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Surgical resection is the only therapeutic approach that produces good survival results for patients with intrahepatic cholangiocarcinoma. However, advanced disease stage and infiltration to vascular structures often require extended and complicated hepatic resections, such that curative operation is not always possible. [ABSTRACT FROM AUTHOR]

The role of adjuvant and palliative chemo- and radiotherapy in the treatment of intrahepatic cholangiocarcinoma (ICC) is controversial. There are no prospective and randomised studies or large series that provide conclusive indications regarding the efficacy of these therapies in ICC. Moreover, the majority of oncologic papers in the literature that address this topic include intrahepatic and extrahepatic (hilar, middle and distal) cancers and even gallbladder carcinoma. Consequently, specific data for each localisation concerning treatment indication, dosage, type of approach and results are lacking. [ABSTRACT FROM AUTHOR]

An analysis of the results of surgery for intrahepatic cholangiocarcinoma (ICC), as reported in the literature is difficult, because the patient-selection criteria are not homogenous, and the series of cases are limited by the rarity of the disease and the prolonged amount of time needed for data collection. Prognostic factors related to the characteristics of the neoplasm were analysed previously. Herein, only the early and late results of surgical operation are considered. [ABSTRACT FROM AUTHOR]

At the time of diagnosis, patients with intrahepatic cholangiocarcinoma (ICC) are frequently found to have disease beyond the limits of surgical therapy, such the presence of intrahepatic satellite nodules, vascular invasion, or regional lymph-nodes metastases. In such patients, the resectability rate varies from 19 to 74% [1-4] Moreover, exploratory laparotomy or R1 resection has a poor prognosis, with median patient survival of 5 months and postoperative complications of 17% [4] Consequently, palliative resection is not justified; instead, there is clearly a need to improve the assessment of resectability, in order to avoid unnecessary laparotomy and to develop an aggressive approach to obtain complete resection (R0). [ABSTRACT FROM AUTHOR]

The staging systems of intrahepatic cholangiocarcinoma (ICC) are based on pathological findings. The most common classification systems are the TNM UICC/AJCC classification (6th edn.) 2002 [1] and the TNM classification of the Liver Cancer Study Group of Japan (LCSGJ) (2nd English edn.) 2003 [2]. [ABSTRACT FROM AUTHOR]

The main prognostic factors of intrahepatic cholangiocarcinoma (ICC) are: gross type (size, multifocality, vascular, serosal and biliary involvement), local extent, lymph-node involvement and microscopic and molecular biological patterns. [ABSTRACT FROM AUTHOR]

About 20-30% of cholangiocarcinomas appear as nodular intrahepatic mass [1,2]: however, intrahepatic cholangiocarcinomas may also be polypoid or focally stenotic. Excluding the nodular intrahepatic type, about three-fourths of cholangiocarcinomas manifest as a focal stricture and one-fourth are polypoid or diffusely stenotic [3]. [ABSTRACT FROM AUTHOR]

The principal end-point of treatment of cholangiocarcinoma is resection with negative margins, but this goal fails in one-half to two-thirds of case [1,2]. Only Nimura's group reports a resectability rate of 80% [1-3]. Therefore most patients with cholangiocarcinoma need palliative treatment of jaundice; moreover, local recurrence with relapse of jaundice, which is the most frequent problem after surgery, also requires palliation. [ABSTRACT FROM AUTHOR]

Local recurrence is a frequent event after surgical resection for cholangiocarcinoma; to achieve better control radiotherapy has been proposed, alone or associated with chemotherapy [1], although other authors have suggested applying chemotherapy alone after surgical resection. However, the role of these treatments is not standardized throughout the various centers that manage biliary neoplasms. [ABSTRACT FROM AUTHOR]

The development of curative surgery for hilar cholangiocarcinoma is based on the precise knowledge of anatomy of the hepatic hilus and of the frequent anatomical variations that may be encountered. For these reasons it would be useful to point out some anatomical details, with particular regard to the anatomy of the hilar and caudate lobe area that are the crucial point of this surgery. Biliary ducts, arterial and portal vessels that are covered by connective tissue arising from the fusion of Glisson's capsule, in the intrahepatic portion, and peritoneum of the hepatoduodenal ligament, in the extrahepatic portion, constitute the plate system. In this space several lymphatic vessels, nerves and a small vascular network are present (Fig. 1). [ABSTRACT FROM AUTHOR]

Curative treatment of hilar cholangiocarcinoma leads to a major reduction of hepatic function due to the need for extended hepatectomy with biliary tract resection; therefore, it is exposed to the risk of postoperative hepatic failure [1,2]. Makuuchi [3] can take the credit, for introducing preoperative embolic occlusion of portal branches (PVE) in patients with hilar cholangiocarcinoma to stimulate compensatory hypertrophy of the future remnant liver (FRL) and prevent the sudden increase of portal pressure after hepatectomy. Diversion of portal flow following PVE entails an improvement of the functional reserve of residual liver and allows extending the indications for surgical therapy even in patients with a marginal hepatic function. [ABSTRACT FROM AUTHOR]

One of the most important factors of morbility in hilar cholangiocarcinoma is the presence of jaundice as a consequence of physiopathologic changes following cholestasis, described in Chap. "Preoperative Assessment of Liver Function". The close association of this complex disease with high operative risk, determined by increased postoperative mortality and morbidity, has led to the belief that preoperative drainage of jaundice would have decreased the risk of a major resection (i.e. pancreaticoduodenectomy or hepatic resection). [ABSTRACT FROM AUTHOR]

Many elements contribute to the optimal selection of patients who will undergo surgery for hilar cholangiocarcinoma, including: Improvement of the preoperative diagnosis in the definition of size, site and tumour extent related to intrahepatic vascularisationFindings of the intraoperative workupKnowledge of the biological behavior of the tumourEffects of biliary obstruction and jaundiceEffects of parenchymal inflammatory process and of cholangitis on clinical course and prognosisNutritional stateAdjuvant therapy [ABSTRACT FROM AUTHOR]

Hilar cholangiocarcinoma often presents in an advanced stage when the disease is not resectable. Despite the evolution of imaging techniques such as CT, MRI, ultrasonography and PET scan, it is often difficult to identify small liver and peritoneal metastases at preoperative staging, and the precise extent of the disease along the hepato-duodenal ligament is difficult to determine. In about 25-46% of patients the condition of non-resectability is confirmed only at laparotomy[1 2] [ABSTRACT FROM AUTHOR]

The only successful treatment of cholangiocarcinoma is curative resection; evaluation of biliary involvement, either longitudinal or radial, loco-regional diffusion and presence of distant metastases are important for planning the therapeutic strategy. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma is a malignant tumour composed of cells resembling those of the bile ducts. According to WHO classification[1] the term cholangiocarcinoma is reserved for carcinomas arising in the intrahepatic bile ducts. For this reason, tumours arising from extrahepatic bile ducts should be designated as extrahepatic bile duct carcinomas. However clinical and pathological differentiation of intrahepatic from extrahepatic bile duct cancers can be difficult. Cancers arising from the bile duct epithelium of the right and left hepatic ducts and at the bifurcation are also considered cholangiocarcinomas and are called "hilar cholangiocarcinomas". Intrahepatic (or peripheral) cholangiocarcinoma is a primary liver cancer and can arise from any portion of the intrahepatic bile duct epithelium[2]. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) is a standard therapeutic approach for the treatment of end-stage acute and chronic liver disease of various etiologies including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Results of LT for these autoimmune liver diseases are good, with a patient survival of 80 to 85% at 5 yr after LT. Transplant recipients, however, experience various complications, such as acute and chronic rejection, recurrence of disease, and chronic hepatitis. Recurrence of disease on the graft may be influenced by the genetic background of the recipient as well as other factors such as the degree of immunosuppression. Interestingly, autoimmunity and autoimmune disease can occur de novo following LT even for non-autoimmune liver diseases. However, the mechanisms that lead to autoimmunity or recurrence of autoimmune liver diseases after LT have not yet been defined. This chapter focuses on recurrence and occurrence of autoimmune diseases in transplanted livers. [ABSTRACT FROM AUTHOR]

In the Western world, hepatitis C virus (HCV)-related end-stage liver disease is the leading indication for liver transplantation (LT). Based on the presence of HCV RNA in the serum, recurrence is immediate and universal, with nearly all patients developing some evidence of histological recurrence. (Acute hepatitis occurs in 60-80% at a median of 4-6 mo post transplantation and chronic hepatitis in 80-100% by 1-4 yr [1-3]. Reports indicate that 20 to 40% of recipients with recurrent HCV disease progress to allograft cirrhosis within 5 yr compared with less than 5% of nontransplant chronic HCV patients; thus, the natural history of recurrent HCV is accelerated compared with the nontransplant setting (4-5). Once cirrhosis develops in the transplant setting, two-thirds will develop decompensation (ascites, variceal hemorrhage, encephalopathy) within 3 yr (15-6). The development of decompensation is associated with a very poor outcome, with only about 10% surviving for 3 yr. Despite this accelerated course, approximately a third of patients demonstrate only minimal fibrosis after 5 yr of follow-up (7). The use of protocol liver biopsies is justified in patients transplanted for HCV based on the increasing probability of severe histological findings (stage 3 or 4) (8-9). [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic pathology ranging from nonalcoholic fatty liver (NAFL; steatosis) at the most clinically benign end of the spectrum to cirrhosis at the opposite extreme, where most liver-related morbidity and mortality occur. Nonalcoholic steatohepatitis (NASH) is a lesion of intermediate severity. NASH is characterized by overt hepatocyte injury and death. It is often accompanied by hepatic infiltration with inflammatory cells (1). Some individuals with NASH gradually accumulate hepatic fibrosis, and eventually develop cirrhosis (2). Over time, hepatocellular carcinomas emerge in a small proportion of individuals with NAFLD-related cirrhosis (3). The pathogenesis of NAFLD is the subject of much research because NAFLD is one of the most common causes of chronic liver disease, particularly in countries such as the United States that are in the midst of an obesity epidemic (4,(5)). [ABSTRACT FROM AUTHOR]

Advances in surgical techniques and ancillary care, in parallel with advances in clinical immunosuppression, are the reasons for the enormous success that has been achieved to date in solid organ transplantation. Such success has also provided a considerable boost in the advancement of our knowledge of immunological tolerance in allogeneic and (relatively more recently) xenogeneic transplantation. Thus, success in human organ transplantation has provided the incentive and foundation for unraveling some of the mysteries of organ transplant acceptance vs failure and has been the foundation for the science of transplantation immunology, which includes to a large extent studies of the fundamental mechanisms of immunological tolerance and the understanding of the concepts involved in self- vs nonself-discrimination. [ABSTRACT FROM AUTHOR]

For the great majority of liver allograft recipients, immunosuppression is required life-long to prevent rejection. Spontaneous tolerance does develop in a small number of recipients. Although major advances have occurred in the numbers and modes of action of immunosuppressive agents available for clinical use, the modes of action of these agents is relatively wide and nonspecific: thus, the need to prevent rejection must be balanced against the risks of immunosuppression, which may be general (such as the increased risk of infection and some malignancies) or drug specific, such as the renal failure associated with the calcineurin inhibitors. Despite advances in care, death associated with rejection remains a concern (Fig. 1). [ABSTRACT FROM AUTHOR]

In no other medical situation is a patient at risk for so many liver diseases as during a hematopoietic cell transplant (HCT). The preparation for transplant includes either liver-toxic myeloablative therapy or intense immunosuppression that allows host microchimerism with allogeneic donor hemaotpoietic cells. As a result, patients are profoundly immunosuppressed until engraftment of infused hematopoietic stem cells; full recovery of immune function is often delayed for a year or longer; and infection with viruses, fungi, and bacteria is common. Recipients of allogeneic stem cells are also at risk for graft-versus-host disease (GVHD) involving the liver, and some patients who have received autologous or syngeneic stem cells may also develop bile duct injury resembling GVHD. Thus, a patient undergoing transplant is at risk for toxic, infectious, and immunologic liver injury. Jaundice after transplant is an ominous prognostic sign, with total serum bilirubin in the 4 to 7 mg/dL range conferring 50% mortality and bilirubin values more than 10 mg/dL conferring more than 70% mortality at d 200 posttransplant (1). Fortunately, the incidence of serious liver injury following transplant has fallen dramatically over the last decade, for several reasons. [ABSTRACT FROM AUTHOR]

It is increasingly clear that, regardless of etiology, inflammatory and immunological mechanisms are involved in the pathogenesis of virtually all hepatobiliary diseases and hepatic fibrogenesis. Studies of immunopathogenetic mechanisms have identified multiple therapeutic targets in both the innate and adaptive immune responses that portend the future ability to prevent hepatic allograft rejection and control progression of chronic viral hepatitis, alcoholic and nonalcoholic fatty liver disease, drug-induced hepatotoxicity, graft-versus-host disease (GVHD), and autoimmune and immune-mediated inflammatory diseases (IMIDs) of the liver. The current availability of multiple immunosuppressive and anti-inflammatory drugs with distinct, complementary sites of action provides the opportunity and impetus to study their therapeutic potentials in both transplant and nontransplant settings. Concurrent immunosuppression of several specific sites involved in immunopathogenesis may ultimately enhance efficacy, while minimizing the dosedependent toxicities of individual drugs. Thus, the goals of this chapter are to review the mechanism(s) of action of established and new immunosuppressive and anti-inflammatory agents and to discuss their current and future therapeutic potentials in the prevention of hepatic allograft rejection and nontransplant hepatobiliary diseases. [ABSTRACT FROM AUTHOR]

The incidence of adverse drug reactions to any given drug may be relatively low, but the total clinical impact of adverse drug reactions is actually substantial because of the number of drugs used and the number of patients treated. It has been estimated that around 7% of patients experience serious adverse drug reactions and that adverse drug reactions are the 4th to 6th leading cause of death (1). Hundreds of drugs and chemicals have been associated with hepatotoxic effects (1-5), and drugs are the most common cause of acute liver failure in the United States and Europe (6,7). In addition, serious druginduced hepatotoxicity has become one of the most frequent causes of postmarketing withdrawal, labeling changes, and restriction in use of medications (Table 1) (8-10). [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is a common cause of liver disease. It accounts for approximately one-half of cases of acute liver failure and significant numbers of deaths in the United States and many other countries (1-5). An estimated 1000 or more drugs have been implicated in causing liver disease on more than one occasion (5). Clinically, DILI mimics all forms of liver diseases, with the liver damage varying in severity from mild and transient increases in serum aminotransferases to fulminant hepatic failure. This represents an important diagnostic and therapeutic challenge for physicians. Idiosyncratic drug toxicity refers to toxic reactions occurring in a small subset of patients; it usually cannot be predicted during preclinical or early phases of clinical trials. The occurrence of idiosyncratic drug hepatotoxicity is also a major problem in all phases of clinical drug development and the most frequent cause of postmarketing warnings and withdrawals (1-5). DILI is usually initiated by a toxic drug and its metabolite, followed by either immune-mediated mechanisms and/or intracellular biochemical mechanisms of hepatocytes (2-5). [ABSTRACT FROM AUTHOR]

Acute liver failure is characterized by the sudden onset of liver failure in a patient without evidence of chronic liver disease. This definition is important, as it differentiates patients with acute liver failure from patients who suffer from liver failure owing to end-stage chronic liver disease. [ABSTRACT FROM AUTHOR]

Alcohol is a widespread, socially-accepted hepatoxin in most countries. Approximately two-thirds of the adult U.S. population drinks at least 18 drinks a year (1), and 7 to 10% of the US population meet the diagnostic criteria for alcohol abuse or alcoholism (2). In industrialized countries, up to 66% of all chronic liver disease is related to alcohol use (3). Alcohol accounts for 40 to 50% of all deaths owing to cirrhosis (1) and remains the most common cause of liver-related mortality (4). However, alcoholic liver disease (ALD) represents a spectrum of histologic changes and clinical outcomes, as shown in Fig. 1. [ABSTRACT FROM AUTHOR]

Many hypotheses have been put forward to explain ethanolinduced liver damage, including direct and indirect toxicity. Despite many years of intensive research, the molecular mechanisms involved in the toxicity of this simple compound have still not been fully clarified. Initial studies investigated the direct toxic effects of ethanol on tissues, but it is now believed that the products of ethanol metabolism are the major factors causing alcoholic liver disease (ALD). The metabolic products and metabolic events induced by alcohol ingestion are varied in nature and vast in scope. Major research interest has focused on the effects of aldehyde production, oxygen radical formation, mitochondrial membrane permeability defects, endotoxins, and infectious agents as factors in hepatocellular dysfunction and cell death. At the same time, increasing evidence suggests that immune-mediated mechanisms are involved in ALD. [ABSTRACT FROM AUTHOR]

The term autoimmune liver diseases in its common use comprises three types of disorders, namely, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), as well as their overlap syndromes. Previous reports (1,2) indicated an incidence (identified patients) of 1 to 2:10.000 for AIH, 1:10.000 for PBC, and 0.5:10.000 for PSC. However, there is a pronounced probability for significantly higher case numbers of unidentified autoimmune liver diseases owing to low severity of symptoms in the early stages, especially for PBC and PSC and also most of AIH cases. There is a predisposition of women to the development of AIH (3-4:1 female/ male patients) and PBC (9:1), whereas PSC predominantly affects men (1:2). [ABSTRACT FROM AUTHOR]

The term "overlap syndrome" has been introduced to the field of hepatology to describe variant forms of autoimmune hepatitis (AIH) which present with the characteristics of AIH on the one hand and primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) on the other hand. There is still controversy over whether these "overlap syndromes" form distinct entities or are only variants of the major autoimmune hepatopathies. Standardization of diagnostic criteria for overlap syndromes has not been achieved so far, and misuse of the term "overlap syndrome" is common in clinical practice (1). [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) in childhood is an inflammatory liver disease characterized histologically by a dense portal tract mononuclear cell infiltrate and serologically by the presence of non-organ- and liver-specific autoantibodies and increased levels of IgG, in the absence of a known etiology. AIH usually responds to immunosuppressive treatment, which should be instituted as soon as a diagnosis is made. In pediatrics, as well as in young adults, AIH often presents acutely and has a more aggressive course than in older patients. In children there are two liver disorders in which the liver damage is likely to arise from an autoimmune attack: classical AIH and AIH/sclerosing cholangitis overlap syndrome (ASC). A possible autoimmune pathogenesis has also been postulated for the so-called post liver transplant de novo AIH, a condition originally described in children and later confirmed in adults. [ABSTRACT FROM AUTHOR]

Autoimmune hepatitis (AIH) is an inflammatory liver disease with a strong female preponderance, characterized by elevated levels of transaminases and immunoglobulin G (IgG), seropositivity for organ and non-organ-specific autoantibodies, and a histological picture of interface hepatitis. The major pathogenic mechanism is believed to be immune reaction against host liver antigens. AIH responds well to immuno-suppressive treatment. The diagnosis should be made as soon as possible because symptomatic AIH, if left untreated, progresses to liver failure requiring transplantation. The development of a panel of marker autoantibodies has allowed the subdivision of AIH in distinct types, type 1 (AIH-1) being positive for antinuclear (ANA) and/or anti-smooth muscle antibodies (SMA) and type 2 (AIH-2) being positive for anti-liver-kidney microsomal antibody type 1 (anti-LKM-1). [ABSTRACT FROM AUTHOR]

Sclerosing cholangitis comprises a spectrum of chronic cholestatic disease of the hepatobiliary system characterized by hepatic inflammation, biliary strictures, and fibrosis. The best studied form is primary sclerosing cholangitis (PSC), which is a slowly progressive disorder eventually resulting in concentric obliterative fibrosis of the bile ducts, biliary cirrhosis, and, in approximately 30% of patients, cholangiocarcinoma. There is a strong association between PSC and inflammatory bowel disease (IBD), with between 75 and 80% of PSC patients of northern European origin having underlying IBD (1,2). Ulcerative colitis is the most common form of IBD associated with PSC, and, interestingly, when considering the pathogenesis of the disease, those PSC patients who have Crohn's disease almost invariably have disease predominantly affecting the colon. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology characterized by hightiter serum antimitochondrial autoantibodies (AMAs) and an autoimmune-mediated destruction of the small and mediumsized intrahepatic bile ducts. From a clinical standpoint, PBC is a peculiar, yet representative, autoimmune disease (Table ). It affects women more frequently than men, with a female-to-male ratio of 9 to 1, and the average age at diagnosis is within the fifth and sixth decades of life, with exceptional cases described in pediatric ages. Epidemiological data indicate a geographical pattern of PBC prevalence and incidence rates, which are higher in northern countries (England, Scandinavia, northern United States). The diagnosis of PBC is made when two of three criteria are fulfilled, i.e., presence of serum AMAs, increased enzymes indicating cholestasis (i.e., alkaline phosphatase) for longer than 6 mo, and a compatible or diagnostic liver histology. Clinical symptoms include fatigue, pruritus, and jaundice. The progression of PBC varies widely for unknown reasons, as represented by certain patients remaining asymptomatic and others reaching liver failure at young ages. [ABSTRACT FROM AUTHOR]

Autoimmune liver diseases are not classical Mendelian autosomal or sex-linked genetic traits. However, there is considerable evidence that our genes play a significant role in determining individual susceptibility to (and progression of) these diseases. In the absence of a "simple" pattern of inheritance, attributable to a single gene locus, autoimmune liver diseases are classified as "genetically complex." Variation at a gene locus gives rise to a number of alleles. When alleles are rare within a population (less than 1%), they are referred to as mutations. When alleles are common, they are referred to as polymorphisms. To the geneticist, "complex traits" are those in which one or more genes (alleles) acting alone or in concert increase or reduce the risk of a disease or syndrome (1). In Mendelian diseases, the permissive alleles are rare in the normal population (i.e., mutations), whereas in complex diseases, the permissive alleles are common (i.e., polymorphisms). Furthermore, it appears that alleles that are permissive for autoimmunity are not themselves abnormal and may be present in a large proportion of the "healthy" population. This finding suggests that inheritance of a specific allele or group of alleles is neither necessary nor sufficient for disease genesis but will simply increase (or reduce) the likelihood (risk) of disease. [ABSTRACT FROM AUTHOR]

Hepatitis A, B, and C virus (HAV, HBV, and HCV) infections can be associated with various extrahepatic manifestations, which can be seen in both acute and chronic infections. Extrahepatic manifestations in acute hepatitis are often seen in hepatitis B, less often in hepatitis C, and only occasionally in hepatitis A. Clinically important extrahepatic manifestations are most often seen in chronic hepatitis C infection. Therefore some of the causative pathomechanisms are explained in more detail for HCV, e.g., the autoimmune syndromes and cryoglobulinemia. [ABSTRACT FROM AUTHOR]

The hepatitis C story involves molecular biologists, virologists, immunologists, mathematicians, epidemiologists, and clinicians. It is one of the most impressive examples in modern medicine in which a combination of expertise from very different fields helped to identify the cause of a major disease and led to the development of effective therapies. [ABSTRACT FROM AUTHOR]

The hepatitis B virus (HBV), a member of the Hepadnaviridae family, is a hepatotropic noncytopathic DNA virus that, despite the presence of an effective prophylactic vaccine, is estimated to infect 300 million people, with a particularly high prevalence in Asia and Africa (1). [ABSTRACT FROM AUTHOR]

Hepatitis A virus (HAV) is a nonenveloped small RNA virus in the hepatovirus genus of the picornavirus family (1) and is the most common defined cause of viral hepatitis worldwide. In the United States, the number of notified cases annually is around 23,000, but estimates of the real number of cases of clinical disease range up to 75,000 per year. The infection is usually transmitted via a fecal-oral route and is associated only with acute forms of viral hepatitis. Much higher virus titers are found in bile and in stool than in blood. Whereas infection in children and the very young is most often unrecognized, most infections in adults are symptomatic and associated with acute icteric hepatitis. Risk factors for a fulminant clinical course include an age greater than 40 yr and some forms of preexisting liver disease. As the incidence of HAV infection among children and adolescents has declined in many countries owing to improved socioeconomic status, these individuals are at increased risk of disease later in life because of the lower prevalence of immunity (2). Diagnosis is made on the medical history, clinical features, and a positive anti-HAV-IgM antibody. [ABSTRACT FROM AUTHOR]

A vast spectrum of illness can result from infection owing to M. tuberculosis, Mycobacterium avium, and Mycobacterium leprae, but the representative organism of this genus is M. tuberculosis. M. tuberculosis infection is estimated to infect 1.6 billion people worldwide or approximately one-third of the world's population, killing about 3 million people each year (1,2). More than 90% of tuberculosis (TB)-related deaths occur in developing countries, and the disease has huge social and economic costs. Nations with a high prevalence of HIV have witnessed the greatest increase in the number of TB cases (3). Diffusion of the infection depends on inhalation of aerosols from individuals with pulmonary infection. The development of the disease occurs in less than 10% of infected persons and is significantly increased by impaired cell-mediated immunity. Liver involvement varies with the stage of pulmonary or systemic infection, being common in the case of miliary disease. However, it had been demonstrated that up to two-third of patients with primary pulmonary TB have some kind of liver involvement (4). [ABSTRACT FROM AUTHOR]

Most tumors of the liver arise from hepatocytes giving rise to hepatocellular carcinoma (HCC), or biliary epithelial cells giving rise to cholangiocarcinoma (CCA), or the tumors are metastatic, often from colon cancer. HCC and CCA are associated with other diseases of the liver, which often incite chronic inflammation. In the case of HCC, chronic viral hepatitis is often present, although other non-inflammatory liver diseases such as hemochromatosis and α1-antitrypsin deficiency also increase the risk of HCC. Inflammatory conditions of the biliary tract, including liver fluke infestation and primary sclerosing cholangitis, are associated with CCA. These findings suggest that the immune response plays an important role in the development of many of these tumors. However, the immune response to tumors may be equally important in preventing the development or progression of liver tumors. Furthermore, directing an immune response against tumor cells has been a goal of many cancer vaccine trials, with some promising results. [ABSTRACT FROM AUTHOR]

The liver is the largest organ in the human body. It synthesizes and processes essential circulating proteins, detoxifies endogenous and exogenous substances, engages in bile formation for the elimination of amphiphilic and water-insoluble molecules from the body, and constitutes a unique immunological site. Its location astride the spanchnic and systemic circulation creates a critical role for immunological processing of antigens in the splanchnic circulation. The liver anatomic structure is well suited for these biological functions, as it contains 80% of the resident macrophages in the body, Kupffer cells, and has a substantial resident population of lymphocytes and dendritic cells. The liver also has a unique ability to be subject to simultaneous damage from multiple sources, owing in part to the propensity of humans to expose themselves to infectious agents. Hepatic injury may arise from the following general causes: infectious; intrinsically immune-mediated; drug-induced (including alcohol); metabolic (including nonalcoholic fatty liver disease); mechanical (especially vascular); and environmental. The immune response, directly or indirectly, plays a crucial role in hepatocellular damage. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis represents a ubiquitous response of the liver to acute or chronic injury. Tremendous progress in understanding the pathophysiology of this wound-healing response has led to realistic expectations for treating fibrosis in patients with chronic liver disease owing to either viral hepatitis or metabolic or autoimmune diseases, among others. There has been continued clarification of the cellular source of extracellular matrix (ECM) in hepatic fibrosis, major advances in understanding signaling and transcriptional events, and exciting insights into the biology of fibrosis progression and resolution (see refs. 1-4 and references therein for more general reviews). [ABSTRACT FROM AUTHOR]

Generally speaking, autoantibodies are B cell generated and also serologically detectable evidence of a loss of tolerance against cellular self structures, which can originate from different subcellular compartments (1-3). Autoantibodies have been described that target membrane-bound proteins of the cell and nuclear membranes and that reside in the cytoplasm or in other organelles such as the endoplasmic reticulum (Table 1) or mitochondria (Table 2). The proteins that are targeted include structural components such as actin or myosin and functional proteins such as metabolizing enzymes including cytochrome P450 (CYP), UDP-glucuronosyltransferases (UGTs), or pyruvate dehydrogenase (PDH). The identification of a specific epitope has stimulated research in an effort to characterize autoantibody-autoantigen reactivity as a tool to gain insight into the mechanisms of and the players involved in autoimmunity. However, the demonstration of a specific autoepitope reactivity does not preclude the possibility of crossreactivity of an exogenous antigen recognized by the immune system that displays homology with endogenous proteins of the body. [ABSTRACT FROM AUTHOR]

Cytokines are soluble peptides secreted by several kinds of cells, they mediate many immune and inflammatory reactions, and regulate several biochemical processes in and around the cells that produce them. They may act on different cell types (pleiotropic effects) and have overlapping effects (redundancy); furthermore, their action may be local or systemic. In most tissues, including the liver, constitutive production of cytokines is absent or minimal. However, as physiologic and pathologic stimuli activate cells, the production of these molecules increases, and they orchestrate the tissue's response to the stimulus. Phenotype of the immune response is a function of the repertoire of cytokines produced in the early phases (1). [ABSTRACT FROM AUTHOR]

The liver's unique location between the gastrointestinal tract and peripheral lymphoid organs and its fenestrated endothelium allow contact with many antigenic substances. These consist of dietary proteins transported from the gut via the portal vein, products of intrahepatic metabolism, and bacterial and viral liver pathogens. According to the different origin of these antigens, the liver has the unique ability to induce either tolerance or inflammatory reactions (1,2) (Table 1). Furthermore, the liver can actively modulate ongoing immune reactions: the intrahepatic inflammatory infiltrate can be increased by chemotactic attraction and activation of leukocytes (3) and decreased by induction of apoptosis of activated intra-hepatic lymphocytes (4). These dual and apparently oppos-4 ing functions are important to understand the mechanisms of tolerance to oral and allograft antigens and the pathogenesis of liver diseases caused by parasitic and viral pathogens. This chapter addresses the unique role of intrahepatic natural killer (NK), natural killer T (NKT), and T cells during this process. [ABSTRACT FROM AUTHOR]

Whereas innate immunity can provide the initial defense against infections, completely effective immunity to an invading microbial organism typically requires an adaptive immune response specific to the invader. Adaptive immune responses in the liver contribute both to effective defense against invading microbes and to a variety of pathologic states. The term adaptive immunity refers to lymphocyte-mediated immune defense tailored to a specific microbial invader. Adaptive immunity can be classified into humoral immunity and cell-mediated immunity, mediated principally by B and T lymphocytes, respectively. Antigens are structures found on microbes that are recognized as foreign by B or T lymphocytes. Antigens elicit specific responses from the lymphocytes expressing cognate antigen receptors. Such specific responses include both clonal proliferation and lymphocyte differentiation into specialized effector cell types with important functions serving to fight microbes. Such functions include the release of antibody (B cells), the killing of infected cells (cytotoxic T cells), and extracellular release of signaling molecules (i.e., cytokines) that can act in an autocrine, paracrine, or endocrine fashion to elicit responses from other immune and nonimmune cells. [ABSTRACT FROM AUTHOR]

The liver is an important site of infectious, parasitic, autoimmune, and malignant diseases. Immune responses and their modulation within the liver are critical to the outcome of these conditions and also in liver transplantation. Immune responses in, or elicited by, the liver can result in tolerance rather than immunity. Hepatic tolerance was demonstrated initially by the acceptance of liver allografts across major histocompatibility complex (MHC) barriers, without immunosuppressive therapy. In addition, the liver appears to play an important role in the induction of oral tolerance, as well as in the development/persistence of certain viral infections and cancer. Underlying mechanisms of this comparative immune privilege have not been validated convincingly. However, in addition to its unique anatomical structure, hepatic APCs might be involved in this process (1). APCs exist in several forms within the liver and exhibit a spectrum of abilities to capture, process, and present antigen to immune effector cells. [ABSTRACT FROM AUTHOR]

Having been ignored by immunologists for years, the liver is now known to be a site of complex immune activity and to play a key role in some of the most important pathologies, including septicemia, metastases, and hepatotropic infections. Even in its healthy state, the liver is presented with an intricate combination of immunological challenges for which it is surprisingly well equipped. These challenges include massive antigenic loads of harmless dietary and commensal products borne by the portal tract, which must be immunologically tolerated, but which may be laced with pathogens or toxins, requiring a swift response. Its blood supply of approx 1.5 L per minute ensures that the liver is the organ most frequently exposed to blood-borne metastatic stimuli, while products of hepatic metabolism may be carcinogenic. The liver immune system must therefore provide protection against pathogens, transformed liver cells, and metastasic cells while at the same time tolerating harmless self and foreign antigens. [ABSTRACT FROM AUTHOR]