Primary biliary cirrhosis is a slowly progressive autoimmune disease of the liver that primarily affects women. Its peak incidence occurs in the fifth decade of life, and it is uncommon in persons under 25 years of age. Histopathologically, primary biliary cirrhosis is characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. These changes occur at different rates and with varying degrees of severity in different patients. The loss of bile ducts leads to decreased bile secretion and the retention of toxic substances within the liver, resulting in further hepatic damage, fibrosis, cirrhosis, and eventually, liver failure.
Serologically, . . .
http://content.nejm.org/cgi/content/full/353/12/1261
Primary Biliary Cirrhosis
Telbivudine versus Lamivudine in Patients with Chronic Hepatitis B
Background Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B.
Methods In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses.
Results At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P=0.005) or a histologic response (64.7% vs. 56.3%, P=0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine.
Conclusions Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265 [ClinicalTrials.gov] .)
http://content.nejm.org/cgi/content/full/357/25/2576
Molecular Basis of Metastasis
Metastasis is the end product of an evolutionary process in which diverse interactions between cancer cells and their microenvironment yield alterations that allow these cells to transcend their programmed behavior. Tumor cells thus populate and flourish in new tissue habitats and, ultimately, cause organ dysfunction and death. Understanding the many molecular players and processes involved in metastasis could lead to effective, targeted approaches to prevent and treat cancer metastasis.
The tumor–node–metastasis (TNM) staging system used for most solid tumors considers the tumor size and degree of local invasion (T), the number, size, and location of lymph nodes (N), and the . . .
http://content.nejm.org/cgi/content/full/359/26/2814
Sorafenib in Liver Cancer — Just the Beginning
Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of death from cancer, resulting in more than 600,000 deaths per year. The major risk factors for hepatocellular carcinoma are chronic hepatitis B or hepatitis C virus infection, alcoholic cirrhosis, and nonalcoholic steatohepatitis.1 Cancer probably develops in the cirrhotic liver through the induction of accelerated cycles of cell injury, death, and regeneration in an altered fibrotic and inflammatory microenvironment. Abnormal immortalized cell clones arise, and these cells develop genetic and epigenetic alterations that provide a survival and proliferative advantage, resulting in unconstrained proliferation, a . . .
http://content.nejm.org/cgi/content/full/359/4/420
Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment
The onset of ascites in a patient with cirrhosis signals the beginning of compromised quality and expectancy of life. This common complication of end-stage liver disease results from a complex pathogenesis that leads to marked renal sodium and water retention. The hepatorenal syndrome is characterized by progression of the renal dysfunction of cirrhotic ascites to a more advanced level of functional renal failure. The evolution of our understanding of the pathogenesis of cirrhosis has been beset by chicken-and-egg conundrums, including dueling theories of circulatory "overflow" as compared with "underfill." The almost metaphysical (but ingenious) concept of reduced "effective blood volume," . . .
http://content.nejm.org/cgi/content/full/354/25/2733
Hepatitis E Virus and Chronic Hepatitis in Organ-Transplant Recipients
Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.
http://content.nejm.org/cgi/content/full/358/8/811
Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B
Background Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase.
Methods In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)–negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations.
Results At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies.
Conclusions Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48.
http://content.nejm.org/cgi/content/full/359/23/2442
Clinical Trial of Lamivudine in Children with Chronic Hepatitis B
ABSTRACT
Background Lamivudine therapy is effective for chronic hepatitis B infection in adults. We evaluated the efficacy and tolerability of lamivudine as a treatment for chronic infection with hepatitis B virus (HBV) in children.
Methods Children with chronic hepatitis B were randomly assigned in a 2:1 ratio to receive either oral lamivudine (3 mg per kilogram of body weight; maximum, 100 mg) or placebo once daily for 52 weeks. The primary end point was virologic response (defined by the absence of serum hepatitis B e antigen and serum HBV DNA) at week 52 of treatment.
Results Of the 403 children screened, 191 were randomly assigned to receive lamivudine and 97 to receive placebo. The rate of virologic response at week 52 was higher among children who received lamivudine than among those who received placebo (23 percent vs. 13 percent, P=0.04). Lamivudine therapy was well tolerated and was also associated with higher rates of seroconversion from hepatitis B e antigen to hepatitis B e antibody, normalization of alanine aminotransferase levels, and suppression of HBV DNA.
Conclusions In children with chronic hepatitis B, 52 weeks of treatment with lamivudine was associated with a significantly higher rate of virologic response than was placebo.
http://content.nejm.org/cgi/content/full/346/22/1706
Strategies for Safer Liver Surgery and Partial Liver Transplantation
The liver possesses the unique ability to regenerate within a short period.1,2,3 This feature has led to the development of innovative strategies in liver surgery and transplantation. The anatomy of the liver is paramount in considering advances in hepatic surgery. The liver is divided into eight segments (Figure 1). In healthy adults, the liver weighs about 1.5 kg (3.3 lb).4 The blood supply of the liver is carried through two major vessels, the hepatic artery and the portal vein. The portal vein carries a large volume of venous blood to the liver from the gut, pancreas, and spleen, . . .
http://content.nejm.org/cgi/content/full/356/15/1545
Acetylcysteine for Acetaminophen Poisoning
A 25-year-old man presents to the emergency department with a toothache. During the evaluation, the physician determines that the patient has been taking large doses of over-the-counter acetaminophen along with an acetaminophen–hydrocodone product for the past 5 days. His . . .
http://content.nejm.org/cgi/content/full/359/3/285
Sorafenib in Advanced Hepatocellular Carcinoma
ABSTRACT
Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma.
Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety.
Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand–foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group.
Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
http://content.nejm.org/cgi/content/full/359/4/378
The Budd–Chiari Syndrome
The Budd–Chiari syndrome is a heterogeneous group of disorders characterized by hepatic venous outflow obstruction at the level of the hepatic venules, the large hepatic veins, the inferior vena cava, or the right atrium.1 Hepatic veno-occlusive disease refers to obstruction of hepatic venous outflow at the level of the central or sublobular hepatic veins, or both.
Pathogenesis
Obstruction of the hepatic venous outflow tract results in increased hepatic sinusoidal pressure and portal hypertension. In the early stages, portal venous perfusion of the liver is decreased, which may result in portal venous thrombosis.2 The ensuing venous stasis and congestion lead to hypoxic . . .
http://content.nejm.org/cgi/content/full/350/6/578
Drug-Related Hepatotoxicity
In this review, we define hepatotoxicity as injury to the liver that is associated with impaired liver function caused by exposure to a drug or another noninfectious agent. The distinction between injury and function is important, because it is mainly when function is impaired that symptoms and clinically significant disease follow. We are especially concerned with serious drug-related hepatotoxicity that is disabling or life-threatening or that requires hospitalization. Although drug-related hepatotoxicity is uncommon — for many drugs, the reported incidence is between 1 in 10,000 and 1 in 100,000 patients1 — its true incidence is difficult to determine. The numbers . . .
http://content.nejm.org/cgi/content/full/354/7/731
Recurrence of Hepatocellular Carcinoma
Although the treatment of hepatocellular carcinoma is evolving, hepatic resection remains the treatment of choice for many patients. Resection is associated with a 5-year survival rate of 50% but also a 70% recurrence rate.1,2,3 Thus, for most patients, resection is not a cure. Recurrence of hepatocellular carcinoma after resection or local ablation with heat generated by high-frequency radio waves can be classified as early or late. Early recurrence occurs within weeks or months after treatment and has been attributed to either incomplete initial treatment or micrometastases within the liver but outside the treated field. Late recurrence, defined as recurrence more . .
http://content.nejm.org/cgi/content/full/359/19/2045
Liver Failure After Partial Hepatic Resection: Definition, Pathophysiology, Risk Factors and Treatment
Liver failure is a dreaded and often fatal complication that sometimes follows a partial hepatic resection. This article reviews the definition, incidence, pathogenesis, risk factors, risk assessment, prevention, clinical features and treatment of post-resectional liver failure (PLF). A systematic, computerized search was performed using key words related to 'partial hepatic resection' and 'liver failure' to review most relevant literature about PLF published in the last 20 years.
The reported incidence of PLF ranges between 0.7 and 9.1%. An inadequate quantity or quality of residual liver mass are key events in its pathogenesis. Major risk factors are the presence of comorbid conditions, pre-existent liver disease and small remnant liver volume (RLV). It is essential to identify these risk factors during the pre-operative assessment that includes evaluation of liver volume, anatomy and function. Preventive measures should be applied whenever possible as curative treatment options for PLF are limited. These preventive measures intend to increase RLV and protect remnant liver function. Management principles focus on support of end-organ and liver function. Further research is needed to elucidate the exact pathogenesis of PLF and to develop and validate adequate treatment options.
http://www.medscape.com/viewarticle/578175
Liver Immunology: Principles and Practice
We enjoyed reading this book because it contains much useful information and many interesting insights into liver immunology. The topic is of great interest because of continuing advances in our understanding of chronic viral infection of the liver, autoimmune liver disease, and liver transplantation. The contributors to this book are mainly from North America and Europe, however, so a truly global representation of topics is lacking. Schistosomiasis, for example, should have received greater attention, and the reasons for the rapid progression of coinfection with HIV and hepatitis C to severe liver disease merit greater discussion.
In the foreword, Ian Mackay . . .
http://content.nejm.org/cgi/content/full/358/17/1874
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