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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in North America, affecting approximately 30% of the population [1]. It is the hepatic manifestation of the metabolic syndrome, and is directly linked to the escalating prevalence of obesity and the associated insulin resistance. Histologically, NAFLD is characterized by a spectrum that ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) which can progress to cirrhosis in 15–20% of subjects [2]. NASH is further distinguished from NAFL by the presence of inflammation and cytologic ballooning with or without Mallory hyaline or pericellular fibrosis in addition to steatosis [3]. Recently, studies have reported that NAFLD may predispose patients to hepatocellular carcinoma (HCC) in the absence of significant fibrosis or cirrhosis, and these subjects also seem to have more features of the metabolic syndrome [4]. [ABSTRACT FROM AUTHOR]

Hepatopulmonary syndrome (HPS) is a pulmonary vascular abnormality characterized by intrapulmonary vascular dilatations (IPVD) and arterial hypoxemia that occurs in the setting of either cirrhotic or noncirrhotic portal hypertension (1-4). The clinical diagnostic triad is shown in Fig. 1. Prevalence rates for HPS in patients undergoing liver transplant evaluation have ranged from 5% to 29% (5). HPS is not age-dependent and can be seen in children; it affects males and females equally. To date, no specific etiology of liver disease has been associated with HPS and the degree of HPS has not been correlated with the severity of liver disease using the Childs-Turcotte-Pugh classification or the model for end-stage liver disease scoring system (MELD) (6). [ABSTRACT FROM AUTHOR]

The liver is very susceptible to increases in venous pressure because of its unique architecture, in contrast to most organs, the liver has large endothelial pores and lacks a basement membrane. Thus, any increase in venous pressure leads to the rapid movement of large volumes of fluid from the vascular space into the interstitial space. The ability of the hepatic lymphatics to remove this excess fluid is limited and, therefore, the excess fluid enters the peritoneal cavity. Thus, obstruction to the venous outflow of the liver [Budd-Chiari syndrome (BCS)] presents clinically with signs of congestion of the liver including ascites, hepatomegaly, and right upper quadrant abdominal pain. It is perhaps this typical presentation that has led clinicians over the years to lump together all vascular obstruction into one general classification regardless of the vessels involved. In this chapter, we will make use of recent classifications of hepatic venous obstruction that allow for a better understanding of how each disease causing the BCS is different in its presentation and management. The term BCS will include hepatic vein occlusion, including combined occlusion of the hepatic veins and the vena cava. Hepatic veno-occlusive disease (VOD) also termed sinusoidal occlusion syndrome (SOS) will be considered separately. Cardiac causes of hepatic outflow obstruction will not be considered. [ABSTRACT FROM AUTHOR]

Increased resistance to portal blood flow leading to portal hypertension is the main cause of morbidity and mortality in patients with chronic liver disease, and reflects two parallel yet interrelated processes. First, the wound healing response to liver injury generates increased extracellular matrix (fibrosis) and the formation of regenerative nodules, which lead to architectural distortion that impedes intrahepatic blood flow. Second, dynamic sinusoidal changes caused by increased contractility of stellate cells in the perisinusoidal space also increase intrahepatic vascular resistance. The relative contribution of each of these components is difficult to quantify and may vary with the etiology and stage of fibrosis, but together they represent a key target for antifibrotic and vasoregulatory therapies. Clearly, the most effective therapy to treat hepatic fibrosis is to remove the causative agent. However, therapies that are able to retard or reverse the fibrotic response and/or inhibit stellate cell contraction could have a dramatic impact on the treatment of patients with chronic liver disease. This chapter reviews the cellular basis of hepatic fibrosis and increased intrahepatic vascular resistance, and how these insights are yielding novel approaches to the treatment of chronic liver disease. [ABSTRACT FROM AUTHOR]

Health status measurement in patients with cirrhosis and portal hypertension has received increasing attention from clinical investigators in recent times. This is based primarily on the continued absence of curative therapies for disease-related complications outside of liver transplantation. Patients with cirrhosis and portal hypertension have significant reductions in health status compared to general and select disease populations. Early detection and treatment of particular symptoms including muscle cramps and subclinical hepatic encephalopathy may afford the opportunity to improve quality of life in selected individuals. The use of health status as a study end point in controlled clinical trials requires further study on the responsiveness of existing liver disease-specific questionnaires. In conjunction with determining health status among patients with cirrhosis and portal hypertension, a number of investigations have sought to determine the cost effectiveness of clinical strategies for the prevention and treatment of disease-related complications. Further investigations of patient-based preferences for health states, however, are needed to fully understand the magnitude of net health benefits received from existing health care programs. [ABSTRACT FROM AUTHOR]

Portal hypertension is a common complication in liver diseases that should be searched for in all cirrhotic patients, as well as in other chronic liver diseases (1). Its main clinical consequence is bleeding from ruptured esophageal or gastric varices, which constitutes the major cause of death and of liver transplantation in patients with cirrhosis, the leading etiology for portal hypertension. [ABSTRACT FROM AUTHOR]

Microvascular exchange in the liver is quite peculiar owing to the porosity of the sinusoidal endothelial cells; the pores in the sinusoidal endothelium allow free passage of macromolecules, which allows the hepatocyte to take up tightly protein bound drugs (1). One of the major changes occurring in cirrhosis is sinusoidal capillarization (2), which leads to a profound impediment of passage of substances into the space of Disse. Sinusoidal capillarization was first described by Hans Popper on a morphological level (2); he—rightfully—predicted that this phenomenon would have important bearings on hepatic function. It lasted almost 20 yr until sinusoidal capillarization was demonstrated functionally using the multiple indicator dilution technique (3)—this study was quite a feat because it applied this demanding technique to humans before studying the phenomenon in animal models. Another important aspect of altered microvascular exchange is loss of the sinusoidal fenestrations that, at least in alcoholic liver disease, occurs before significant fibrosis is seen (4). [ABSTRACT FROM AUTHOR]

Noncirrhotic portal hypertension (NCPH) encompasses a group of diseases of varied etiology. The characteristic features of this group are increase in portal pressure caused by prehepatic or intrahepatic causes, with absence of liver cirrhosis, as well as of hepatic venous outflow obstruction. The wedged hepatic venous pressure is normal or only mildly elevated. Table 1 lists the common causes of NCPH. The most commonly encountered diseases in this group are noncirrhotic portal fibrosis (NCPF) [alternatively called idiopathic portal hypertension (IPH)l and extrahepatic portal vein obstruction (EHPVO). Together, these two entities constitute 20-30% of total cases of portal hypertension (PHT) in developing countries like India (1-3). In the following discussion, we will describe these two conditions in detail. Other prominent causes of NCPH like schisosamiasis, Nodular regenerative hyperplasia, and Partial nodular transformation will be described briefly. [ABSTRACT FROM AUTHOR]

The survival of children with portal hypertension has improved over the past decade owing to significant improvements in both medical and surgical therapy. These improvements have included progress in the pharmacologic control of acute portal hypertensive hemorrhage and improved efficacy and safety of endoscopic methods to treat acute esophageal variceal hemorrhage. However, despite these changes, there remains a significant role for advanced surgical therapy using portocaval shunts in children with gastrointestinal hemorrhage were significant sequela of portal hypertension. In addition, patience with both irreversible liver disease and portal hypertension have benefited from the improved success with pediatric liver transplantation as a definitive treatment for children with end-stage liver disease. This review will primarily examine the role of surgical therapy for children with progressive portal hypertension. [ABSTRACT FROM AUTHOR]

Pregnancy is a normal physiological state characterized by numerous hemodynamic changes. These hemodynamic changes, although necessary for a normal pregnancy, pose a special problem in the presence of portal hypertension. In North America, cirrhosis of the liver is the most common cause of portal hypertension. Although rare, the occurrence of pregnancy is not altogether unknown in this population. This is caused by reduced fertility as a consequence of anovulatory cycles, altered endocrine metabolism, and a relatively older age of these patients (1-6). Most women with well-compensated early chronic liver disease and those with the liver disease in remission, can expect to have normal fertility (3,7). Subjects with liver diseases that progress slowly, such as primary biliary-cirrhosis, are particularly likely to have preserved fertility until the disease becomes quite advanced (8-12). Also, in patients with noncirrhotic portal hypertension (NCPH) the hepatic synthetic functions are relatively well preserved and so is the fertility (13,14). Pregnancy in a patient with portal hypertension is a unique problem that needs specialized care to prevent potentially life-threatening complications such as gastrointestinal hemorrhage, it is therefore important to understand the effect of pregnancy on portal hypertension and vice versa so that untoward incidents like fetal morbidity and mortality and gastrointestinal hemorrhage can be avoided. [ABSTRACT FROM AUTHOR]

The hepatorenal syndrome (HRS) is defined as the development of renal failure in patients with severe liver disease in the absence of any other identifiable cause of renal pathology. Although classically associated with cirrhosis, it is now recognized that a similar syndrome occurs in patients with acute liver failure (1). It is diagnosed following the exclusion of other causes of renal failure in patients with severe liver disease such as hypovolemia, drug nephrotoxicity, sepsis, or glomerulonephritis. The causes of renal failure in/and liver disease are listed in Table 1. [ABSTRACT FROM AUTHOR]

The spontaneous bacterial infections that commonly occur in the setting of advanced liver disease include spontaneous bacterial peritonitis (SBP) and spontaneous bacteremia (SB). SBP occurs only in the setting of liver disease: usually advanced cirrhosis, severe subacute liver injury (e.g., alcoholic hepatitis), or fulminant liver failure. All cirrhotic patients with ascites can develop SBP. The prevalence of SBP in unselected cirrhotic patients with ascites admitted to a hospital ranges between 10 and 30% (1-3). [ABSTRACT FROM AUTHOR]

Abnormal renal sodium handling is an early and common complication of liver cirrhosis and eventually results in ascites formation. At least 50% of patients will develop ascites within 10 yr of diagnosis of cirrhosis (1). The presence of ascites predisposes the cirrhotic patients to further complications such as the development of spontaneous bacterial peritonitis and renal impairment, which significantly worsens the prognosis of these patients. The presence of ascites is also an indication for liver transplantation. Therefore, effective management of ascites is essential for improving the well being and survival of these patients. [ABSTRACT FROM AUTHOR]

Ascites, the accumulation of fluid in the peritoneal cavity, is the most common complication of cirrhosis and portal hypertension (1). In a prospective study of patients with compensated cirrhosis of all etiologies, the cumulative probability of developing ascites ranges from 35% to 50% in 5 yr (1,2). Although cirrhosis is the cause of ascites in more than 75% of patients, other less common causes of ascites are peritoneal malignancy (12%), cardiac failure (5%), and peritoneal tuberculosis (2%) (3), and these should be considered in the differential diagnosis of ascites. With the increasing use of in vitro fertilization, ascites secondary to severe ovarian hyperstimulation syndrome is being increasingly recognized (4). [ABSTRACT FROM AUTHOR]

Approximately 10% of portal hypertension-related gastrointestinal hemorrhage occurs from lesions in the stomach. These lesions are mainly gastric varices and, less commonly, portal hypertensive gastropathy and gastric vascular ectasia. Bleeding from varices other than esophageal or gastric, termed ectopic varices, is infrequent and accounts for fewer than 5% of all portal hypertension-related bleeding. [ABSTRACT FROM AUTHOR]

Transjugular intrahepatic portosystemic stent-shunt (TJPSS) is a nonsurgical means of diverting blood from the portal circulation through the hepatic parenchyma to the systemic circulation, thereby creating a portosystemic shunt. Hie internal jugular vein is first entered percutaneously, and a catheter is passed through the superior vena cava, right atrium, inferior vena cava, and, in most cases, the right hepatic vein under fluoroscopic guidance. A needle is inserted through the catheter to puncture the hepatic parenchyma, creating a tract to link the hepatic vein and usually the right portal vein. This tract is kept patent using an expandable metal stent. Where successful, this results in immediate decompression of the portal circulation and elimination of portal hypertension. [ABSTRACT FROM AUTHOR]

Surgeons have played a role in the management of portal hypertension since Eck performed the first end-to-side portacaval shunt (the Eck fistula) in dogs at the end of the 19th century (1). Several surgeons in the early 1900s attempted to manage variceal bleeding with various procedures, but it was in the 1940s that there was the first systematic use of surgical shunts to control variceal bleeding by the Columbia Presbyterian Group in New York. [ABSTRACT FROM AUTHOR]

John Brown, Royal Physician at Saint Thomas Hospital in London, was the first clinician to describe the gross appearance of the liver in a patient with cirrhosis, portal hypertension, and ascites. He noted marked ascites in his patient, a soldier of the King's Guard. Following multiple unsuccessful paracenteses, the solider expired. At autopsy, a nodular liver was observed by Dr. Brown. It was left, however, to Rene Laennec to first use the term "cirrhosis" to describe a shrunken tawny-colored liver with a nodular granular consistency. [ABSTRACT FROM AUTHOR]

Portal hypertension is responsible for the major complications of cirrhosis including the development of ascites, variceal hemorrhage, portal systemic encephalopathy, and the hepatorenal syndrome. Until the late 1970s, surgically created shunts were the primary treatment for the complications of portal hypertension. Although shunts successfully lowered portal pressure, they were complicated by progressive liver failure, hepatic encephalopathy, and, in the case of primary prophylaxis, an increase in mortality compared to supportive medical treatment (1). Endoscopic sclerotherapy was popularized in the 1970s and 1980s as the primary medical therapy for the control of initial variceal hemorrhage and the prevention of recurrent hemorrhage. Sclerotherapy for primary prophylaxis was extensively studied in randomized controlled trials (RCT) but two very well designed RCTs had to be terminated by the external monitoring committees because of a higher mortality in patients treated with sclerotherapy when compared to a medical control group (2). Most recently, sclerotherapy has essentially been replaced by endoscopic variceal ligation. However, endoscopic therapy does not alter portal pressure and is ineffective for nonesophageal variceal hemorrhage and portal hypertensive gastropathy. [ABSTRACT FROM AUTHOR]

To understand the possible strategies to prevent and treat esophageal variceal bleeding in cirrhotic patients, a brief summary of the mechanisms leading to variceal formation and rapture, as well as of the natural history of variceal bleeding, is necessary. [ABSTRACT FROM AUTHOR]

Variceal bleeding is is one of the more frequent and severe complications of cirrhosis. Mortality of a variceal bleeding episode has decreased in the last two decades from 40% to 20% owing to the implementation of effective treatments and i mprovement in general medical care. The management of variccs includes the screening and surveillance of cirrhotic patients to detect varices and its progression, which allows to establish effective prophylactic treatment, the treatment of the acute bleeding episode, and the prevention of variceal rebleeding. These should be based on the knowledge of the natural history and pathophysiology of variceal formation, progression, and rupture, which is the topic covered in this chapter. [ABSTRACT FROM AUTHOR]

Portal hypertension is defined as an increased pressure in the portal vein, but is better evaluated by the pressure gradient between the portal vein and the inferior vena cava, with a normal value lower than 5 mmHg. This gradient represents the real perfusion pressure within the portal and hepatic circulation, which is, under normal conditions, a high-flow/low-resistance system, considering the high portal blood flow (between 700 and 1000 mL/min). The various causes of an increased portal venous resistance, which are discussed in specific chapters in this book, are characterized by changes in the anatomic architecture (fibrous scars delineating nodules, distal venous thrombosis, collagenization of the space of Disse, and loss of the normal elasticity of the sinusoidal endothelium), changes in splanchnic hemodynamics (increased splanchnic blood flow), and changes in the intra-hepatic vascular resistance (vasoconstriction of the sinusoids related to the transformation of stellate cells into myofibroblasts). [ABSTRACT FROM AUTHOR]

The concept that chronic liver disease and portal hypertension are accompanied by widespread alterations in vascular tone that have important clinical consequences has developed over the last 50 yr and relevant mechanisms for systemic vascular changes are outlined in Chapter 5. However, it has been only over the last 15 yr that specific cardiopulmonary abnormalities associated with the presence of liver disease and portal hypertension have been widely appreciated and submitted to investigation. These abnormalities include cirrhotic cardiomyopathy and two distinct alterations in the pulmonary vasculature: the hepatopulmonary syndrome (HPS) characterized by microvascular dilatation and portopulmonary hypertension (POPH) characterized by vasoconstriction and remodeling. These entities may share pathogenetic mechanisms with systemic vascular alterations and with each other, although each has unique features. Here, we will address our current understanding of the pathogenesis of these cardiopulmonary complications of portal hypertension. [ABSTRACT FROM AUTHOR]

The cardiovascular system mainly develops during embryogenesis and only to a limited extent in postnatal life. This is a complex process that involves proliferation, migration, and differentiation of endothelial cells and, in a final step, recruitment of smooth muscle cells to form mature vessels. These are key events in the formation of new vessels that are spatially and temporally orchestrated through two very-well-differentiated mechanisms of new blood vessel formation: vasculogenesis and angiogenesis. [ABSTRACT FROM AUTHOR]

The mechanisms responsible for ascites formation in liver disease have aroused interest throughout the history of medicine. The Egyptians and Greeks believed that there was a relationship between liver disease and ascites. In 300 bc, Erasitratus of Cappadoccia described ascites as a consequence of "hardness of the liver" or liver disease. Several centuries later, physicians discovered the relationship between advanced liver disease and the development of ascites. Numerous studies addressing this issue have discovered that alterations in systemic and splanchnic circulation, as well as functional renal abnormalities, are the culprit of this dreaded complication of cirrhosis. Renal abnormalities occur in the setting of a hyperdynamic state characterized by an increased cardiac output, a reduction in total vascular resistance and an activation of neurohormonal vasoactive systems. This circulatory dysfunction, a consequence of intense arterial vasodilation in the splanchnic circulation, is considered a primary feature in the pathogenesis of ascites. The main factor responsible for local vasodilation seems to be the overproduction of extra-hepatic nitric oxide (NO). Splanchnic vasodilation by decreasing effective arterial blood volume causes homeostatic activation of vasoconstrictor and antinatriuretic factors triggered to compensate for a relative arterial underfilling. The net effect is avid retention of sodium and water as well as renal vasoconstriction in advanced stages. The mechanisms of ascites formation and sodium and water retention in patients with cirrhosis are discussed in this chapter. [ABSTRACT FROM AUTHOR]

This chapter will discuss some consequences of the hepatic hemodynamic disturbances that accompany portal hypertension. Fibrosis or other mechanisms that lead to a restriction of blood flow through the liver have enormous consequences to the entire cardiovascular system, endocrine processing system, and metabolic homeostasis in general. Many systems have evolved to compensate for the disturbances that result from portal hypertension but some regulatory systems result in a worsening of homeostasis as a result of confusion at the afferent end of the signaling process. For example, does the liver respond to a decrease in portal blood flow the same if the decrease is caused by vasoconstriction of the superior mesenteric artery and subsequent reduction in intestinal blood flow as it does if blood flow to the hepatic parenchymal cells is reduced because of portacaval shunt formation? This chapter represents a conceptual focus on our own areas of expertise with no attempt to provide a detailed literature review. Although the references arc few, more detailed references are available in the cited reviews and original articles. The approach taken is to evaluate the effects of increases and decreases in intra-hepatic portal flow on four vital hepatic areas: the hepatic blood reservoir, hepatic arterial blood flow, the hepatorenal reflex, and liver cell mass. [ABSTRACT FROM AUTHOR]

Portal hypertension due to cirrhosis is associated with a chronic hyperkinetic syndrome (1-3). This syndrome is characterized by elevated cardiac output, low arterial pressure, and low systemic vascular resistance (2,3). Splanchnic circulation is also hyperdynamic, i.e., blood flow is elevated and vascular resistance is low in arteries that supply splanchnic organs (1,4). Systemic and splanchnic alterations are interrelated: decreased systemic vascular resistance (systemic vasodilation) is largely due to the decrease in splanchnic arterial resistance (splanchnic vasodilation) (5). Finally, in cirrhosis, there is in vivo and ex vivo arterial hyporeactivity to different receptor-dependent and -independent vasoconstrictors (6-14). A hyperkinetic syndrome also occurs in extrahepatic portal hypertension (15), but it is less marked than that observed in cirrhosis. [ABSTRACT FROM AUTHOR]

The intrahepatic circulatory system consists of three major microvascular components, including: (1) the terminal portal venule (TPV) and hepatic arteriole; (2) the sinusoids (corresponding to the capillary bed); and (3) the terminal hepatic venule (THV). Each of the functional units in theory represents a putative resistance site. The major pre- and postsinusoidal components have been presumed to reflect contraction of vascular smooth muscle cells (TPV and THV). At the sinusoidal level, the major cellular components include endothelial cells and stellate cells, either of which could have a regulatory role. Dynamic changes in endothelial fenestrae have been demonstrated, and raise the possibility that sinusoidal endothelial cells could be involved in blood flow regulation (1). From an ultrastructural standpoint, stellate cells possess long and extensive cytoplasmic processes that essentially encircle many if not all sinusoidal endothelial cells (2,3). This anatomic relationship in the sinusoid suggests that stellate cells function as liver-specific pericytes (pericytes are smooth muscle-like cells that are felt to control capillary blood flow in a wide variety of tissues (4). [ABSTRACT FROM AUTHOR]

The term portal hypertension or, more strictly, portal venous hypertension, refers explicitly to a pathologic elevation of pressure in the veins that carry blood from the splanchnic organs (including the spleen) to the liver. Implicit in the working definition of portal hypertension is the necessary condition that the rise in portal pressure is not simply a consequence of an increase in systemic venous pressure, as might occur with congestive heart failure for example, but is intrinsically part of an increase in the pressure gradient between the portal venous inflow to the liver and its hepatic venous outflow. Increased pressure in the hepatic veins from any cause, such as hepatic vein thrombosis, a suprahepatic inferior vena cava web, right heart dysfunction, constrictive pericarditis, or any other comparable anatomic and/or functional lesion, elevates portal pressure above its normal baseline value and can cause splenomegaly and ascites. Notwithstanding, without secondary structural changes in the liver, however subtle, portal pressure elevation that is solely caused by impaired hepatic venous drainage does not lead to the formation of esophagogastric varices and the other pathophysiologic complications of an increased portal-systemic pressure gradient that are discussed in detail in this book. It is now self-evident that in health splanchnic blood percolates from the portal vein through low-resistance intrahepatic vascular channels (sinusoids) to the hepatic veins—but this was not always conventional wisdom. Ideas about the splanchnic and hepatic vascular architecture and blood flow have evolved over millennia (1), as have concepts of the nature of portal hypertension (2), although the time frame for the latter is only a couple of hundred years at most. [ABSTRACT FROM AUTHOR]