Recent milestones in the understanding of gastric acid secretion and treatment of acid-peptic disorders include the (1) discovery of histamine H(2)-receptors and development of histamine H(2)-receptor antagonists, (2) identification of H(+)K(+)-ATPase as the parietal cell proton pump and development of proton pump inhibitors, and (3) identification of Helicobacter pylori as the major cause of duodenal ulcer and development of effective eradication regimens. This review emphasizes the importance and relevance of gastric acid secretion and its regulation in health and disease. We review the physiology and pathophysiology of acid secretion as well as evidence regarding its inhibition in the management of acid-related clinical conditions.

Living donor liver transplantation (LDLT) has been controversial since its inception. Begun in response to deceased donor organ shortage and waiting list mortality, LDLT was initiated in 1989 in children, grew rapidly after its first general application in adults in the United States in 1998, and has declined since 2001. There are significant risks to the living donor, including the risk of death and substantial morbidity, and 2 highly publicized donor deaths are thought to have contributed to decreased enthusiasm for LDLT. Significant improvements in outcomes have been seen over recent years, and data, including from the National Institutes of Health-funded Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL), have established a survival benefit from pursuing LDLT. Despite this, LDLT still composes less than 5% of adult liver transplants, significantly less than in kidney transplantation where living donors compose approximately 40% of all transplantations performed. The ethics, optimal utility, and application of LDLT remain to be defined. In addition, most studies to date have focused on posttransplantation outcomes and have not included the effect of the learning curve on outcome or the potential impact of LDLT on waiting list mortality. Further growth of LDLT will depend on defining the optimal recipient and donor characteristics for this procedure as well as broader acceptance and experience in the public and in transplant centers.

The liver is unique among transplanted organs with respect to its interaction with the host immune system. There is evidence, both anecdotal and documented, that some liver recipients who cease taking immunosuppressive drugs maintain allograft function, suggesting robust tolerance is in place. Moreover, recipients of human liver allografts require less immunosuppression than do other organ recipients, and liver transplants confer protection on other organ grafts from the same donor. Hence, the liver shows features of immune privilege. Still, the liver can display destructive immunologic processes such as rejection in approximately one quarter of patients. The understanding of the cellular and molecular mechanisms operant in tolerance vs allograft rejection is important for developing new agents to improve long-term outcome, minimize infectious complications (including recurrence of hepatotropic viruses), and deliver immunosuppression without long-term toxicity. This review describes the unique aspects of the hepatic immune response, the pathways involved in T-cell activation and alloantigen recognition, effector cells and pathways mediating liver allograft rejection, the role of regulatory T cells, and targets of current and future immunosuppressive agents.

Hepatitis C is one of the most common indications for liver transplantation in the United States, accounting for approximately 40%-45% of all liver transplants. Unfortunately, recurrent disease is universal in patients who are viremic before transplantation. This can lead to cirrhosis in at least 25% of patients 5 years after liver transplantation, and recurrent hepatitis C is now emerging as an important but occasionally contentious indication for retransplantation. Several attempts have been undertaken to identify patients at high risk for severe recurrent disease who may benefit from treatment, but unfortunately antiviral therapy frequently is ineffective and often is associated with numerous side effects. Although we have made significant strides in understanding the natural history of this disease in nontransplant patients, this does not hold true for the transplant population in which several uncertainties covering virtually the entire spectrum of liver transplantation persist. Despite these concerns, on a more practical level, it is usually only in the postoperative setting that clinicians truly can assess the impact of their interventions on the natural history of recurrent hepatitis C, for example, by adjusting immunosuppression or prescribing antiviral therapy. Preoperative and perioperative (including donor) factors often are outside the control of hepatologists and transplant surgeons. This review is not an inclusive review of the literature but summarizes what we believe are the more controversial topics of this disease.

Patients should be considered for liver transplantation if they have evidence of fulminant hepatic failure, a life-threatening systemic complication of liver disease, or a liver-based metabolic defect or, more commonly, cirrhosis with complications such as hepatic encephalopathy, ascites, hepatocellular carcinoma, hepatorenal syndrome, or bleeding caused by portal hypertension. While the complications of cirrhosis can often be managed relatively effectively, they indicate a change in the natural history of the disease that should lead to consideration of liver transplantation. Referral to a liver transplant center is followed by a detailed medical evaluation to ensure that transplantation is technically feasible, medically appropriate, and in the best interest of both the patient and society. Patients approved for transplantation are placed on a national transplant list, although donor organs are allocated locally and regionally. Since 2002, priority for transplantation has been determined by the Model of End-Stage Liver Disease (MELD) score, which provides donor organs to listed patients with the highest estimated short-term mortality.

The diagnosis and treatment of hepatocellular carcinoma (HCC) have witnessed major changes over the past decade. Until the early 1990s, HCC was a relatively rare malignancy, typically diagnosed at an advanced stage in a symptomatic patient, and there were no known effective palliative or therapeutic options. However, the rising incidence of HCC in several regions around the world coupled with emerging evidence for efficacy of screening in high-risk patients, liver transplantation as a curative option in select patients, ability to make definitive diagnosis using high-resolution imaging of the liver, less dependency on obtaining tissue diagnosis, and proven efficacy of transarterial chemoembolization and sorafenib as palliative therapy have improved the outlook for HCC patients. In this article, we present a summary of the most recent information on screening, diagnosis, staging, and different treatment modalities of HCC, as well as our recommended management approach.

End-stage liver disease in children presents a challenging array of medical and psychosocial problems for the health care delivery team. Many of these problems are similar to those encountered by caregivers of adults with end-stage liver disease, such as the development of complications of cirrhosis, including ascites, spontaneous bacterial peritonitis, and esophageal variceal hemorrhage. However, the natural history of disease progression in children and their responses to medical therapy can differ significantly from that of their adult counterparts. Children with end-stage liver disease are especially vulnerable to nutritional compromise; if not effectively managed, this can seriously impact long-term outcomes and survival both before and after liver transplantation. Moreover, close attention must be given to vaccination status and the clinical setting at which health care is delivered to optimize outcomes and the delivery of high-quality pediatric health care. In this review, we address important components of the evaluation and management of children with chronic end-stage liver disease.

The hepatic complications of chronic hepatitis C (CHC) usually occur only after progression to cirrhosis has taken place. Progression to cirrhosis, however, is extremely variable and depends on a broad set of host and viral factors that modify the rate at which fibrosis develops in a given individual. Despite their inherent limitations, studies of the natural history of CHC have identified several nonmodifiable factors associated with disease progression. These include age at acquisition of infection, sex, and race. More recent reports suggest important roles for host genetic polymorphisms and viral factors. Of greater immediate relevance to patients and their clinicians are the potentially modifiable factors, which include excessive alcohol consumption; smoking (tobacco and marijuana); insulin resistance; and coinfection with hepatitis B virus, human immunodeficiency virus type 1, or schistosomiasis. Unfortunately, to date, there are no reliable predictive models that can accurately estimate the risk of CHC disease progression.

The increasing prevalence of obesity, insulin resistance, and the metabolic syndrome has significant implications for the future of chronic liver disease. The resultant increase in the number of patients with nonalcoholic fatty liver disease (NAFLD) is expected to translate into increased numbers of patients with end-stage liver disease (cirrhosis), liver failure, and hepatocellular carcinoma. It is particularly important to identify the patients who are at greatest risk of these aforementioned complications of chronic liver disease, those nonalcoholic fatty liver disease patients with nonalcoholic steatohepatitis. Currently liver biopsy is the gold standard for diagnosis, but less invasive, highly accurate, and affordable screening tools are required. These tools may include radiologic or laboratory studies to identify patients noninvasively who may benefit from therapeutic interventions. Clinical scoring systems that may be used in general practice as initial screening tools also may prove useful. Most therapeutic modalities available or under development target the major pathways thought essential in the pathogenesis of nonalcoholic steatohepatitis and often are directed at reducing body mass index and improving insulin resistance via pharmacologic, surgical, dietary, or exercise regimens. Other potential therapeutic agents directed at cytoprotection or reduction of fibrosis are under investigation. This article focuses on diagnosis and therapy available and under development for this chronic liver disease.

Hepatic fibrosis is the final common pathway for many different liver insults. Originally considered to be irreversible, hepatic fibrosis is now known to be a dynamic process with a significant potential for resolution. The diagnosis and quantitation of fibrosis have traditionally relied on liver biopsy. However, there are a number of drawbacks including the invasive nature of the procedure, sampling error, and interobserver variability. This article reviews the current role of liver biopsy in the assessment of hepatic fibrosis and discusses the role of the newer noninvasive methods including serum markers and radiologic tests.

Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, post-transcriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.

Derangements in apoptosis of liver cells are mechanistically important in the pathogenesis of end-stage liver disease. Vulnerable hepatocytes can undergo apoptosis via an extrinsic, death receptor-mediated pathway, or alternatively intracellular stress can activate the intrinsic pathway of apoptosis. Both pathways converge on mitochondria, and mitochondrial dysfunction is a prerequisite for hepatocyte apoptosis. Persistent apoptosis is a feature of chronic liver diseases, and massive apoptosis is a feature of acute liver diseases. Fibrogenesis is stimulated by ongoing hepatocyte apoptosis, eventually resulting in cirrhosis of the liver in chronic liver diseases. Endothelial cell apoptosis occurs in ischemia-reperfusion injury. Natural killer and natural killer T cells remove virus-infected hepatocytes by death receptor-mediated fibrosis. Lastly, activated stellate cell apoptosis leads to slowing and resolution of apoptosis. This review summarizes recent cellular and molecular advances in the understanding of the injury mechanisms leading to end-stage liver disease.

Colorectal cancer is the fourth most common noncutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Over the past 12 years, significant progress has been made in the systemic treatment of this malignant condition. Six new chemotherapeutic agents have been introduced, increasing median overall survival for patients with metastatic colorectal cancer from less than 9 months with no treatment to approximately 24 months. For patients with stage III (lymph node positive) colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy for the inclusion of oxaliplatin in such adjuvant treatment programs. For patients with stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at higher risk for disease recurrence. Ongoing randomized clinical trials are evaluating how best to combine currently available therapies, while smaller studies are evaluating new agents, with the goal of continued progress in prolonging life among patients with metastatic colorectal cancer and increasing cure rates among those with resectable disease.

CRC development is a multi-step process that spans 10 to 15 years, thereby providing an opportunity for early detection and even prevention. The poor survival rate of advanced CRC has prompted the emphasis on prevention of this disease. CRC screening and removal of adenomas is an effective intervention, and is the cornerstone of prevention. However, screening efforts have had limited impact due to less than optimal compliance with guidelines. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent or even reverse the development of adenomas in the large bowel, thus interfering with the multi-step progessing from adenoma to carcinoma. This effect is of particular importance to individuals with a hereditary prediposition to colorectal neoplasia and to those who are especially susceptile to the environmental causes of CRC. NSAIDs have drawn the most attention as chemoprevention agents. Sulindac and celecoxib are effective in promoting poly regression in high risk individuals with Familial Adenomatous Polyposis (FAP). In the more common sporadic setting the APROVe (refecoxib), APC and PreSAP (Celecoxib) trials have shown a significant reduction in adenoma recurrence but important concerns exist regarding cardiovascular toxicity associated with selective COX-2 inhibitors. These landmark studies are very important, as they provide a proof of concept that we can prevent high risk adenomas that can lead to CRC development. The ideal chemopreventive agent remains to be discovered with great emphasis on need not to harm. Possibly, combinations of agents will maximize effectiveness while limiting drug toxicity. Finally, personalized approaches will include the ability to predict risk and toxicity.

Transient elastography has been studied in a multitude of liver diseases for the staging of liver fibrosis with variable results. A meta-analysis was performed to assess the overall performance of transient elastography for the diagnosis of liver fibrosis and to analyze factors influencing the diagnostic accuracy.