Saturday, March 21, 2009
Effects of Alcohol
It is well known that heavy alcohol consumption can lead to severe liver disease including cirrhosis and hepatocellular carcinoma, but the effects of alcohol on HCV and its treatment are less well studied. As described in the December 15, 2008 Journal of Infectious Diseases, E. McCartney and colleagues performed a laboratory study using cultured Huh-7 cells to examine the effects of alcohol metabolism on HCV replication and the antiviral activity of interferon. They found that exposing the cells to ethanol significantly increased HCV replication, which was dependent on oxidative stress; when the researchers added NAC to the cell cultures, ethanol no longer increased HCV replication. Furthermore, the anti-HCV activity of interferon was also reduced in the presence of ethanol. "These in vitro results mimic what is often noted clinically," the researchers concluded, supporting the recommendation that people with chronic hepatitis C should avoid alcohol or consume only small amounts.
Effect of Diet in People with HCV
Chronic hepatitis C is associated with various metabolic complications such as insulin resistance, but the effects of diet on liver fibrosis progression and response to treatment are not well-understood. As reported in the December 2008 American Journal of Gastroenterology, C. Loguercio and colleagues studied 1084 chronic hepatitis C patients – 432 of whom were treated with interferon-based therapy – and 2326 uninfected control subjects. At baseline, there were no differences between the two groups with regard to dietary habits, metabolic status, or alcohol consumption; about half were classified as overweight and about 60% reported drinking alcohol. In a logistic regression analysis, intake of carbohydrates, lipids such as cholesterol, polyunsaturated fatty acids, and alcohol were independent risk factors for liver damage. In addition to heavier alcohol consumption, intake of some dietary components (including unsaturated fatty acids, iron, zinc, vitamin A, and niacin) differed significantly between treatment responders and non-responders. "Our results show that dietary composition is related to the extent of liver damage,” the study authors concluded. "This suggests that HCV patients may benefit from instructions regarding their diet."
Liver Disease with Undetectable HCV RNA
People infected with HCV (as indicated by antibodies in the blood) who have an undetectable viral load are usually considered to have inactive disease, and undetectable HCV RNA six months after completion of treatment is regarded as a cure. But a study in the December 2008 Hepatology suggests hidden HCV may still cause liver disease progression. M. Hoare and colleagues studied 172 HCV antibody positive but HCV RNA negative individuals who underwent liver biopsies between 1992 and 2000. After 102 were excluded for having other possible causes of liver damage, the remaining 70 participants were analyzed after a median seven years of follow-up.
Within this group, 5.7% became HCV RNA positive during follow-up, but the rest had continued undetectable viral load. Only five participants had normal liver biopsies; 82% had some fibrosis, with 24% having moderate to advanced fibrosis (Ishak stage 2-3). HCV RNA negative individuals had fewer CD4 T-cells and more CD8 T-cells than uninfected control subjects, but the same number as patients with detectable viral load. These findings suggest that HCV antibody positive people with undetectable HCV RNA have an ongoing immune response in the liver, supporting the view that the virus may persist in the liver in a majority of these cases.
Within this group, 5.7% became HCV RNA positive during follow-up, but the rest had continued undetectable viral load. Only five participants had normal liver biopsies; 82% had some fibrosis, with 24% having moderate to advanced fibrosis (Ishak stage 2-3). HCV RNA negative individuals had fewer CD4 T-cells and more CD8 T-cells than uninfected control subjects, but the same number as patients with detectable viral load. These findings suggest that HCV antibody positive people with undetectable HCV RNA have an ongoing immune response in the liver, supporting the view that the virus may persist in the liver in a majority of these cases.
Current Status of Therapy in Autoimmune Liver Disease
Abstract
Therapeutic strategies for autoimmune liver diseases are increasingly established. Although proportionately uncommon, specialist centers have with time refined the best approaches for each disease, based on an improved understanding of the spectrum of presentation. The major treatment aims are to prevent end-stage liver disease and its associated complications. As a result of drugs such as ursodeoxycholic acid, predniso(lo)ne and azathioprine, both primary biliary cirrhosis and autoimmune hepatitis are now less commonly indications for liver transplantation. Unfortunately, the same inroads in treatment efficacy have as yet not been made for primary sclerosing cholangitis, although the recognition that a subset of patients may have a treatable secondary sclerosing cholangitis (IgG4 related) is helping a proportion. With better biological understanding, more specific interventions are expected that will benefit all those with autoimmune liver diseases.
Introduction
Autoimmune liver diseases are chronic inflammatory processes in which an immunological attack is directed against hepatocytes and/or the biliary epithelium [Kumagi et al. 2008]. Table 1 illustrates the presently recognized common disease divisions. Such divisions may be artificial since broadly it is suggested that 10% of those with primary biliary cirrhosis (PBC) will have features of autoimmune hepatitis (AIH) [Chazouilleres et al. 1998; Czaja, 1998], 10% of adults with AIH have radiological evidence for sclerosing cholangitis (SC) [Abdalian et al. 2008] and a similar number of those with primary sclerosing cholangitis (PSC) will have histological evidence of AIH [van Buuren et al. 2000]. The rate of overlap seems higher in children with AIH, in whom 50% will have sclerosing cholangitis on endoscopic retrograde cholangiopancreatography (ERCP) [Gregorio et al. 2001].
The diseases reflect a balance of environmental and genetic factors [Weismuller et al. 2008; Mackay, 2007] and whilst broadly autoimmune in etiology, both immune and nonimmune pathways are likely involved in tissue damage. Once the balance is tipped towards tissue destruction a chronic process ensues and clinicians are now well placed to modify disease by direct immunosuppression (e.g. predniso(lo)ne/azathioprine) or indirect modification to the bile acid milieu (e.g. ursodeoxycholic acid [UDCA]). These diseases are uncommon, may progress slowly, and are recognized now to have a broad spectrum of presentation. Together these make clinical trial design and interpretation harder but herein we review the basis for the use of disease-modifying agents. Symptom control is covered more fully elsewhere [Hirschfield et al. 2008] and similarly the management of the poorly defined autoimmune overlap syndromes is also not detailed [Rust and Beuers, 2008].
Therapeutic strategies for autoimmune liver diseases are increasingly established. Although proportionately uncommon, specialist centers have with time refined the best approaches for each disease, based on an improved understanding of the spectrum of presentation. The major treatment aims are to prevent end-stage liver disease and its associated complications. As a result of drugs such as ursodeoxycholic acid, predniso(lo)ne and azathioprine, both primary biliary cirrhosis and autoimmune hepatitis are now less commonly indications for liver transplantation. Unfortunately, the same inroads in treatment efficacy have as yet not been made for primary sclerosing cholangitis, although the recognition that a subset of patients may have a treatable secondary sclerosing cholangitis (IgG4 related) is helping a proportion. With better biological understanding, more specific interventions are expected that will benefit all those with autoimmune liver diseases.
Introduction
Autoimmune liver diseases are chronic inflammatory processes in which an immunological attack is directed against hepatocytes and/or the biliary epithelium [Kumagi et al. 2008]. Table 1 illustrates the presently recognized common disease divisions. Such divisions may be artificial since broadly it is suggested that 10% of those with primary biliary cirrhosis (PBC) will have features of autoimmune hepatitis (AIH) [Chazouilleres et al. 1998; Czaja, 1998], 10% of adults with AIH have radiological evidence for sclerosing cholangitis (SC) [Abdalian et al. 2008] and a similar number of those with primary sclerosing cholangitis (PSC) will have histological evidence of AIH [van Buuren et al. 2000]. The rate of overlap seems higher in children with AIH, in whom 50% will have sclerosing cholangitis on endoscopic retrograde cholangiopancreatography (ERCP) [Gregorio et al. 2001].
The diseases reflect a balance of environmental and genetic factors [Weismuller et al. 2008; Mackay, 2007] and whilst broadly autoimmune in etiology, both immune and nonimmune pathways are likely involved in tissue damage. Once the balance is tipped towards tissue destruction a chronic process ensues and clinicians are now well placed to modify disease by direct immunosuppression (e.g. predniso(lo)ne/azathioprine) or indirect modification to the bile acid milieu (e.g. ursodeoxycholic acid [UDCA]). These diseases are uncommon, may progress slowly, and are recognized now to have a broad spectrum of presentation. Together these make clinical trial design and interpretation harder but herein we review the basis for the use of disease-modifying agents. Symptom control is covered more fully elsewhere [Hirschfield et al. 2008] and similarly the management of the poorly defined autoimmune overlap syndromes is also not detailed [Rust and Beuers, 2008].
A 56-year-old man with sudden onset of portosystemic encephalopathy years after severe electrocution trauma.
A 56-year-old white male painter, with a history of major electrocution and deep thermal injury, developed mental status changes initially ascribed to an acute neurological event. Unexpectedly, magnetic resonance imaging (MRI) of the head showed areas of high signal intensity in the basal ganglia, which can be observed in advanced liver disease. An electroencephalogram (EEG) suggested metabolic encephalopathy and coexistent elevation of ammonia, indicative of significant liver disease. The patient had had a long history of right upper quadrant pain and fluctuation in liver tests following the electrocution trauma. For these symptoms, he underwent surgery 7 years prior to his current presentation of portosystemic encephalopathy, and was found to have a gangrenous acalculous cholecystitis. Intraoperative cholangiogram suggested possible strictures within the right hepatic ducts. Multiple liver biopsies, however, showed only steatosis. Current evaluation including liver biopsy, MRI, magnetic resonance angiography (MRA), and magnetic resonance cholangiopancreatography (MRCP), revealed progression to biliary cirrhosis with large bile duct obstruction, and hepatic artery thrombosis/occlusion with evidence of left lobe atrophy and right lobe compensatory hypertrophy. The pathobiology of ischemic bile duct injury is discussed herein. The case is an example of serious late sequelae of an occupational injury.
Abnormalities of lipid metabolism in nonalcoholic fatty liver disease.
Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver abnormality in the United States and is strongly associated with the metabolic syndrome. Although many of the risk factors are well defined, the pathogenesis of NAFLD remains poorly understood. Recent studies have implicated several important cellular processes and signaling pathways that are affected by abnormal lipid metabolism, resulting in specific biochemical, histological, and clinical changes associated with NAFLD. Pharmacotherapy for NAFLD is limited and treatments are mainly to minimize risk factors. Understanding the disease pathogenesis is therefore important in identifying individuals with increased susceptibility for disease progression so lifestyle and risk modifications can be initiated early on. In this review, recent advances in the study of abnormal lipid metabolism and its impacts on histology and dysregulation of various cellular processes implicated in the genesis of NAFLD will be discussed.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver abnormality in the United States and is strongly associated with the metabolic syndrome. Although many of the risk factors are well defined, the pathogenesis of NAFLD remains poorly understood. Recent studies have implicated several important cellular processes and signaling pathways that are affected by abnormal lipid metabolism, resulting in specific biochemical, histological, and clinical changes associated with NAFLD. Pharmacotherapy for NAFLD is limited and treatments are mainly to minimize risk factors. Understanding the disease pathogenesis is therefore important in identifying individuals with increased susceptibility for disease progression so lifestyle and risk modifications can be initiated early on. In this review, recent advances in the study of abnormal lipid metabolism and its impacts on histology and dysregulation of various cellular processes implicated in the genesis of NAFLD will be discussed.
Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.
Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, College of Medicine, Rochester, Minnesota 55905, USA.
Nonalcoholic fatty liver disease (NAFLD) is characterized by insulin resistance, which results in elevated serum concentration of free fatty acids (FFAs). Circulating FFAs provide the substrate for triacylglycerol formation in the liver, and may also be directly cytotoxic. Hepatocyte apoptosis is a key histologic feature of NAFLD, and correlates with progressive inflammation and fibrosis. The molecular pathways leading to hepatocyte apoptosis are not fully defined; however, recent studies suggest that FFA-induced apoptosis contributes to the pathogenesis of nonalcoholic steatohepatitis. FFAs directly engage the core apoptotic machinery by activating the proapoptotic protein Bax, in a c-jun N-terminal kinase-dependent manner. FFAs also activate the lysosomal pathway of cell death and regulate death receptor gene expression. The role of ER stress and oxidative stress in the pathogenesis of nonalcoholic steatohepatitis has also been described. Understanding the molecular mediators of liver injury should promote development of mechanism-based therapeutic interventions.
Nonalcoholic fatty liver disease (NAFLD) is characterized by insulin resistance, which results in elevated serum concentration of free fatty acids (FFAs). Circulating FFAs provide the substrate for triacylglycerol formation in the liver, and may also be directly cytotoxic. Hepatocyte apoptosis is a key histologic feature of NAFLD, and correlates with progressive inflammation and fibrosis. The molecular pathways leading to hepatocyte apoptosis are not fully defined; however, recent studies suggest that FFA-induced apoptosis contributes to the pathogenesis of nonalcoholic steatohepatitis. FFAs directly engage the core apoptotic machinery by activating the proapoptotic protein Bax, in a c-jun N-terminal kinase-dependent manner. FFAs also activate the lysosomal pathway of cell death and regulate death receptor gene expression. The role of ER stress and oxidative stress in the pathogenesis of nonalcoholic steatohepatitis has also been described. Understanding the molecular mediators of liver injury should promote development of mechanism-based therapeutic interventions.
Mechanisms of disease progression in nonalcoholic fatty liver disease.
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic pathology, ranging from simple steatosis (also called nonalcoholic fatty liver or NAFL) in its most benign form, to cirrhosis in its most advanced form. Nonalcoholic steatohepatitis (NASH) is an intermediate level of hepatic pathology. Hepatocyte accumulation of triglyceride is a hallmark of NAFL and NASH, but this sometimes subsides once cirrhosis has developed. Triglyceride storage per se is not hepatotoxic. Rather, it is a marker of increased exposure of hepatocytes to potentially toxic fatty acids. NAFL progresses to NASH when adaptive mechanisms that protect hepatocytes from fatty acid-mediated lipotoxicity become overwhelmed and rates of hepatocyte death begin to outstrip mechanisms that normally regenerate dead hepatocytes. This triggers repair responses that involve activation of hepatic stellate cells to myofibroblasts. The myofibroblasts generate excessive matrix and produce factors that stimulate expansion of liver progenitor populations. The progenitor cells produce chemokines to attract various kinds of inflammatory cells to the liver. They also differentiate to replace the dead hepatocytes. The intensity of these repair responses generally parallel the degree of hepatocyte death, resulting in variable distortion of the hepatic architecture with fibrosis, infiltrating immune cells, and regenerating epithelial nodules. As in other types of chronic liver injury, cirrhosis ensues in patients with NAFLD when repair is extreme and sustained, but ultimately unsuccessful, at reconstituting healthy hepatic epithelia.
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic pathology, ranging from simple steatosis (also called nonalcoholic fatty liver or NAFL) in its most benign form, to cirrhosis in its most advanced form. Nonalcoholic steatohepatitis (NASH) is an intermediate level of hepatic pathology. Hepatocyte accumulation of triglyceride is a hallmark of NAFL and NASH, but this sometimes subsides once cirrhosis has developed. Triglyceride storage per se is not hepatotoxic. Rather, it is a marker of increased exposure of hepatocytes to potentially toxic fatty acids. NAFL progresses to NASH when adaptive mechanisms that protect hepatocytes from fatty acid-mediated lipotoxicity become overwhelmed and rates of hepatocyte death begin to outstrip mechanisms that normally regenerate dead hepatocytes. This triggers repair responses that involve activation of hepatic stellate cells to myofibroblasts. The myofibroblasts generate excessive matrix and produce factors that stimulate expansion of liver progenitor populations. The progenitor cells produce chemokines to attract various kinds of inflammatory cells to the liver. They also differentiate to replace the dead hepatocytes. The intensity of these repair responses generally parallel the degree of hepatocyte death, resulting in variable distortion of the hepatic architecture with fibrosis, infiltrating immune cells, and regenerating epithelial nodules. As in other types of chronic liver injury, cirrhosis ensues in patients with NAFLD when repair is extreme and sustained, but ultimately unsuccessful, at reconstituting healthy hepatic epithelia.
Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive.
Department of Pediatric Gastroenterology, CHUQ, Quebec City, Quebec, Canada.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and many other parts of the world. Its prevalence continues to rise-currently affecting approximately 20 to 30% of adults and 10% of children in the United States. NAFLD represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign nonprogressive clinical course, to steatohepatitis or NASH, a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Although currently a combination of noninvasive clinically available laboratory and imaging tests may help in the diagnostic evaluation of a patient with suspected NAFLD, a liver biopsy remains the only reliable way to precisely diagnose NASH and establish the severity of liver injury and presence of fibrosis. It also provides important information regarding prognosis as well as response to therapeutic interventions. However, a liver biopsy is an invasive and costly procedure, which is poorly suited as a diagnostic test for a condition that may affect about one-third of the U.S. population. This review provides a concise overview of the role of liver biopsy versus noninvasive diagnostic tools for the differentiation of fatty liver from nonalcoholic steatohepatitis as well as for the determination of presence and extent of fibrosis. In particular, this review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on potential future markers under investigation.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and many other parts of the world. Its prevalence continues to rise-currently affecting approximately 20 to 30% of adults and 10% of children in the United States. NAFLD represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign nonprogressive clinical course, to steatohepatitis or NASH, a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Although currently a combination of noninvasive clinically available laboratory and imaging tests may help in the diagnostic evaluation of a patient with suspected NAFLD, a liver biopsy remains the only reliable way to precisely diagnose NASH and establish the severity of liver injury and presence of fibrosis. It also provides important information regarding prognosis as well as response to therapeutic interventions. However, a liver biopsy is an invasive and costly procedure, which is poorly suited as a diagnostic test for a condition that may affect about one-third of the U.S. population. This review provides a concise overview of the role of liver biopsy versus noninvasive diagnostic tools for the differentiation of fatty liver from nonalcoholic steatohepatitis as well as for the determination of presence and extent of fibrosis. In particular, this review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on potential future markers under investigation.
Current and emerging therapies in nonalcoholic fatty liver disease.
University of Texas Health Science Center at San Antonio, Texas, USA.
The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.
The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.
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