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PubMed1983

Dual role of the liver in regulating circulating polymeric IgA in man: studies on patients with liver disease.

The human liver probably removes circulating polymeric IgA by two routes: (1) secretory component-mediated endocytic transport of polymeric IgA from portal tract blood vessels into bile across biliary epithelial cells and (2) uptake with possible catabolism by hepatocytes and/or sinusoidal phagocytic cells by uncharacterized receptor(s). Failure of either clearance mechanism due to liver disease results in elevated serum polymeric IgA levels. In patients with cholestasis, the raised serum polymeric IgA concentration is due to reflux of biliary secretory immunoglobulin into the blood.

Alkaline Phosphatase↗
PubMed2001

Prevention in liver disease.

Prevention has become an important component of medical therapy for a variety of diseases. Preventive strategies in liver disease are relatively underdeveloped and have focused mainly on specific complications of chronic liver disease and vaccination for viral hepatitis. Although public health initiatives designed to prevent certain forms of liver disease are in place, they seem to be underutilized and their utility has not been evaluated. The development of a comprehensive approach using public health initiatives in conjunction with strategies by health care providers is important because of the potential for decreasing the human and health care costs associated with hepatic dysfunction. This article reviews the available literature regarding prevention for health care providers, includes a summary of ongoing public health initiatives, and suggests an approach to prevention in liver disease. It is intended to raise awareness and encourage implementation of preventive strategies in hepatology.

Adult↗
PubMed2005

Hemostatic defects in end stage liver disease.

End stage liver disease results in a complex and variably severe failure of hemostasis that predisposes to abnormal bleeding. The diverse spectrum of hemostatic defects includes impaired synthesis of clotting factors, excessive fibrinolysis, disseminated intravascular coagulation, thrombocytopenia, and platelet dysfunction. Hemostasis screening tests are used to assess disease severity and monitor the response to therapy. Correction of hemostatic defects is required in patients who are actively bleeding or require invasive procedures. Fresh frozen plasma, cryoprecipitate, and platelet transfusion remain the mainstays of therapy until larger trials confirm the safety and efficacy of recombinant factor VIIa in this population.

Blood Coagulation Disorders↗
PubMed2005

Apoptosis in liver diseases--detection and therapeutic applications.

The liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and dietary antigens. Amongst the hepatitis viruses, only hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. Of the different antiviral defense systems employed by the tissue, apoptosis significantly contributes to the prevention of viral replication, dissemination, and persistence. Loss of tolerance to the liver autoantigens may result in autoimmune hepatitis (AIH). This review outlines the recent findings that highlight the role and mechanisms of apoptotic processes in the course of liver diseases. Among factors that contribute to liver pathology, we discuss the role of tumor necrosis factor (TNF)-alpha, HBx, ds-PKR, TRAIL, FasL, and IL-1alpha. Since TNF and FasL-induced hepatocyte apoptosis is implicated in a wide range of liver diseases, including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure, these items will be discussed in greater detail in this review. We also highlight some recent discoveries that pave the way for the development of new therapeutic strategies by protecting hepatocytes (for example by employing Bcl-2, Bcl-XL or A1/Bfl-1, IAPs, or synthetic caspase inhibitors), or by the induction of apoptosis in stellate cells. The assessment of the severity of liver disease, as well as monitoring of patients with chronic liver disease, remains a major challenge in clinical hepatology practice. Therefore, a separate chapter is devoted to a novel cytochrome c-based method useful for the diagnosis and monitoring of fulminant hepatitis.

Apoptosis↗
PubMed1976

Immunodeficiency, xanthomas and obstructive liver disease.

Chronic obstructive liver disease and secondary hyperlipidemia developed in an immunodeficient boy. Sequential addition of cholestyramine and phenobarbital to his medical regimen, following an initial response to bile drainage, resulted in the disappearance of xanthomas and pruritus, and the restoration of normal serum concentrations of lipids and bile acids. This improvement may result from shifting the bile acid pool from the peripheral blood compartment to the enterohepatic circulation.

Bile Acids and Salts↗
PubMed2003

[Alcoholic liver disease].

Ethanol toxicity on liver is a function of duration of alcoholism, amount of daily intake of alcohol and patient's nutrition. The threshold of alcohol toxicity on the liver is about 40 g of ethanol daily in men and 20-30 g in women, however liver cirrhosis develops in no more than 8-20% of patients exceeding this values. Ethanol is oxidized in the liver to acetaldehyde--a compound considerably more toxic than ethanol itself. Despite small amount of alcohol dehydrogenase (ADH) found in gastric mucosa, the metabolism of ethanol in this site may have an important hepatoprotective effect. The oxidation of ethanol is associated with a change of hepatocyte redox homeostasis, which leads to a number of metabolic disorders such as lactic acidosis, hyperlipidaemia and hyperuricaemia. Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, in particular cytochrome CYP2E1. This fact is responsible for development in alcoholic liver associated with rise of oxygen consumption, excessive production of free radicals and increased metabolism of ethanol, vitamin A and testosterone. Ethanol and acetaldehyde have a deleterious effect, both the direct and indirect, on hepatocytes e.g., generating radical oxygen species and damaging intestinal mucosal barrier. Cellular oxidative stress that is caused by both an excess of free radicals and the antioxidatives' deficiency (glutathion, vitamin E, phosphatidylcholine), may be the principal factor responsible for progression of alcoholic liver disease. Among other factors accelerating alcohol-related liver lesion there are certain drugs, high fat diet, infection with HCV and genetic factors (female sex, enzymatic polymorphic forms of ADH and ALDH, hemochromatosis). Great importance in pathogenesis of necrotic and inflammatory hepatic events is being attributed to portal endotoxaemia and cytokines induced within the liver, in particular TNF-alpha and interleukin 8. These cytokines play a key role in development of alcoholic hepatitis, which clinical severity ranges from subclinical to fatal forms. Apart from abstinence, the treatment of alcohol liver disease is based on hyperalimentation, since alcoholism is generally associated with protein malnutrition. In severe forms of alcohol hepatitis corticosteroids are recommended.

Alcoholism↗
PubMed2004

Molecular characterization of hepatocystin, the protein that is defective in autosomal dominant polycystic liver disease.

BACKGROUND & AIMS: Autosomal dominant polycystic liver disease is characterized by the presence of numerous cysts spread throughout the liver parenchyma. Recently, we discovered that polycystic liver disease is caused by mutations in the protein kinase C substrate 80K-H gene, which encodes a protein named hepatocystin. Previous studies have identified hepatocystin as a protein kinase C substrate, a component of a cytosolic signal transduction complex, a receptor for advanced glycation end products, a vacuolar protein, and the beta subunit of endoplasmic reticulum glucosidase II. Thus, the exact localization and cellular function of hepatocystin remain unclear. METHODS: The localization and biochemical properties of normal and polycystic liver disease mutant forms of hepatocystin were examined by using a combination of immunofluorescence microscopy, immunoblotting, metabolic labeling, immunoprecipitation, and carbohydrate analyses. RESULTS: Normal hepatocystin localizes to the endoplasmic reticulum, where it assembles with the glucosidase II alpha subunit. The 1338-2A-->G truncating mutation in hepatocystin observed in some polycystic liver disease patients produces a protein that is not retained in the endoplasmic reticulum but is secreted into the medium. This mutant protein fails to assemble with the glucosidase II alpha subunit. As a consequence, mutant hepatocystin is undetectable in liver cysts. In addition, levels of normal hepatocystin and of the glucosidase II alpha subunit are substantially reduced in liver and Epstein-Barr virus-immortalized B lymphoblasts from patients with polycystic liver disease. CONCLUSIONS: These findings are consistent with a role of hepatocystin in carbohydrate processing and quality control of newly synthesized glycoproteins in the endoplasmic reticulum. Therefore, altered endoplasmic reticulum processing of some key regulator of cell proliferation may underlie polycystic liver disease.

Calcium-Binding Proteins↗
PubMed2005

Histopathology of pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common in children and adolescents. However, standard histological criteria for pediatric NAFLD and NASH are undeveloped. We reviewed consecutive patients ages 2 to 18 years with biopsy-proven NAFLD diagnosed between 1997 and 2003. Biopsies were evaluated by two pathologists for individual features of steatohepatitis. Agglomerative hierarchical cluster analysis demonstrated two different forms of steatohepatitis. Type 1 was characterized by steatosis, ballooning degeneration, and perisinusoidal fibrosis; type 2 was characterized by steatosis, portal inflammation, and portal fibrosis. The study included 100 children with NAFLD. Simple steatosis was present in 16% of subjects, and advanced fibrosis was present in 8%. Type 1 NASH was present in 17% of subjects, and type 2 NASH was present in 51%. Boys were significantly (P < .01) more likely to have type 2 NASH and less likely to have type 1 NASH than girls. The NASH type differed significantly (P < .001) by race and ethnicity. Type 1 NASH was more common in white children, whereas type 2 NASH was more common in children of Asian, Native American, and Hispanic ethnicity. In cases of advanced fibrosis, the pattern was generally that of type 2 NASH. In conclusion, type 1 and type 2 NASH are distinct subtypes of pediatric NAFLD, and type 2 is the most common pattern in children. NASH subtypes should be considered when interpreting liver biopsies and planning studies of the pathophysiology, genetics, natural history, or response to treatment in pediatric NAFLD.

Adolescent↗
PubMed1976

[Relevance of biochemistry in diagnosis and development of alcoholic liver disease (author's transl)].

In a group of 205 patients with alcoholic diseases of liver the diagnostic relevance of biochemical tests (GOT, GPT, AP, GGTP, BSP) was reconsidered with discriminatory process (separation of diagnosis). The group contained 16 patients with nutritional-caused and 41 cases with alcoholic-caused fatty-infiltration of liver. 148 patients showed a toxic chronic liver disease; 52 a chronic hepatitis and 96 cirrhosis of liver. Laparoscopy and morphology guaranteed the clinical diagnosis and therefore the accuracy of biochemistry in separation of diagnosis was given. The biochemical tests were not able to offer a separation of fatty-infiltration with reference to cause, changes of the process in toxic hepatitis and cirrhosis were announced. Intersection in several cases was noticed and biochemical tests were not able to substitute endoscopy and morphology for clinical and diagnostic use in all cases. In every regard the enzyme-tests,--above mentioned--, and determination of sulfobromthalein are aptly to development of diseases and deficiency of alcohol.

Alanine Transaminase↗
PubMed1983

IgA subclasses in liver tissues in alcoholic liver disease.

Examination of liver biopsy specimens from 59 patients with alcoholic liver disease and 21 nonalcoholics by immunofluorescence and immunoperoxidase methods using fluorescein-conjugated and peroxidase-labeled antisera against IgA, IgA1, IgA2, and S-IgA showed that 47 of 59 biopsy specimens from alcoholics and 0 of 21 from non-alcoholics showed a "continuous" pattern of IgA and IgA-subclass deposition (P less than 0.001). Grading the intensity of immunofluorescence on 1-4 scale, biopsies with the continuous pattern showed grade 3-4 activity against IgA2 and S-IgA and only grade 1-2 activity against IgA1. Biopsies with the discontinuous pattern showed only grade 1-2 activity against S-IgA, IgA2, and IgA1. Grade 3-4 activity was persistent in all the 47 specimens with the continuous pattern, despite pretreatment with blocking anti-IgA1, whereas 20 and 38 biopsies showed the same activity after blocking with anti-IgA2 and anti-S-IgA sera, respectively. It is concluded from these studies that IgA2 subclass formed a major subclass component contributing to the continuous pattern of IgA deposition in hepatic tissues and that the major source for this IgA in alcoholics was probably derived from the gastrointestinal tract.

Fluorescent Antibody Technique↗
PubMed2006

Extensive mutational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease.

Autosomal dominant polycystic liver disease (PCLD) is characterized by progressive development of multiple (> 20) liver cysts. Two separate genes, PRKCSH and SEC63, have been identified to cause familial PCLD. We designed this study with two goals: to assess the relative contribution of PRKCSH and SEC63 mutations in a cohort of unrelated patients with a variable number of liver cysts, and to assess the effect of these mutations on the severity of the PCLD phenotype. We selected patients with two or more liver cysts on radiological studies and excluded those with renal cysts. A total of 51 patients entered the study and three groups were distinguished: A, 2-10 cysts (18 patients); B, 11-20 cysts (nine patients); and C, more than 20 cysts (24 patients). In total we found that eight patients with multiple liver cysts (16%) had PRKCSH (5) or SEC63 (3) mutations. Two patients (11%) from group A had missense mutations (1 PRKCSH and 1 SEC63). Six patients (25%) with more than 20 liver cysts had mutations (4 PRKCSH and 2 SEC63), of which five mutations were chain-terminating. In conclusion, both PRKCSH and SEC63 mutations are associated with polycystic liver disease. Frequency and severity of mutations is higher among patients with more than 20 liver cysts, but also patients with as few as eight liver cysts can be mutation carriers.

Calcium-Binding Proteins↗
PubMed1986

Alterations in relative proportions of microheterogenous forms of human alpha 1-acid glycoprotein in liver disease.

To determine whether liver damage correlates with typical changes in alpha 1-acid glycoprotein (alpha 1-AGP) carbohydrate branching, we selected patients with liver disease determined by histological liver findings. The severity of their illness was assessed by a clinical classification depending on the presence singly or together of four clinical complications (jaundice, ascites, hepatic encephalopathy and weight loss). An alpha 1-AGP crossed immunoelectrophoresis with Concanavalin A, an easy-to-perform method, revealed 3 or 4 subpopulations, the areas of which were calculated. A ratio R was determined as the most anodic peak area relative to the other ones. In our experimental conditions a ratio R value exceeding 1 correlated with the presence of one or more clinical complications. These results, evidencing fluctuations in the proportion of the carbohydrate variants of alpha 1-AGP, lead us to propose such a ratio as an index for grading liver damage. The sensitivity of this test was 86% and its specificity was 83%.

Clinical Laboratory Techniques↗
PubMed2001

Early-onset liver disease complicated with acute liver failure in Alstrom syndrome.

We report a case of Alstrom syndrome with evidence of extensive hepatic disease diagnosed at five years of age, who subsequently developed acute liver failure and died at eight years of age. Such a case, with the patient dying before the age of ten, has not been described before. The biochemical findings during our patient's liver failure raised the question of a possible mitochondrial function defect in this syndrome. Further investigation of this possibility is needed.

Abnormalities, Multiple↗
PubMed1995

Growth hormone, insulinlike growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease.

The liver is the major source of circulating insulinlike growth factor-I (IGF-I) and has been suggested as a major source of at least two of the major binding proteins that modify its bioavailability. We aimed to assess the direct effects of liver dysfunction on serum levels of IGF-1 and its major binding proteins by measuring fasting levels of growth hormone, IGF-1, IGFBP-1, IGFBP-3, insulin, C peptide, and glucose in 35 patients with cirrhosis and during an oral glucose tolerance test in 16 of those patients. Serum levels of growth hormone (GH) were high in the patients: median, 12.0 mU/L (range, 1 to 87) compared with normals, 0.95 mU/L (0.1 to 20) (P < .0005) and serum IGF-1 levels were low: 81 ng/mL (38 to 153) versus 193 ng/mL (151 to 235) (P < .0001). Serum IGFBP-3 levels were low in the patients: 1.59 mg/L (0.46 to 4.43) compared with normals, 5.41 (4.34 to 6.11) (P < .0001), and there was a significant negative correlation between IGFBP-3 levels and Childs Pugh score (r = .63 P < .0001). Fasting IGFBP-1 levels were significantly higher in the patients 31 ng/mL (11 to 92) than normals, 14 (7 to 20) (P < .0001). There was no correlation between fasting insulin and IGFBP-1 levels despite high fasting insulin levels. A decrease in IGFBP-1 levels was seen during the glucose tolerance test (GTT) in all patients. In conclusion, there are significant changes in the levels of two of the major IGF-1 binding proteins that may further limit the bioavailability of already low circulating IGF-1 levels. Substrate availability appears to be a stronger influence on fasting IGFBP-1 levels than does insulin, and the close correlation of IGFBP-3 with liver function indicates a dominant regulatory role of the hepatocyte.

Adult↗
PubMedDate not supplied

[The impact of alcohol and chronic liver disease of micronutrients metabolism].

Liver disease, alcohol and malnutrition are combinations usually associated with micronutrient impairment. Chronic liver disease courses with lower storage and activation of vitamin-coenzymes related to their malabsorption. Alcohol worsens the picture by reducing food intake, increasing micronutrients utilization and decreasing their absorption secondary to either intestinal or pancreatic injuries. Other concurrent causes would be drug treatments, urinary losses, protein deficiency and oxidative stress. As consequences the clinical signs are anemia, liver steatosis, oxidative stress and immunosuppression.

Alcoholism↗
PubMed2001

Liver disease and diabetes mellitus.

The liver plays an important role in the pathogenesis of NIDDM. More importantly to the clinician is the myriad of situations in which the care of the patient with diabetes is affected by or causes an effect to the liver. Patients with underlying diabetes can present with abnormal liver chemistries, which can represent findings as benign as hepatic steatosis or as severe as cirrhosis of the liver. The medications used to treat diabetes can be potent hepatotoxins. Several primary liver diseases are associated with increased risk of the development of diabetes. Epidemiologically, there seems to be a correlation between diabetes mellitus, the most common endocrinologic disease, and hepatitis C, the leading cause of chronic liver disease in the United States. In the management of end-stage liver disease, both cirrhosis and orthotopic liver transplantation promote glucose intolerance and diabetes in a number of patients through various mechanisms including insulin resistance and impaired insulin secretion. These relationships highlight both the importance of the liver as an endocrine organ and the multisystem aspects of the patient with diabetes mellitus.

Chemical and Drug Induced Liver Injury↗