| NEW TREATMENTS OF HEPATORENAL SYNDROME |
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Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis,
characterized by renal failure and major abnormalities in the systemic circulatory function.
Renal failure is caused by intense vasoconstriction of the renal circulation. The syndrome is
probably the final consequence of an extreme underfilling of the arterial circulation,
secondary to vasodilatation in the splanchninc vascular bed and a decrease in cardiac
output due to central hypovolemia. The diagnosis of HRS is based on the exclusion of
other causes of renal failure. The survival of patients with HRS is very short, particularly
when there is rapidly progressive renal failure (type-1 HRS). Liver transplantation is the
best therapeutic option but its applicability is low. During the past few years effective
treatment for HRS, such as vasoconstrictor drugs (vasopressin analogues, /-adrenergic
agonists) associated with intravenous albumin infusion and transjugular intrahepatic
portosystemic shunts (TIPS), have been introduced. They improve circulatory function,
normalize serum creatinine, and may improve survival. Sequential treatment with vasoconstrictors
plus albumin and TIPS is an attractive therapeutic possibility. Plasma volume
expansion with albumin at infection diagnosis in patients with spontaneous bacterial
peritonitis and the administration of pentoxiphilline in patients with severe alcoholic
hepatitis significantly reduce the development of type-1 HRS.
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| INCREASED LIVER CHEMISTRY IN AN ASYMPTOMATIC PATIENT |
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A 38-year-old real estate agent presents to the office for evaluation of abnormal liver test results that were noticed when he underwent testing for a new life insurance policy.
The patient has no complaints, exercises regularly, and takes no medications. He is married, has 2 young children, and does not smoke. He rarely drinks alcohol. His physical examination reveals no abnormalities. His body mass index is 24 kg/m2.
Laboratory evaluation shows an alanine transaminase level of 76 U/L (normal, 10–40 U/L), an aspartate transaminase level of 53 U/L (normal, 10–40 U/L), an alkaline phosphatase level of 110 U/L (normal, 25–100 U/L), an albumin level of 4.3 g/dL, and a total bilirubin level of .7 mg/dL.
A complete blood count and coagulation parameters are normal. Retesting 1 month later shows an alanine transaminase level of 71 U/L and an aspartate transaminase level of 50 U/L.
How should the increased transaminase levels be evaluated?
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| DIAGNOSIS AND MANAGEMENT OF CHOLESTATIC LIVER DISEASE |
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Cholestasis (slowing of bile flow) may be acute or chronic
and affect any age group. In infants and children the causes
often are congenital or inherited and as a result of improved
management some affected children now survive to
adulthood. Although jaundice is a hallmark of cholestasis it
may be absent, particularly in adults with chronic cholestatic
liver disease most of whom are entirely asymptomatic.
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| GUIDELINES FOR THERAPY OF AUTOIMMUNE LIVER DISEASE |
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The principle of therapy for chronic inflammatory liver diseases is the removal of
causal agents. For autoimmune liver diseases, however, total removal of causal agents and
immune cells is impossible. Therefore, autoimmune liver diseases are presently treated by
suppression of the immune response. Autoimmune hepatitis is characteristically responsive
to corticosteroids, often used in combination with azathioprine to obtain a steroidsparing
effect. For primary biliary cirrhosis, ursodeoxycholic acid is safe and is the first
choice for treatment. Treatment of this autoimmune liver disease should also address
various symptoms and complications arising from any associated autoimmune diseases,
particularly cholestasis and cirrhosis-related complications. For primary sclerosing
cholangitis there are no established immunomodulatory therapies, but medical, endoscopic,
and surgical treatments are applicable to this disease. Liver transplantation
becomes indicated during the eventual end stages of each of these immune-mediated
liver diseases.
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| REPORT OF THE MONOTHEMATIC EASL CONFERENCE ON LIVER TRANSPLANTATION FOR VIRAL HEPATITIS |
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This EASL monothematic conference aimed to review in a 2-day meeting the most recent aspects of liver transplantation for viral hepatitis. Experts from Europe
and overseas exchanged their views and expertise on the different aspects of liver transplantation and viral hepatitis,
and presented the most updated information available at the time of the conference which was held in Paris, France, January 12–14, 2006.
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| CURRENT DIAGNOSIS AND MANAGEMENT OF PRIMARY SCLERO |
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Primary sclerosing cholangitis (PSC) is an important liver disease with major morbidity and mortality. The diagnosis of PSC is
confirmed by magnetic resonance cholangiopancreaticography, and endoscopic retrograde cholangiopancreaticography is
performed in patients needing therapeutic endoscopy.
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| EVOLVING CONSENSUS IN PORTAL HYPERTENSION |
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Portal hypertension is the haemodynamic abnormality
associated with the most severe complications of cirrhosis,
including ascites, hepatic encephalopathy and bleeding
from gastroesophageal varices. Variceal bleeding is a
medical emergency associated with a mortality that, in
spite of recent progress, is still in the order of 20% at 6
weeks. The evaluation of diagnostic tools and the design and
conduct of good clinical trials for the treatment of portal
hypertension have always been difficult. Awareness of these
difficulties has led to the organisation of a series of meetings
aimed at reaching consensus on the definitions of some key
events related to portal hypertension and variceal bleeding,
and at producing guidelines for the management of patients
and for the conduct of trials in this field. Such meetings took
place in Groningen, the Netherlands in 1986, in Baveno,
Italy in 1990 (Baveno I)and in 1995 (Baveno II)in
Milan, Italy in 1992, in Reston, USA, in 1996 and in
Stresa, Italy, in 2000 (Baveno III). All these meetings
were successful and produced consensus statements on
some important points, although several issues remained
unsettled.
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| BACTERIAL INFECTIONS IN CIRRHOSIS: TREATMENT AND PROPHYLAXIS |
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Bacterial infections are a well-described complication of cirrhosis. In recent prospective series, bacterial infections are present or develop during admission in a third of hospitalized cirrhotic patients (1,2). Two factors play an important role in the development of bacterial infections in these patients: the severity of liver disease and admission for gastrointestinal (GI) hemorrhage (3). About half the cirrhotic patients admitted with GI hemorrhage will
develop a bacterial infection and, in patients with variceal hemorrhage, infection has been shown to be associated with failure to control bleeding (4,5) and with early variceal rebleeding (6,7).
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| ADVANCES IN THE PATHOGENESIS AND TREATMENT OF TYPE-1 AND TYPE-2 HEPATORENAL SYNDROME |
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Hepatorenal syndrome (HRS) is a frequent complication
in patients with advanced cirrhosis and ascites. It is
characterized by an intense renal vasoconstriction,
which leads to very low renal perfusion and glomerular
filtration rate (GRF).
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| EVALUATION OF THE PATIENT FOR LIVER TRANSPLANTATION |
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These recommendations provide a data-supported approach.
They are based on the following: (1) formal review
and analysis of the recently published world
literature on the topic (Medline search); (2) American
College of Physicians Manual for Assessing Health Practices
and Designing Practice Guidelines; (3) guideline
policies, including the AASLD Policy on the Development
and Use of Practice Guidelines and the AGA Policy
Statement on Guidelines; (4) the experience of the authors
in the specified topic.
Intended for use by physicians, these recommendations
suggest preferred approaches to the diagnostic, therapeutic,
and preventive aspects of care. They are intended
to be flexible, in contrast to standards of care, which are
inflexible policies to be followed in every case. Specific
recommendations are based on relevant published information.
In an attempt to characterize the quality of evidence
supporting recommendations, the Practice
Guidelines Committee of the AASLD requires a category
to be assigned and reported with each recommendation
(Table 1). These recommendations are fully endorsed by
the AASLD and the American Society of Transplantation.
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| MANAGEMENT OF H C V IN SPECIAL POPULATIONS |
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The most common chronic blood-borne infection in the United States is caused by hepatitis C virus. An estimated 3.9 million people (1.8%) in the United States have been infected with the hepatitis C virus, excluding certain subpopulations who are at high risk for hepatitis C virus infection. Among these subpopulations are an estimated 255,000 (15%) of prison inmates and 175,000 (22%) of homeless people.
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| PATHOGENESIS AND TREATMENT OF HEPATORENAL |
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Hepatorenal syndrome (HRS) is a functional renal failure that frequently develops
in patients with advanced cirrhosis and severe impairment in systemic circulatory function.
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| AASLD POSITION PAPER: THE MANAGEMENT OF ACUTE LIVER FAILURE |
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These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of recently-published world literature on the topic Medline search, (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the AGA Policy Statement on Guidelines (4) the experience of the authors in the specified topic.
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| STATINS AND HEPATOTOXICITY: FOCUS ON PATIENTS |
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Statins are among the most widely prescribed medications in the western world.1 Their benefit in the primary and secondary prevention of cardiovascular
disease is unequivocal. The results from clinical trials have shown that statins decrease the mortality from coronary
artery disease and decrease the incidence of myocardial infarction, revascularization procedures, stroke
and peripheral vascular disease.2 Currently, six statins are available for clinical use including lovastatin which is
available in a generic form in the United States. These medications are widely prescribed and more than 10 million
prescriptions were written in the United States in the year 2003 alone3 (Table 1). Numerous clinical trials and
extensive clinical experience have established that currently available statins have an excellent safety profile.
Although clinically significant liver injury is extremely rare from statins, asymptomatic elevations in liver enzymes
are common in patients who are placed on statins.
Because of this phenomenon and due to the information contained within the package inserts, potential hepatotoxicity
from statins has become a source of concern for physicians who prescribe them. In clinical practice, gastroenterologists and hepatologists are often asked to see patients who developed liver enzyme elevations after prescribing
statins and also about the safety of prescribing statins in hyperlipidemic individuals with asymptomatic liver enzyme elevations. This article discusses various aspects of statin hepatotoxicity including the safety of statins in patients with nonalcoholic fatty liver disease (NAFLD) and the merits of current product labeling (Table 2). The issue of using statins in patients with known or
suspected fatty liver disease is particularly relevant as statins are now available without a prescription in some
parts of the world (United Kingdom) and thus a large number of individuals with undiagnosed fatty liver disease may consume statins without their knowledge.
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| THE USE OF VASOCONSTRICTORS IN PATIENTS WITH CIRRHOSIS: TYPE 1 HRS AND BEYOND |
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In patients with cirrhosis and type 1 hepatorenal syndrome (HRS), systemic vasodilation,
which is mainly attributable to splanchnic vasodilation, plays a critical role in the activation
of endogenous vasoconstrictor systems, resulting in renal vasoconstriction and functional
renal failure. It has been suggested that the use of splanchnic (and systemic) vasoconstrictors
such as terlipressin (a vasopressin analog) or alpha-1-adrenoceptor agonists (midodrine or
noradrenaline) may improve renal function in patients with type 1 HRS. Six studies (with
only one randomized study in a small series of patients) have shown that terlipressin improves
renal function in these patients.
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| LIVER DISEASE IN PREGNANCY |
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Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes, including coincidental liver disease (most commonly viral hepatitis or gallstones) and underlying
chronic liver disease.
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| BACTERIAL INFECTIONS, SEPSIS, AND MULTIORGAN FAILURE IN CIRRHOSIS |
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Bacterial infections are an important complication of cirrhosis, particularly in hospitalized patients.
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| ANTIFIBROTIC THERAPY IN CHRONIC LIVER DISEASE |
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The response to injury is one of wound healing and, subsequently, fibrosis. This response is generalized, occurring in diverse organ systems. Injury and wounding
in the liver ultimately lead to cirrhosis in many patients (although not all patients), and are the result of many
different diseases. The fact that various diseases result in cirrhosis suggests a common pathogenesis. Study over the past 2 decades has shed considerable light on
the pathogenesis of fibrosis and cirrhosis. A growing body of literature indicates that the hepatic stellate cell
is a central component in the fibrogenic process.
Stellate cells undergo a transformation during injury that has been termed activation. Activation is complex and multifaceted, but one of its most prominent features is the synthesis of large amounts of extracellular matrix, resulting in deposition of scar or fibrous tissue.
The fibrogenic process is dynamic; it is
noteworthy that even advanced fibrosis (or cirrhosis) is reversible. The best antifibrotic therapy is treatment of the underlying disease.
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| MANAGEMENT OF PRE–LIVER TRANSPLANTATION PATIENT - PART II |
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Entregamos este mes la segunda parte de este artículo, para que sea descargada en su totalidad.
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| TREATMENT CHALLENGES AND INVESTIGATIONAL OPPORTUNITIES IN AUTOIMMUNE HEPATITIS |
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New drugs and advances in molecular biology afford opportunities to upgrade the treatment of autoimmune hepatitis. The aims of this study were to define treatment problems, identify possible solutions, and stimulate investigations to improve patient care. A clinical subcommittee of the International Autoimmune Hepatitis Group reviewed current management difficulties and proposed corrective actions. The asessment of new front-line and salvage
therapies for adults and children were given top priority. Cyclosporine and mycophenolate mofetil were endorsed as drugs worthy of rigorous study in severe disease, and budesonide was endorsed for study as front-line therapy in mild disease. Diagnostic criteria and treatment
regimens for children required codification, and pharmacokinetic studies were encouraged to develop optimal dosing schedules based on therapeutic ranges. Collaborative efforts were proposed to help understand racial, geographical, and genetic factors affecting outcome and to establish definitions and therapies for variant syndromes and graft dysfunction after transplantation. The development of experimental animal models was deemed essential for the study of site-specific molecular interventions, and gene therapy was endorsed as a means of bolstering reparative processes. In conclusion, evolving pharmacological and technical
advances promise to improve the treatment of autoimmune hepatitis, and investigations of
these advances are timely, feasible, and necessary.
(HEPATOLOGY 2005;41:207–215.)Albert J. Czaja,1 Francesco B. Bianchi,2 Herschel A. Carpenter,1 Edward L. Krawitt,3 Ansgar W. Lohse,4
Michael P. Manns,5 Ian G. McFarlane,6 Giorgina Mieli-Vergani,6 Gotaro Toda,7 Diego Vergani,6
John Vierling,8 and Mikio Zeniya7
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| MANAGEMENT OF HEPATOCELLULAR CARCINNOMA |
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These recommendations provide a data-supported approach to the diagnosis, staging and treatment of patients diagnosed with hepatocellular carcinoma (HCC). They
are based on the following: (a) formal review and analysis of the recently-published world literature on the topic (Medline search through early 2005); (b) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines.1 (c) guideline policies, including the AASLD Policy on the Development
and Use of Practice Guidelines and the AGA Policy Statement on Guidelines2; (d) the experience of the authors in the specified topic. We have also reviewed the guidelines
prepared at the time of the Monothematic Conference of the European Association for the Study of the Liver (EASL)3and the practice of authors experienced in the field. Intended for use by physicians, these recommendations
suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific
recommendations are based on relevant published information.
In an attempt to characterize the quality of evidence supporting recommendations, the Practice
Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1). These recommendations are fully endorsed by the American Association for the Study of Liver Diseases.
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| MANAGEMENT OF PRE-LIVER TRANSPLANTATION PATIENTS |
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Este artículo es recomendado para aquellos médicos involucrados con pacientes que cumplen criterios para trasplante hepático. Es una revisión completa y concisa del enfoque que un centro de trasplantes realiza en los pacientes con indicación para trasplante de hígado.
Liver transplantation (LT) has emerged as the standard of care for patients with irreversible acute and chronic liver failure and various metabolic disorders (e.g., primary oxaluria, familial amyloidotic polyneuropathy).
1 Due to the increasing incidence of end-stage liver disease and the limited number of grafts available for transplantation, the number of patient awaiting orthotopic LT has grown to 17,471 as of June 29, 2004.2 In 2003, 5,350 patients received an orthotopic LT. Most of the waitlisted candidates are followed in the community for their medical as well as hepatologic care.2 The limited number of transplants performed, along with long waiting periods, increase the chances of liver-associated complications and can make the management of these patients very challenging for the primary care provider.
The aim of this article is to delineate the care of cirrhotic patients, with an emphasis on pre-LT workup and a focus on comprehensive medical care, complications related to portal hypertension, and surveillance, including screening for hepatocellular carcinoma (HCC).
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| MANAGEMENT OF ASCITES IN CIRRHOSIS |
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The term ascites is derived from the Greek word askos referring to a bag or sack. Ascites are defined as the pathologic accumulation of fluid within the peritoneal cavity. Cirrhosis of the liver is the most common cause of ascites and accounts for almost 85% of all cases of ascites (1). Numerous other disorders, however, including malignancy, cardiac failure, pancreatitis, and tuberculosis also can cause ascites. Ascites are the most common complication of cirrhosis,
and approximately 50% of subjects with compensated cirrhosis will develop ascites over a 10-year period. The onset of ascites is associated with worsened quality of life, increased risk of spontaneous bacterial peritonitis, and renal failure (2). After development of ascites, only 50% of patients will survive for 2 to
5 years (3,4). The principles of management of cirrhotic ascites and the relevant pathophysiology are discussed.
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| AASLD SINGLE-TOPIC RESEARCH CONFERENCE ON HEPATOCELLULAR CARCINOMA |
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The goal of the American Association for the Study of Liver Disease (AASLD) single-topic conference on hepatocellular carcinoma (HCC) was to highlight areas of research necessary to further our understanding of the pathogenesis and management of this disease.
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| NONINVASIVE TESTS FOR LIVER FIBROSIS |
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The field of noninvasive markers for the assessment of hepatic fibrosis has seen
tremendous growth in the last two decades. Surrogate markers are gradually being substituted for biomarkers that reflect the complex balance between synthesis and degradation of the extracellular matrix. Coupled with these promising tests are artificial
intelligence networks devised by sophisticated statistical instruments that incorporate a battery of laboratory tests and biomarkers with imaging modalities. Recently, gene identification and protein analysis have shown promise in identifying selected patients with mild or advanced fibrosis. Despite such progress, an important limitation of these tests is the frequent inability to detect mild fibrosis although patients at the end of the histological spectrum (i.e., advanced fibrosis or cirrhosis) are readily identified. With time, it is anticipated a combination of serological and radiological tests together with
genetic and proteomic investigations will provide accurate assessment of fibrosis in a costeffective and timely manner.
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| HEPATITIS C VIRUS AND KIDNEY DISEASE |
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Hepatitis C virus (HCV) infection remains frequent in patients on renal replacement therapy and has an adverse impact
on survival in infected patients on chronic hemodialysis as well as renal transplant (RT) recipients.
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| CORTICOSTEROIDS FOR ALCOHOLIC HEPATITIS - WHAT IS NEXT? |
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Alcoholic hepatitis (AH) is observed in approximately 20% of heavy drinkers. The treatment of AH remains controversial and will, in the near future, constitute one of the main challenges to clinicians involved in the management of severe alcoholic liver disease (1). Individual data from the last three randomized controlled trials (RCT), prospective studies and a recent RCT constantly showed
that patients with Maddrey function (DF) R32 treated by corticosteroids had a 2-month survival of 80% (2–5). Nevertheless, the efficacy of corticosteroids is still considered as a controversial issue for some authors.
Alternative therapies are required to improve the prognosis of patients with a severe form of AH (6). Progress in
understanding the pathogenesis of AH is opening up an exciting new era and is lending impetus to future evaluation
of new drugs targeting the TNF pathways (7–13). However, the classical view that considers a treatment effective only
when it improves survival needs to be modified. Indeed, the sample size of future studies comparing new drugs to
corticosteroids will never be sufficient to detect a difference in short-term survival [14]. Clinicians need to promote new primary endpoints in future randomized controlled trials evaluating drugs in patients with severe AH (Table 1). We suggest that a treatment should be declared successful in patients demonstrating biological improvement and who remained alive 1 or 2 months.
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| COAGULATION DISORDERS AND HEMOSTASIS IN LIVER DISEASE: PATHOPHYSIOLOGY AND CRITICAL ASSESSMENT... |
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Stephen H. Caldwell,1 Maureane Hoffman,2 Ton Lisman,3 B. Gail Macik,1 Patrick G. Northup,1 K. Rajender Reddy,4
Armando Tripodi,5 Arun J. Sanyal6 and the Coagulation in Liver Disease Group
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| HBV DRUG RESISTANCE: MECHANISMS, DETECTION AND INTERPRETATION |
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Tim Shaw, Angeline Bartholomeusz, Stephen Locarnini
Victorian Infectious Diseases Reference Laboratory, Locked Bag 815, Carlton South, Vic. 3053, Australia
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| CHOLANGIOCARCINOMA: MODERN ADVANCES IN UNDERSTANDING A DEADLY OLD DISEASE |
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Cholangiocarcinomas are tumors that arise anywhere in the biliary tract, presumably of cholangiocyte origin. The global
incidence of this rare disease is on the rise. Several known risk factors exist, and link chronic biliary inflammation to the pathogenesis of cholangiocarcinoma.
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| HEPATOTOXICITY OF DRUGS USED FOR TREATMENT OF OBESITY |
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Obesity is an incre asingly preval ent problem with m any associated health risks.
Obese patients may present with liver diseases directly attributable to their obesity, such as nonalcoholic steatohepatitis (NASH). However, many such individuals are prescribed various potentially hepatotoxic medications for obesity itself, as well as for the complications of obesity. Clinically, it may be difficult to distinguish the two. Furthermore, many of these medications are in common use, and some are not commonly recognized as potentially injurious to the liver. While some medications have predictable hepatotoxicity, many more have associated idiosyncratic reactions. We review the literature and casereports of hepatotoxicity associated with four categories of medications: those used primarily in the treatment of obesity, those used in the treatment of diabetes mellitus, those used in the treatment of hyperlipidemia, and those used in the treatment of hypertension. For each class, we present the described epidemiology, clinical presentation, pathology, and prognosis.
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| IMMUNOSUPPRESSION IN LIVER TRANSPLANTATION |
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Early mythology depicts two saints in a life-anddeath struggle to save a limb from a foregone fate.
Saints Cosmos and Damien replaced a cancerous leg with a limb from a deceased Moor. This illustration was mere fantasy until the latter part of the previous century
with the seminal surgeries performed by Dr. Joseph Murray on identical twins and, later, Dr. Starzls pioneering orthotopic liver transplant (OLT). Immunosuppression itself has come from the dark ages to where it stands today: a careful balancing act between toxicity and rejection.1-3 This article is designed as an overview of current immunosuppression in OLT and will not delve into areas such as basic science or pipeline preview.
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