Showing papers in "Seminars in Liver Disease in 2004"

The epidemiology of cholangiocarcinoma.

Abstract: The incidence rates of cholangiocarcinoma (CC) vary greatly among different areas of the world, and this variation is related to distribution of risk factors. Intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) have different epidemiological features. Recent data show that the incidence and mortality rates of ICC have been increasing in several areas around the world. On the other hand, the incidence and mortality rates of ECC have been decreasing. For example, in the United States, the age-adjusted incidence rates of ICC increased by 165% from 0.32 per 100,000 in 1975 to 1979 to 0.85 per 100,000 in 1995 to 1999, whereas ECC declined by 14%. In the meantime, there has been very little improvement in long-term survival, which remains dismal (3.5%). Men are affected 1.5 times more than women are, and Asians are affected almost 2 times more than whites and blacks. There are few well-established risk factors for CC, including primary sclerosing cholangitis, liver fluke infestations, hepatolithiasis, Thorotrast exposure, and choledochal cysts. None of these risk factors can explain the recent increasing trends of ICC in the United States. Some data, however, point to a potential role for chronic liver disease, hepatitis C, and probably hepatitis B infections in the development of ICC.

Molecular virology of hepatitis B virus.

Abstract: Hepatitis B virus (HBV) has evolved a unique life cycle that results in the production of enormous viral loads during active replication without actually killing the infected cell directly. Because HBV uses reverse transcription to copy its DNA genome, mutant viral genomes emerge frequently. Particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antiviral drugs), readily select out these escape mutants. Which particular viral mutations or combination of mutations directly affect the clinical outcome of infection are not known. Further studies are clearly needed to identify the pathogenic basis and clinical sequelae arising from the selection of these mutants.

The natural history of hepatitis C.

Abstract: Hepatitis C virus (HCV) is the most common cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) in the United States and infects an estimated 170 million people worldwide. In the United States, overall hepatitis C prevalence is 1.8% and is higher in African Americans and Hispanics than it is in white Americans. The age distribution places 65% of all subjects with anti-HCV antibodies between 30 and 49 years of age. Before serological screening of blood products was initiated, hepatitis C was most commonly transmitted by transfusion of contaminated blood products, but now it is acquired primarily via intravenous drug use. Only 10 to 25% of infected adult patients spontaneously resolve their infection, and the remaining 75% remain persistently viremic and often asymptomatic. Progression of liver disease in 20 to 30% of patients can lead to compensated and eventually decompensated cirrhosis or hepatocellular carcinoma, or both. This article looks briefly at the epidemiology and natural history of hepatitis C.

Epidemiology of alcoholic liver disease.

Abstract: Alcohol is one of the main causes of end-stage liver disease worldwide, and alcoholic liver disease is the second most common reason for liver transplantation in the United States. Beginning in the 1970s, there was a gradual decline in alcoholic cirrhosis-related mortality in many countries. However, in the past few years, alcoholic liver disease mortality rates in several countries have stabilized or started to increase. There are significant ethnic and gender differences in alcoholic cirrhosis-related mortality rates. Furthermore, alcohol use increases the risk for liver disease in those infected with hepatitis C. A better understanding of the epidemiology of alcoholic liver disease will allow for improved diagnosis and management of this common problem.

Liver transplantation for unresectable perihilar cholangiocarcinoma.

Abstract: Patients with unresectable, stage I and II perihilar cholangiocarcinoma were treated with neoadjuvant external beam irradiation, brachytherapy, and 5-fluorouracil and/or oral capecitabine prior to liver transplantation. Fifty-six patients underwent treatment between 1993 and 2003. Four patients died and 4 had disease progression prior to completion of neoadjuvant therapy. Forty-eight patients underwent operative staging and 14 had findings precluding transplantation. Twenty-eight patients underwent transplantation and 6 patients are awaiting transplantation. Three patients died from perioperative complications, and 4 developed recurrent disease 22 to 63 months after transplantation. Actuarial patient survival was 54% at 5 years for all 56 patients, 64% for 48 operatively staged patients, and 84% for 34 patients with negative staging operations. Actuarial survival was 88% at 1 year and 82 % 5 years after transplantation. Neoadjuvant chemoradiotherapy with liver transplantation achieves excellent results for patients with localized, regional lymph node negative, hilar cholangiocarcinoma.

Surgical management of cholangiocarcinoma.

Abstract: Biliary tract cancer affects approximately 7500 Americans each year. Tumors arising from the gallbladder are the most common; those of bile duct origin, or cholangiocarcinoma, are less frequently encountered, constituting approximately 2% of all reported cancers. Although cholangiocarcinoma can arise anywhere within the biliary tree, tumors involving the biliary confluence (i.e., hilar cholangiocarcinoma) represent the majority, accounting for 40 to 60% of all cases. Twenty to 30% of cholangiocarcinomas originate in the lower bile duct, and approximately 10% arise within the intrahepatic biliary tree and will present as an intrahepatic mass. Complete resection remains the most effective and only potentially curative therapy for cholangiocarcinoma. For all patients with intrahepatic cholangiocarcinoma and nearly all patients with hilar tumors, complete resection requires a major partial hepatectomy. Distal cholangiocarcinomas, on the other hand, are treated like all periampullary malignancies and typically require pancreaticoduodenectomy. Most patients with cholangiocarcinoma present with advanced disease that is not amenable to surgical treatment, and even with a complete resection, recurrence rates are high. Adjuvant therapy (chemotherapy and radiation therapy) has not been shown clearly to reduce recurrence risk.

The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis.

Abstract: Fatty liver disease involves the accumulation of triglycerides in hepatocytes, necrosis of hepatocytes, inflammation, and often fibrosis with progression to cirrhosis. The two-hit model summarizes the important early metabolic events leading to hepatocellular necrosis in nonalcoholic steatohepatitis (NASH). In this article, we provide evidence of lipid release from hepatocytes in posttransplant fat necrosis and in NASH and quantify vascular obliteration in a series of biopsies with NASH. Obliteration of small hepatic veins ( 30 microm) is associated with fibrotic collapse lesions that are not easily resorbed. Based on these observations, we propose a new four-step model that includes the later events that lead to cirrhosis after necrosis has occurred. This model is applicable to nonalcoholic fatty liver disease (NAFLD), alcoholic disease, postjejunoileal bypass disease, and posttransplant fat necrosis. The first step is steatosis facilitated by insulin, and the second is necrosis induced by intracellular lipid toxicity or lipid peroxidation, or both, modified by alcohol, drugs, and ischemia. The third step is release of bulk lipid from hepatocytes into the interstitium leading to direct and inflammatory injury to hepatic veins. The fourth step is venous obstruction with secondary collapse and ultimately fibrous septation and cirrhosis.

Liver biopsy sampling in chronic viral hepatitis.

Abstract: In chronic viral hepatitis, liver biopsy is performed to grade and stage liver damage. Liver biopsy samples are usually taken with a needle using a percutaneous procedure. This method produces a core of tissue representing approximately 1/50,000th of the liver mass, which raises concern about how representative a needle biopsy can be. A critical review of the literature reveals methodological limits unacceptable in this era of evidence-based medicine. Integrating earlier experience with more recently produced data indicates that a biopsy sample 2 cm or more in length containing at least 11 complete portal tracts should be reliable for grading and staging chronic viral hepatitis.

Serum and bile markers for cholangiocarcinoma.

Abstract: Surgery remains the only curative treatment option for cholangiocarcinoma (CC). Currently, both early identification of CC in affected individuals at high risk and accurate diagnosis of unexplained biliary strictures are problematic. However, growing insights into biochemical and molecular mechanisms underlying biliary carcinogenesis have suggested serum and bile markers for the diagnosis of CC. These tools include tumor antigens or products (e.g., carbohydrate antigen [CA] 19-9), cytokines (e.g., interleukin-6), metabolic products (e.g., lactate), proteases (e.g., trypsinogen-2), regulatory peptides (e.g., pancreatic polypeptide), and (epi-)genetic lesions (e.g., K-ras and p53 mutations, p16 I N K 4 a or p14 A R F promoter hypermethylation). In this article we discuss these new potential tumor markers for the diagnosis of CC.

Magnetic resonance imaging of cholangiocarcinoma.

Abstract: Cholangiocarcinoma arises from the bile ducts and is the most common primary malignancy of the biliary tree. Cholangiocarcinoma is classified according to its growth pattern: mass-forming, periductal-infiltrating, or intraductal-growing type. The majority of cholangiocarcinomas occur at the common hepatic duct (CHD) and its bifurcation, also referred to as Klatskin's tumor, but they also can occur in more peripheral branches within the hepatic parenchyma. Microscopically, cholangiocarcinoma represents an adenocarcinoma with a glandular appearance arising from the epithelium of the bile ducts. On magnetic resonance (MR) images, cholangiocarcinomas appear hypointense on T1-weighted images, and hyperintense on T2-weighted images. Central hypointensity can be seen on T2-weighted images and correspond to fibrosis. On dynamic MR images, cholangiocarcinomas show moderate peripheral enhancement followed by progressive and concentric filling in the tumor with contrast material. Pooling of contrast within the tumor on delayed MR images is suggestive of peripheral cholangiocarcinoma. The role of MR imaging in hilar cholangiocarcinoma is to confirm/reach a diagnosis and to assess resectability. Hilar cholangiocarcinoma shows the same signal intensity pattern of peripheral tumors both on T1- and T2-weighted images. On magnetic resonance cholangiopancreatography (MRCP) images, hilar cholangiocarcinoma appears as a moderately irregular thickening of the bile duct wall (>/=5 mm) with symmetric upstream dilation of the intrahepatic bile ducts. The aim of preoperative investigation in Klatskin tumors typically requires the evaluation of the level of biliary obstruction, the intrahepatic tumor spread, and the vascular involvement; it also needs to show any atrophy-hypertrophy complex. Because of its intrinsic high tissue contrast and multiplanar capability, MR imaging and MRCP are able to detect and preoperatively assess patients with cholangiocarcinoma, investigating all involved structures such as bile ducts, vessels and hepatic parenchyma. The main reason for surgical/imaging discrepancy is represented by the microscopic diffusion along the mucosa and in the perineural space.

The pathology of cholestasis.

Abstract: Hepatic formation of bile is critical to survival and is one of the most easily disrupted liver functions. Liver biopsy is performed to obtain a definitive diagnosis of cause, to exclude potential etiologies, or simply to assist in development of a differential diagnosis. Parenchymal changes of cholestasis (feathery degeneration of hepatocytes, dilated bile canaliculi with retained bile, Kupffer cell phagocytosis of bile that has leaked into the sinusoidal space) are nonspecific and may be seen with both nonobstructive and obstructive cholestasis. The portal tract changes of obstruction are characteristic: bile ductular proliferation, inspissated bile in bile ducts, portal tract edema, neutrophilic inflammation, and cholate stasis of periportal hepatocytes. Uncorrected obstruction incites robust fibrogenesis by portal tract myofibroblasts, engendering a characteristic jigsaw pattern of fibrous septa. Diseases with specific histological features include primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia, and graft-versus-host disease. However, the pathologist is cautioned not to overinterpret the cholestatic liver biopsy and to apply rigorous criteria for specific causal diagnoses. Most of the histological features of cholestasis are nonspecific. Hence, both practicing physician and pathologist should have sound knowledge of the pathology of cholestasis.

Alcohol and hepatitis C.

Abstract: Alcohol abuse and hepatitis C virus (HCV) infection coexist with chronic liver disease in many patients. The mechanism of injury in these patients is probably multifactorial and involves, but is not limited to, a combination of diminished immune clearance of HCV, oxidative stress, emergence of HCV quasi-species, hepatic steatosis, increased iron stores, and increased rate of hepatocyte apoptosis. In patients with HCV infection, alcohol consumption is known to cause accelerated progression of liver fibrosis, higher frequency of cirrhosis, and increased incidence of hepatocellular carcinoma (HCC). These patients also have decreased survival as compared with patients with either alcohol abuse or HCV liver injury alone. Alcohol abuse causes decreased response to interferon treatment in HCV patients. It is therefore necessary for patients with HCV infection to abstain from alcohol consumption.

The natural history of chronic hepatitis b virus infection

Abstract: Three stages of chronic hepatitis B virus (HBV) infection are recognized: the immune tolerant phase, the chronic hepatitis B phase, and the inactive hepatitis B carrier phase. Active liver disease is most often found in persons with elevated aminotransferase levels and HBV DNA levels >10(5) copies/mL. Possible risk factors for developing liver disease include older age, male gender, presence of hepatitis B e antigen (HBeAg), HBV genotype, mutations in the precore and core promoter regions of the viral genome, and coinfection with hepatitis D (delta) virus. All persons chronically infected with HBV should be followed every 6 to 12 months with aminotransferase levels. Those with elevated levels should be tested for HBeAg and its antibody (anti-HBe) as well as HBV DNA levels to determine if they are in need of further evaluation with a liver biopsy and are candidates for antiviral therapy. Future research will help clarify the outcome of chronic HBV infection.

Canals of Hering: recent insights and current knowledge.

Abstract: The canals of Hering (CoH) begin in the lobules, are lined partially by cholangiocytes and partly by hepatocytes, and conduct bile from bile canaliculi to terminal bile ducts in portal tracts. They are not readily apparent on routine histological staining but are highlighted by the biliary cytokeratins CK19 and CK7. There is on average 1 CoH per 10 microm of bile duct length. The canals represent the true hepatocytic-biliary interface that thus lies within the lobule and not at the limiting plate. The CoH are destroyed early in primary biliary cirrhosis, perhaps explaining lobular "hepatitis" in this disease. They may also be the primary sites of scarring in methotrexate toxicity. Most intriguingly, the CoH have been speculated to harbor intraorgan stem cells of the liver, perhaps forming the hepatic stem cell "niche" and have been demonstrated to proliferate in disease states.

Nutrition and alcoholic liver disease.

Abstract: Malnutrition is a common finding in chronic alcoholics, and protein calorie malnutrition (PCM) is universal and predictive of survival in patients with established alcoholic liver disease (ALD). These patients also demonstrate frequent deficiencies of folate, thiamine, pyridoxine, and vitamin A, which enhance the likelihood of anemia, altered cognitive states, and night blindness. The etiologies of malnutrition in ALD patients are multiple and interactive and include anorexia with inadequate dietary intake, abnormal digestion of macronutrients and absorption of several micronutrients, increased skeletal and visceral protein catabolism, and abnormal interactions of ethanol and lipid metabolism. Numerous, and mostly inadequately controlled, studies have evaluated the potential efficacies of oral, enteral, and parenteral nutrition approaches to treatment of ALD, with mixed results on liver function, clinical improvements, and short- or long-term survival. Targeted metabolic treatments include supplementation with S-adenosylmethionine (SAM) or phosphatidylcholine derivatives, each with promising experimental bases but inconclusive clinical trials.

An update on the molecular genetics of hepatocellular carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is associated with multiple risk factors and is believed to arise from preneoplastic lesions, usually in the background of cirrhosis. Extensive studies on HCC and its precursors have demonstrated complex and heterogeneous genetic or chromosomal abnormalities along the way from preneoplastic lesions to HCCs. These genetic abnormalities include loss of heterozygosity, microsatellite instability, gene alterations, and aberrant global gene expression profiles. Although some genetic alterations involving the p53 family, Rb family, and Wnt pathways are particularly important in the development of HCCs, the molecular pathogenesis of HCC differs with etiology in some extent. Recent studies using DNA microarray technique have identified some unique gene expression profiles in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-associated HCCs. Gene expression profiling also allows people to distinguish HCCs from normal tissue or preneoplastic lesions and to evaluate metastatic or recurrent potentials. These unique genes or gene products associated with malignant transformation and recurrent or metastatic potentials may serve as molecular markers for early diagnosis, prediction of prognosis, and responsiveness to therapy. To date, information that has accumulated for the past several decades is still incomplete, and we still are faced with a great challenge in deciphering the molecular mechanisms of HCCs.

Cellular signaling mechanisms in alcohol-induced liver damage.

Abstract: Chronic excessive alcohol intake is associated with multiple liver defects ranging from mild steatosis to advanced cirrhosis However, the mechanisms by which chronic ethanol intake affects liver function remain a matter of intense debate and investigation The liver is the major site of ethanol metabolism in the body, and a wide range of metabolic alterations is associated with ethanol intake As a result, the liver is exposed to dramatic changes in redox state, transient hypoxia, episodes of oxidative stress, and the products of ethanol metabolism, such as acetaldehyde, acetate, and fatty acid ethyl esters Chronic ethanol consumption is associated with increased levels of circulating endotoxins and proinflammatory cytokines that affect liver function A major source of the increase in circulating proinflammatory cytokines is the Kupffer cells, which are sensitized to generate tumor necrosis factor alpha (TNF-alpha) through multiple mechanisms In addition, the hepatocytes themselves are more susceptible to external stress In isolated hepatocytes, this effect of chronic ethanol is evident in a greater sensitivity to proapoptotic challenges and, more specifically, to the cytotoxic actions of TNF-alpha The mechanism by which hepatocytes are sensitized to external stress remains poorly characterized but may involve defects in mitochondrial function and oxidative defense mechanisms, the activation of death-promoting signaling pathways, and the inactivation of survival pathways In this article, we emphasize the role of the stress-activated mitogen-activated protein kinase (MAPK) cascades in the onset of cell injury and their regulation by the phosphoinositide-3-kinase/Akt signaling cascade, which appears to function as the central integrating module of the stress-signaling machinery in the cell We also discuss the complications and challenges of extrapolating these findings to the conditions in vivo and what we can learn from these studies regarding the nature of the liver defects associated with chronic alcohol consumption

Hepatitis C and nonalcoholic fatty liver disease.

Abstract: Hepatitis C virus (HCV) and nonalcoholic fatty liver disease (NAFLD) are the two most common causes of chronic liver disease in North America. NAFLD represents a spectrum of liver lesions that occur in individuals who either do not consume any alcohol or only consume alcohol in quantities generally considered not to be harmful to the liver. This spectrum consists of isolated hepatic macrovesicular steatosis at one end and nonalcoholic steatohepatitis (NASH) at the other. Hepatic steatosis is present in approximately 50% of the subjects with HCV. Genotype 3 is independently associated with hepatic steatosis. In those with genotype 1 infection, steatosis is associated with features of the metabolic syndrome. The presence of hepatic steatosis correlates with the stage of hepatic fibrosis in patients with HCV. This has been related to the presence of insulin resistance. Hepatic steatosis also adversely affects the virologic response rates to anti-HCV therapy. In this article, we will review the epidemiology of HCV and NAFLD, their impact on each other, and the course of the liver disease in individuals afflicted with both conditions.

Diagnosis and therapy of alcoholic liver disease.

Abstract: Alcoholic liver disease (ALD) presents considerable challenges to clinicians. Screening for alcohol abuse and alcoholism should be routine and repeated annually with close attention to signs and symptoms of liver disease. In patients with evidence of liver dysfunction or injury, consideration should be given to performance of liver biopsy for diagnosis and prognosis and prior to initiation of medication with the potential for significant side effects. Therapy depends on the spectrum of pathological liver injury: alcoholic fatty liver, alcoholic hepatitis, and cirrhosis. Abstention is the foundation of therapy for an alcohol problem. Alcoholic fatty liver should improve with abstention, but the similarity to the pathogenesis of nonalcoholic fatty liver and potential for progressive injury merits consideration of lipotropic agents. The continuing mortality, poor acceptance of corticosteroids, and identification of tumor necrosis factor-alpha (TNF-alpha) as an integral component has led to studies of pentoxifylline and, recently, anti-TNF antibody to neutralize cytokines in the therapy of severe alcoholic hepatitis. Antioxidant therapy of alcoholic cirrhosis has significant promise but will require large clinical trials.

The Molecular Pathogenesis of Cholangiocarcinoma

Abstract: Cholangiocarcinoma is rising in clinical importance because of increasing incidence, poor prognosis, and suboptimal response to therapy. Recent investigations into the underlying molecular mechanisms involved in cholangiocarcinogenesis and tumor growth have contributed greatly to our understanding of this disease. To review this topic, we discuss the molecular mechanisms in sections reflecting the unique features that allow cancer cells to develop and maintain a growth advantage. Through a better understanding of these mechanisms, improved and more specific diagnostic, therapeutic, and preventative strategies may be developed and hopefully improve the outcome of this devastating disease.

Immunologic mechanisms of alcoholic liver injury.

Abstract: Clinically, the association of alcoholic liver disease (ALD) with circulating auto-antibodies, hypergammaglobulinemia, antibodies to unique hepatic proteins, and cytotoxic lymphocytes reacting against autologous hepatocytes strongly suggests altered immune regulation with an increased activity toward normal self-proteins (loss of tolerance). Experimentally, there are several immune responses generated specifically recognizing self-proteins that are modified by metabolites of alcohol. These data strongly suggest that immune reactions may play a significant role in inducing and sustaining an inflammatory cascade of tissue damage to the liver. Additional support for this comes from the observation that the histological appearance of livers with ALD is that of a chronic active hepatitis-like inflammatory disease. Therefore, the hypothesis that immune mechanisms are involved in recurrent alcoholic hepatitis, although not summarily proven, is reasonable, supported by clinical and experimental evidence, and the subject of this article.

Predictors of response to therapy for chronic hepatitis C.

Abstract: Pretreatment prediction of successful interferon-based therapy is less accurate than is prediction based on serum hepatitis C virus (HCV) RNA measurements taken during the first few weeks of therapy. Virological response, defined as loss of detectable virus RNA during the first weeks of treatment, identifies interferon-sensitive virus strains. Studies on viral decline kinetics have shown that interferon-based therapies produce a two-phase reduction in viral RNA levels. Sustained virological response is associated with rapid biphasic viral decline kinetics, resulting in elimination of virus from the blood within 4 to 12 weeks. Rapid viral elimination correlates positively with low incidence of relapse in end-of-treatment virological responders and is, therefore, an important parameter for determining duration or type of therapy. This article reviews the various patient and viral factors that help predict response to various interferon-based therapies, ranging from interferon alone to the new pegylated interferons.

Clinical Aspects of Fatty Liver Disease

Abstract: The global emergence of obesity as an epidemic has made fatty liver disease a public health problem in the Western world. The increased incidence of obesity has been paralleled by an increase in metabolic syndrome in the same cohort of patients. The net consequence of insulin resistance in a large majority of these obese individuals is hepatic steatosis, which over time in a proportion of these patients progresses to steatohepatitis and cirrhosis. Despite the increased awareness among physicians regarding its presence, the diagnostic process has been hampered by the lack of sensitive and specific population-based screening tests. Liver biopsy remains the gold standard for diagnosis as well as for grading and staging of the disease process but its precise role in the diagnostic conundrum continues to be debated.

Treatment of chronic hepatitis C infection with peginterferons plus ribavirin.

Abstract: Interferon monotherapy provided the first hope for patients with chronic hepatitis C that the virus could be permanently eradicated. An important development in treating this disease was the recognition that the effects of interferon could be greatly enhanced by combining it with ribavirin, a nucleoside analogue. This combination regimen essentially doubled the sustained virological response rates seen with interferon alone. Recently, modified forms of interferon have been developed that-when used in combination with ribavirin-demonstrate even better efficacy. Thus, peginterferon alfa-2a (Hoffman La-Roche, Nutley, NJ) and peginterferon alfa-2b (Schering-Plough, Kenilworth, NJ) are the latest innovations for the treatment of chronic hepatitis C. The addition of a polyethylene glycol molecule to the native interferon protein favorably alters the pharmacokinetic profile, allowing for once-weekly administration, and leads to superior efficacy compared to standard interferon preparations. This article reviews the data from clinical trials of peginterferon alfa-2a and peginterferon alfa-2b.

Treatment with interferons (including pegylated interferons) in patients with hepatitis B.

Abstract: Studies of 4 to 6 months of treatment with interferon for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection have shown clearance of HBeAg to be higher in treated patients than it is in controls by approximately 25%. These results are considerably better than those with antiviral agents. Therefore, the recent European Association for the Study of the Liver (EASL) Consensus Committee recommended the use of interferon alpha for this condition. Treatment with pegylated interferons in several trials has shown better results still. Lamivudine in combination with interferon, however, did not improve the results at 6 months after the end of therapy. In HBeAg-negative chronic HBV infection, pegylated interferon alpha is superior to lamivudine, and, again, combination with lamivudine does not improve the results. Side effects in all studies have been tolerable. Thus, these observations in chronic HBV infection, whether HBeAg-positive or HBeAg-negative, suggest an important, even primary, role for pegylated interferon therapy.

Morphological changes of early human hepatocarcinogenesis.

Abstract: Recent advances in liver imaging, surgery, and transplantation have drawn attention to a variety of lesions that are found in chronically diseased, usually cirrhotic, livers. Several studies have established the precancerous nature of dysplastic foci and dysplastic nodules and have delineated the morphological features of small hepatocellular carcinoma. Dysplastic foci represent incidental findings on microscopic examination of hepatic specimens, whereas dysplastic nodules are detected grossly, and often radiologically. Dysplastic foci commonly consist of proliferating hepatocytes with small cell change, which is cytologically reminiscent of well-differentiated hepatocellular carcinoma. Dysplastic nodules may show evidence of cytological or structural atypia, or both, that is insufficient for the diagnosis of hepatocellular carcinoma. The evolution of dysplastic nodules to hepatocellular carcinoma within several months to a few years of follow-up is well-documented. Small hepatocellular carcinoma with indistinct margins has been identified as an early, well-differentiated neoplasm that usually measures less than 15 mm in greatest dimension. As this lesion grows larger, it may transform into nodular hepatocellular carcinoma with distinct margins.

Liver pathology in obesity.

Abstract: Obesity-related liver disease, particularly nonalcoholic fatty liver disease and its more severe form nonalcoholic steatohepatitis, is being increasingly recognized as a common liver disease in developed countries and represents hepatic manifestation of the metabolic syndrome Nonalcoholic steatohepatitis results in progressive fibrosis, cirrhosis, and end-stage liver disease, with its increased incidence of hepatocellular carcinoma Liver biopsy remains the gold standard in detection, evaluation, staging, and grading of nonalcoholic steatohepatitis Liver biopsy also provides an important tool to detect concomitant liver disease that may accelerate the progression of steatohepatitis in these patients Surgical or drug-induced weight loss has been documented to reduce the amount of inflammation, to induce regression of fibrosis, and, in some cases, to cause a reversal of cirrhosis in obese patients with steatohepatitis Pretreatment or intraoperative liver biopsy should be performed to assess the presence of steatohepatitis, and stage and grade of steatohepatitis This article will discuss obesity-related liver diseases, focusing on pathologic features in liver biopsies from obese patients, obesity-related hepatocellular carcinoma, and the effect of weight loss treatment on histopathology

Past, present, and future hepatitis C treatments.

Abstract: Conventional interferon (IFN) alfa has been used for many years in the treatment of chronic hepatitis C. However, few patients achieve sustained virological responses with IFN. Combining IFN with ribavirin improves efficacy considerably, but at the expense of diminished tolerability attributable to ribavirin. Pegylated interferons have improved pharmacokinetic profiles, may be administered once weekly, and are more effective than IFN is alone or in combination with ribavirin. In addition to enhanced efficacy, pegylated interferon alfa-2a (40 kD) also improves health-related quality of life during therapy compared with IFN-based therapy. New adjuvant agents have the potential to further improve sustained response rates and tolerability; however, pegylated interferons will likely remain the backbone of therapy in the foreseeable future. Therapies under development and evaluation for patients with HCV infection include adjunctive use of the antiviral agent amantadine and the immunomodulatory agent thymalfasin. Novel small molecules include the ribavirin analogues, viramidine and levovirin, and BILN 2061, an inhibitor of HCV serine protease. Other therapeutic strategies that have reached the clinic include antisense oligonucleotides (ISIS 14803), nuclease-resistant ribozymes targeting HCV RNA (Heptazyme), human monoclonal antibodie, and human antibody fragments directed at HCV helicase.

Management of hepatitis B in liver transplantation patients.

Abstract: The success of orthotopic liver transplantation for patients with hepatitis B virus (HBV) disease has been compromised by reinfection. Prophylaxis has dramatically lowered the rate of reinfection and increased patient survival. Long-term treatment with hepatitis B immunoglobulin (HBIg), although expensive, is effective. New antiviral nucleoside analogs have also been evaluated. In patients with cirrhosis and replicative HBV infection, lamivudine before transplantation and in combination with HBIg post transplantation reduces reinfection, but the rate of resistance mutation is rather high, reaching 25% at 2 years. Adefovir has been used as a rescue therapy and prior to transplantation in lamivudine-resistant patients, significantly improving liver function and reducing HBV DNA levels. Patients with active viral replication should receive preoperative antiviral therapy with lamivudine. HBIg therapy may be discontinued in selected patients after transplantation, albeit with caution, because low levels of HBV DNA have persisted. Antiviral therapy has improved the prognosis after graft infection.

The histopathology of regeneration in massive hepatic necrosis.

Abstract: Massive hepatic necrosis (MHN) is a condition that offers an opportunity to study the remarkable ability of the liver to become repopulated with hepatocytes. A maximal regenerative stimulus is expected in cases of MHN (Roskams et al. APMIS Suppl 1991;23:32-39). Sequential chronological observations, after a severe degree of liver cell loss, permit study of the human equivalent of the situation in animal models in which circulating and bone marrow-derived stem and liver progenitor cells are recruited to the hepatopoietic process. To date, the bone marrow and circulating precursors have not been identified morphologically in human material. We present data that suggest that the circulating liver progenitor could have a lymphoblastoid morphological appearance. Similar cells are seen among the cellular infiltrate of MHN. We have found that combinations of markers, such as CD117/CD133 positive CD45/tryptase negative are useful to isolate these cells using cell-sorting technology. This may facilitate their expansion in vitro and the development of their use for therapeutic purposes. In MHN, the residual portal tracts and ductular reaction with the associated lymphoid infiltrate (some of which are probably liver cell progenitors derived from the circulation) constitute the fundamental regenerative community unit in which hepatopoiesis takes place. Defining the hepatopoietic process is hindered by the lack of morphological transitional forms in the period between the progenitors within the circulation and when they assume recognizable hepatocytic form as "metaplastic" hepatocytes associated with the ductular reaction. By achieving a better comprehension of these processes of liver cell restoration, we will be better placed to accelerate liver recovery in MHN, for example by the administration of granulocyte colony stimulating factor (GCSF). Thus, more patients will be able to restore their own livers and avoid liver transplantation.