Chapter 1: Pathophysiology and Classification of Liver Cirrhosis and Portal Hypertension

Liver cirrhosis and portal hypertension (PHT) are common clinical encounters. Chronic liver disease and cirrhosis is the 12th leading cause of death in the United States, according to the Centers for Disease Control and Prevention (CDC). Deaths related to chronic liver disease and cirrhosis have increased 3.3% between 2009 and 2010.1,2 Liver disease continues to account for a substantial portion of health-care utilization in the United States and worldwide and is a significant cause of morbidity.³ Understanding the pathophysiology of cirrhosis and PHT is imperative to identify patients at highest risk for complications. Such knowledge would enable early intervention and potentially alter the clinical course of patients with chronic liver disease toward a favorable outcome. This chapter discusses the definition, pathophysiology, and classification of cirrhosis and PHT.

Liver Anatomy and Function

The liver is a wedge-shaped organ located in the upper right quadrant of the abdomen nestled just beneath the diaphragm. It is the largest organ in the body, weighing approximately 1400 g in women and 1800 g in men. The liver attaches to the diaphragm and anterior abdominal wall, via a series of ligaments. Its posterior and inferior surfaces lie over the kidney, adrenal glands, stomach, gallbladder, and colon. A fibrous sheath known as Glisson’s capsule encases the entire organ.^4,5

“Cantlie’s” imaginary line, extending from the gallbladder fossa to the inferior vena cava (IVC), grossly separates the liver into its right and left lobes. The right lobe makes up about 70% of the liver’s mass with the left lobe accounting for the remainder. In the 1950s, a French surgeon named Couinard further subdivided the liver into eight independently functioning segments based on the branching patterns of the portal triads and hepatic veins. Dr. Couinard numbered the segments clockwise beginning with the caudate lobe now designated as segment I ( Fig. 1.1).⁴ The left lobe contains the left lateral segment (segments II and III) and the left medial segment (segment IV) in addition to segment I. Four other segments make up the right lobe, with segments V and VIII comprising the right anterior lobe and segments VI and VII the right posterior lobe. Segment IV further subdivides into IVA and IVB. Segment IVA is cephalad and sits just below the diaphragm while IVB sits caudally and adjacent to the gallbladder fossa.

The liver forms the interface between the digestive system and the blood. It is the site where nutrients, drugs, and other substances entering the gastrointestinal tract undergo a first round of processing. In this sense, the liver acts as the gatekeeper by allowing passage of useful substances while eliminating others.⁶ Blood flows into the liver through a dual supply system that includes the hepatic artery and portal vein (PV). The PV delivers most of the hepatic blood (75%–80%) and provides the main route of entry for all materials absorbed by the intestine except for chylomicrons ( Fig. 1.1; Fig. 1.2).

The PV originates from the stomach, intestine, and spleen and terminates in the porta hepatis, where it divides into right and left branches carrying with it nutrient-rich but oxygen-poor blood to the liver.⁷ The hepatic artery arises from the celiac trunk and supplies the remaining 25% of the 1500-mL blood volume entering the liver each minute, which unlike portal blood is high in oxygen ( Fig. 1.1). Because of the dual blood supply, most patients can tolerate some obstruction of the PV or hepatic artery. In rare cases, thrombosis or some other type of occlusion caused, for example, by Banti’s syndrome or hepatocellular carcinoma (HCC), may create potentially lethal complications.⁶

Splenic and superior mesenteric veins unite to form the PV at the second lumbar vertebra from where it travels 6 to 9 cm before reaching the liver hilum, subsequently branching off into the left and right branches. From the celiac axis, the common hepatic artery ascends to the hepatoduodenal ligament and gives rise to the gastric, gastroduodenal, and proper hepatic artery, which then divides into left and right arterial branches at the liver hilum.^5,6 Intrahepatic branching from the PV, hepatic artery, and bile duct run together within the portal tract and terminate at the corners of the liver lobules. Within the lobules, interconnected plates of hepatocytes branch and join together rather freely to form a spongelike structure. Spaces between these plates contain the sinusoids, which are lined by endothelial and Kupffer cells.⁷ The Kupffer cells break down aged erythrocytes and recycle them, remove unwanted material entering from the portal system, and act as antigen-presenting cells in adaptive immunity. Other fat-storing cells called stellates reside in the perisinusoidal space and help maintain the extracellular matrix (ECM) of this compartment, which is composed of collagens (types I, II, and IV), among other molecules.⁸ The stellate cells store much of the body’s vitamin A and assist with local immunity. After cell injury, they become activated and induce collagen production, resulting in hepatic fibrosis.

Fig. 1.1 Illustrations of the different liver segments. IVC: inferior vena cava.

Fig. 1.2 Anatomy of the portal circulation. IVC: inferior vena cava; LGV: left gastric vein; LRV: left renal vein; PV: portal vein; SGV: short gastric veins; SMV: superior mesenteric vein; SV: splenic vein.

Blood flows from the periphery to the center of each lobule, carrying essential oxygen and nutrients with it. Distributing venules running within the lobules lead into the sinusoids and converge into veins at the lobule center and then eventually merge into hepatic veins, which empty into the IVC ( Fig. 1.1). Hepatocytes located near the lobule’s periphery and close to its blood supply carry out the more aerobic tasks such as protein synthesis; those less exposed to oxygen and nutrients at the lobular center play a larger role in detoxification and glycogen metabolism. Contrary to blood flow, bile drains from the center of the lobule to its periphery through the tubular canaliculi located at the interface of adjoining hepatocytes.⁵ At the periphery, the bile empties into special ductules composed of cholangiocytes and eventually reaches the intrahepatic bile ducts in the portal spaces. These ducts subsequently enlarge and unite to form the right and left hepatic ducts for transporting bile away from the liver ( Fig. 1.1).

The liver serves many functions.⁹ It plays a critical role in carbohydrate metabolism by storing glycogen, converting fructose and galactose to glucose, carrying out gluconeogenesis, and removing excess glucose from the blood as needed. Because of the glucose buffering action provided by the liver, hypoglycemia commonly occurs in individuals with liver failure. The liver also supports fat metabolism, manufactures lipoproteins and all major plasma proteins, except for the immunoglobulins, and preserves cholesterol homeostasis. Blood originating from the gut or elsewhere in the body is mostly detoxified by the liver. Kupffer cells trap and break down bacteria and other particulates, and the cytochrome p450 enzymes biochemically transform drugs and other foreign chemicals into metabolites, which are then excreted into the bile for elimination via the digestive tract. Bile secreted by the liver aids in the absorption of lipids and fat-soluble vitamins (A, D, E, and K) and serves as the vehicle for removing bilirubin.

Liver Cirrhosis: Definition, Classification, and Epidemiology

Definition of Cirrhosis

Cirrhosis is the end result of the common histologic pathway for a multitude of chronic liver diseases. The term cirrhosis was first introduced by Laennec in 1826, being derived from the Greek term scirrhus. It was used to describe the orange or tawny surface of the liver observed at autopsy.

Hepatic fibrosis is defined as an excess deposition of the components of ECM (i.e., collagens, glycoproteins, proteoglycans) within the liver. Fibrosis is the wound-healing response of organ systems, which in the liver can progress to the different stages of liver fibrosis and eventually cirrhosis. Sustained signals of inflammation associated with chronic liver disease are required for significant fibrosis to accumulate. Inflammation acts as the driving force for the ever-expanding accumulation of ECM components, eventually leading to cirrhosis and hepatic failure.⁸ A variety of factors, including infection, drugs, metabolic disorders, and immune-mediated liver injury, can stimulate the fibrogenic process, in turn marked by excessive synthesis and deposition of collagen in the ECM. Myofibroblasts drive matrix production in response to cytokines and growth factors released by activated Kupffer cells. At the early stage of fibrogenesis, certain proteolytic enzymes, such as the matrix metalloproteinases, can usually remove the excess matrix material, thereby reversing the process.8

Liver fibrosis is a dynamic process, resulting from the equilibrium between fibrogenesis and altered matrix degradation, and may be reversible before the establishment of advanced architectural changes in the liver. The excess deposition of ECM proteins disrupts the normal architecture of the liver, which alters the normal functioning of the organ, ultimately leading to PHT. This resultant PHT is the earliest and most important consequence of cirrhosis and underlies most of the clinical complications of the disease. Cirrhosis is defined histologically as a diffuse alteration in the liver architecture with the concomitant development of regenerative nodules. Clinicians consider cirrhosis as the end stage of a chronic condition, which becomes irreversible when presenting in advanced stages. Liver transplantation represents the only cure for patients who have reached this disease stage, with the expected 1- and 8-year survival rates set at 83% and 61%, respectively.¹⁰ Achieving cirrhosis reversibility depends on the stage of the disease and the level of which Kupffer cells and macrophages can retard progression. Reversing fibrosis therapeutically can be manifested by 2 different approaches. One approach involves treating the underlying disease such as autoimmune hepatitis, hepatitis B or C virus, or abstaining from alcohol. The second approach demands developing antifibrotic agents, which to date have shown success only in animal models.^8,11 There are challenges in defining validated endpoints, recruiting sufficient numbers of patients, and overcoming high risk of failure because clinical trials involving these agents have hampered antifibrotic drug development.

The etiology of cirrhosis ( Table 1.1) varies according to the region with hepatitis C and alcoholism predominating in Western countries and hepatitis B in parts of East Asia and Africa. Although the exact worldwide prevalence of cirrhosis is unknown, mortality rates from the disease show favorable trends in most areas of the world, especially in North America, Australia, and part of Southern Europe, likely because of declines in alcohol consumption in these regions.^12,13

Table 1.1 The Most Common Etiologies of Cirrhosis8,13

HBV: hepatitis B virus; HCV: hepatitis C virus; IBD: inflammatory bowel disease; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; PAN: polyarteritis nodosa; PBC: primary biliary cirrhosis; PSC: primary sclerosing cholangitis; UC: ulcerative colitis.

A poor correlation frequently exists between hepatic histologic findings and the clinical picture. Some patients with cirrhosis are completely asymptomatic and have a reasonably normal life expectancy. On the other hand, individuals may manifest a variety of severe symptoms of end-stage liver disease and have a poor survival. Common clinical features may stem from decreased hepatic synthetic function (e.g., coagulopathy), decreased detoxification capacity (e.g., portosystemic encephalopathy), or PHT (e.g., ascites).

Classification of Cirrhosis

Cirrhosis had been historically classified on the basis of a mixture of pathogenesis, morphologic appearances, and etiology. However, since then there has been a general recognition that such mixtures are confusing and unwarranted and that any one classification should be restricted to a specific base or axis. Hence, morphologic and etiologic classifications are considered as complementary rather than as alternatives. As such, the complete characterization of cirrhosis in an individual study would have to take into account the morphology, etiology, stage of evolution, disease activity, and complications of the disease.¹⁴ Based on this, the subdivision of cirrhosis is better described as a characterization rather than a classification. Historically, this morphologic categorization has been made as micronodular, macronodular, or mixed type determined to some extent by the underlying disease process. This may allow for the different patterns to be studied epidemiologically, in turn allowing for their correlation with various etiologies.¹⁴

1. Micronodular pattern: This describes a cirrhotic liver in which the vast majority of nodules are smaller than 3 mm in size. The nodules in such cirrhotic livers rarely contain portal tracts or central veins. Early in the course of disease evolution, micronodules tend to predominate; in a later stage, larger nodules may develop. Examples of cirrhosis with this type of nodular pattern include those related to steatosis (alcoholic or otherwise), bile ductal and venous outflow obstruction, and hemochromatosis. These livers are usually normal in size or even enlarged.¹⁴

2. Macronodular pattern: Most nodules in this type of cirrhosis are larger than 3 mm in size, with the size varying considerably, and some nodules being several centimeters in size. Nodules in this type of cirrhosis may contain portal tracts and central veins, although their relationship to each other is not maintained architecturally. The separating fibrous septae may be of the fine, reticulate type or the broad, thickened variety. Examples of this cirrhosis with this type of nodularity include that related to hepatotropic viruses (hepatitis B and C), Wilson’s disease, and autoimmune hepatitis. These livers are usually shrunken but may be normal in size.¹⁴

3. Mixed pattern: The nodules in this type are both micronodular and macronodular, approximately in equal proportions.¹⁴

Epidemiology of Cirrhosis

The estimated prevalence of cirrhosis, as identified from autopsy studies, ranges from 4.5% to 9.5% of the general population, reflecting hundreds of millions of patients affected with cirrhosis worldwide.^15,16 However, the precise incidence or prevalence of cirrhosis is difficult to ascertain because cirrhosis is often clinically silent.¹⁷ Up to 40% of patients with cirrhosis are asymptomatic and may remain so for more than a decade.18,19 Currently, a liver biopsy is required to establish the diagnosis of cirrhosis. However, the recent availability of accurate, validated, noninvasive diagnostic tools such as FibroScan and FibroTest may make the specter of population screening in the near future a feasible option.²⁰

Nonetheless, in the absence of comprehensive and measurable indices for measuring the incidence and prevalence of cirrhosis in the general population, much of the epidemiologic data for this condition have been derived from disease-related mortality. Understandably, though, for a variety of reasons, the death rate is not always a valid surrogate for measuring the prevalence of cirrhosis, making it difficult to estimate the true prevalence and burden of the disease, especially in the absence of hepatic decompensation.²¹

In 2001, 771,000 people were estimated to have died from cirrhosis, ranking it 14th and 10th as leading cause of death in the world and in developed countries, respectively.²² Worldwide, deaths from cirrhosis have been projected to increase, making it the 12th leading cause of death in 2020.²³ According to a World Health Organization (WHO) database that incorporates mortality data from 41 countries, age-adjusted mortality rates from cirrhosis were the highest in some countries in Central and South America and in southern Europe in the early 1980s.²⁴ In southern European countries, mortality rates in the early 2000s decreased by more than 50% compared with earlier decades, but rates in Northern European countries reportedly show a gradual yet continued increase.^25,26 Chronic liver disease and cirrhosis is the 12th leading cause of death in the United States, according to the CDC. Deaths related to chronic liver disease and cirrhosis increased 3.3% between 2009 and 2010.^1,2 Liver disease continues to account for a substantial portion of health-care utilization in the United States and worldwide and is a significant cause of morbidity.³

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