summarized in Box 135.1 .

Prehepatic portal hypertension comprises 5% to 10% of portal hypertension patients in the United States and Europe. In other parts of the world, such as India, this may be the etiology in a higher percentage of portal hypertension patients. Prehepatic portal venous obstruction results from thrombosis, invasion by malignant tumor, or constriction from external surrounding processes. Portal and splenic vein thrombosis is the most common cause of prehepatic portal hypertension. Portal vein thrombosis may be associated with umbilical vein catheterization or other causes of sepsis and dehydration in infancy. In the adult patient the hypercoagulable syndromes should be sought in patients with a newly diagnosed portal or splenic vein thrombosis, with a full hematologic work-up. Other etiologies include pancreatitis and pancreatic tumors, with the later portending a poor prognosis related to the cancer. Prehepatic portal vein thrombosis is typically associated with few downstream signs of liver injury except in preexisting cirrhosis.

Extrinsic pressure on the portal vein from lymph nodes or other tumors can occasionally lead to portal hypertension, but this is unusual because the vein normally passes around surrounding masses. Finally, hepatic artery-to-portal venous fistulas, usually secondary to a liver biopsy, can occur and if large can lead to portal hypertension. Fistulas are diagnosed with radiologic imaging and can usually be managed with endoluminal angiographic techniques for their occlusion.

One important variant of portal hypertension is left-sided (sinistral) portal hypertension with isolated splenic vein thrombosis, a normal portal vein, and no intrahepatic block. The most common causes of this are pancreatitis and carcinoma of the body and tail of the pancreas. This is increasingly recognized on computed tomographic (CT) scan, with large collaterals coming from the splenic hilus up to the fundus of the stomach. From a portal hypertension perspective, this is readily handled with splenectomy, but clearly an understanding of the underlying pathology is most important in prognosis.

The intrahepatic causes of portal hypertension account for 90% of the cases in the United States and Europe. Most patients with an intrahepatic block have cirrhosis, which has multiple etiologies. These include alcohol, hepatitis B, hepatitis C, the cholestatic liver diseases (primary sclerosing cholangitis and primary biliary cirrhosis), hemochromatosis, and the other metabolic causes of cirrhosis. Although hepatitis C and alcoholic liver disease account for the majority of cirrhosis in adults, nonalcoholic fatty liver disease is an increasing cause of cirrhosis in the developed world. Portal hypertension due to cirrhosis is thought to be primarily a function of increased hepatic vascular resistance in the hepatic sinusoids due to fibrosis, scarring and distortion of the microvasculature, as well as dysregulation of contractile elements, including hepatic myofibroblasts. In the course of patient evaluation, full definition of the underlying disease is important for management. It is the natural history, activity, and rate of progression of the underlying liver disease that ultimately sets the prognosis.

Schistosomiasis is still an important cause of portal hypertension on a worldwide basis. Still seen in the Middle and Far East and in South America, the pathologic block in schistosomiasis is fibrosis of the terminal portal venules. Although it is an intrahepatic disease process, presinusoidal obstruction of the terminal portal venous branches is balanced by an increase in hepatic arterial inflow. Lobular architecture is preserved and total hepatic inflow is typically normal. Prototypical Symmers clay pipestem fibrosis is present in all patients. In addition, many patients with schistosomiasis may also have hepatitis as a concomitant disease with implications of liver function impairment.

Congenital hepatic fibrosis is a relatively rare cause of an intrahepatic block in the United States and Europe, but it is important to recognize because it is usually associated with preserved liver function. However, more recently there have been reports of progression of congenital hepatic fibrosis to end-stage liver disease requiring liver transplantation. A similar entity is seen in India as noncirrhotic portal fibrosis, which is a cause for portal hypertension in that country. The implication of preserved liver function is that there is a broader range of options for treatment, particularly for variceal bleeding.

Portal hypertension due to posthepatic venous outflow obstruction is occasionally due to constrictive pericarditis. It is much more commonly attributed to a broad category of Budd-Chiari syndrome and the occasional patient with a constrictive pericarditis. Classic Budd-Chiari syndrome involves thrombosis of the main hepatic veins, but other etiologies, such as inferior vena cava (IVC) webs, may cause this syndrome. The outflow block leads to an increase in sinusoidal pressure, centrilobular hepatocyte injury, and ultimately fibrosis, scarring, and cirrhosis. These are exceedingly rare syndromes, accounting for 1% to 2% of the cases of portal hypertension.

Clinical Manifestation of Portal Hypertension