Copper kinetics in liver disease

The plasma clearance and the liver uptake of intravenously administered (64)Cu were significantly impaired in four patients with Wilson's disease. These defects were unlikely to be simply expressions of the high liver copper concentration as the plasma clearance and hepatic uptake of (64)Cu were normal in four patients with primary biliary cirrhosis, in whom the liver copper concentration was raised to a degree comparable to that in Wilson's disease. The normal liver uptake and plasma clearance of (64)Cu in three patients with other forms of hepatocellular disease suggest that impaired liver cell function does not have a significant effect. The precise nature of the defect in copper transport in Wilson's disease remains to be elucidated; it is possible that delayed uptake of copper by the hepatic lysosomes may account for the toxic effects of the metal.     

Mitochondrial enzyme activities in liver biopsies from patients with alcoholic liver disease

The hypothesis that mictochondrial damage is a significant factor in the pathogenesis of alcoholic liver disease (ALD) was investigated by enzymic analysis of mitochondrial fractions isolated from needle biopsy specimens from control patients, patients with fatty liver due to chronic alcoholism, and from patients with other forms of liver disease. Enzymes associated with the inner and outer mitochondrial membranes showed normal levels in ALD. Enzymes associated with the mitochondrial matrix, glutamate dehydrogenase, malate dehydrogenase and aspartate aminotransferase showed significantly raised levels in ALD, but the levels in patients with non-alcoholic liver disease was normal. In addition, analysis of the mitochondria by sucrose density gradient centrifugation revealed no differences between control tissue and liver from patients with alcoholic liver disease. These results do not indicate that there is significant mitochondrial damage in ALD. The raised mitochondrial matrix enzymes may represent an adaptive response to the ethanol load.     

Cognition in liver disease.

BACKGROUND: Cognitive dysfunction has been observed in a range of liver diseases including chronic hepatitis C virus, alcoholic liver disease, primary biliary cirrhosis and Wilson's disease. Such dysfunction may range from mild cognitive changes to overt hepatic encephalopathy, and represents a significant complication of liver disease that may negatively impact the patient's quality of life, and normal activities of daily living (e.g., driving). METHOD: This article reviews the published evidence relating to cognitive dysfunction in liver disease. OUTCOME: Issues of definition, diagnosis, epidemiology, aetiology, treatment and outcome are discussed. Particular attention is devoted to identifying the mild cognitive changes that occur in liver diseases of different aetiology.     

Angiogenesis in chronic liver disease

Background: Chronic liver disease is characterized by inflammation and fibrosis. As a consequence angiogenesis leading to new vasculature may have prognostic value in disease progression. Interfering with angiogenesis may be a potential target to avoid progression of liver disease. Hence we planned to evaluate the CD34 and vascular endothelial growth factor (VEGF), the markers for angiogenesis in chronic liver disease.Method: Liver biopsies from 79 patients of chronic liver disease and 21 cases of HCC (M: F = 4:1, age range 22 to 80) were stained for routine HE, CD 34 and VEGF immunostaining (Dako Corp &; Santa Cruz respectively). Etiologies of chronic liver disease were alcoholic liver disease, HBV, HCV infection, NAFLD, autoimmune liver disease, and cryptogenic liver disease. Thirty biopsies from normal liver obtained at autopsy were taken as controls. Expressions of CD 34 and VEGF were compared with the stage of fibrosis. Results: Out of 79 patients, angiogenesis was seen in 45.5% cases of chronic liver disease. None of the case with normal liver histology was CD 34 or VEGF positive. No significant correlation of angiogenesis was found between any etiologies of chronic liver disease. CD 34 was positive in 18/21 (85.7%) cases of hepatocellular carcinoma. CD 34 and VEGF positivity was 20.9% and 46.5% in stage 1 and 2 fibrosis while it was 75% and 80% in stage 3 and 4 fibrosis respectively. VEGF appeared more common as compared to CD 34 in early fibrosis. Conclusion: Angiogenesis was present in 45.5% cases of chronic liver disease. It was proportional to the increase in stage of fibrosis. Expression of VEGF was commonly found in early stages of fibrosis. Hence, therapeutic strategies of inhibiting VEGF expression may be of importance in preventing the progression of chronic liver disease in its early stage.     

Changes in liver and spleen volumes in alcoholic liver disease

Liver and spleen volumes were determined using computed tomography in 57 subjects with alcoholic liver disease and 76 subjects with nonalcoholic liver disease, in order to clarify the clinical characteristics and pathogenetic mechanisms of portal hypertension in alcoholic liver disease. The liver volumes in alcoholic liver disease were significantly larger than those in nonalcoholic liver disease, except in cases of decompensated liver cirrhosis. The increase in liver volume in alcoholic liver disease showed a significant correlation with the degree of hepatocytic ballooning. Overlapping of values for liver volume between alcoholic and nonalcoholic liver disease was quite small, suggesting that determination of liver volumes could be helpful for making etiological diagnoses in chronic liver disease. Spleen volumes were increased in the advanced cases of both alcoholic and nonalcoholic liver disease. The correlations between liver and spleen volumes were quite different between alcoholic and nonalcoholic liver disease. In nonalcoholic liver disease, a negative correlation was obtained, while, on the other hand, it was significantly positive in alcoholic liver disease. This appears to suggest that the pathogenetic mechanism of portal hypertension may differ between the diseases. After abstinence from alcohol, the decrease in liver and spleen volumes showed a statistically significant correlation, suggesting that ballooning of the hepatocytes may play a role in the augmentation of portal hypertension in alcoholic liver disease.     

Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology

BACKGROUND/AIMS: The significance of abnormal liver function tests in the absence of diagnostic serology is unclear. The aim of this study was to report liver biopsy findings in a large group of patients with unexplained abnormal liver biochemistry. METHODS: Histological findings were examined in 354 patients who underwent liver biopsy to investigate abnormal liver function tests. RESULTS: Six percent of patients had a normal liver biopsy while 26% were found to have some degree of fibrosis and 6% were cirrhotic. Thirty four and 32% of biopsies suggested non-alcoholic steatohepatits or fatty liver respectively. Other diagnoses included cryptogenic hepatitis, drug toxicity, primary and secondary biliary cirrhosis, autoimmune hepatits, alcohol-related liver disease, primary sclerosing cholangitis, haemochromatosis, amyloid and glycogen storage disease. Patient management was directly altered in 18% of patients due to liver biopsy findings and three families were entered into screening programmes for inheritable liver disease. CONCLUSIONS: The finding of abnormal liver function tests in the absence of diagnostic serology may indicate significant liver disease. Liver biopsy yields a range of liver diseases of diverse nature and extent. Liver diseases may be uncovered for which specific treatment is indicated.     

Recurrent nonviral liver disease following liver transplantation

Recurrent disease after liver transplantation is well recognized and remains a potential cause of premature graft loss. The rates of recurrence are difficult to establish because of the lack of consistency in diagnostic criteria and approaches to diagnosis. Owing to the fact that recurrent parenchymal disease may occur in the presence of normal liver tests, those centers that use protocol biopsies will report greater rates of recurrence. It is important to recognize that rates of recurrence vary according to indication and show little correlation with rates of graft loss from recurrent disease. Recurrance rates are greatest for primary sclerosing cholangitis and autoimmune hepatitis, and low reccurrance rates are reported for alcoholic liver disease and recurrent primary biliary cirrhosis. The impact of recurrent nonalcoholic fatty liver disease is not yet clear. Patients and clinicians need to be aware of the possibility of recurrent disease in the differential diagnosis of abnormal liver tests, and management stategies may require alteration to reduce the impact of disease recurrence on outcome. Finally, an understanding of which diseases do recur after transplantation and identification of the risk factors may lead to a better understanding of the pathogenetic mechanisms of these conditions.     

Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage

Objective: Only 30% of alcoholics develop cirrhosis, suggesting that the development of alcohol-induced liver injury requires one or more additional factors. Animal studies have shown that gut-derived endotoxin is one such factor. Because increased intestinal permeability has been shown to cause endotoxemia, we hypothesized that increased gastrointestinal permeability contributes to the pathogenesis of alcoholic liver disease. This study aimed to measure gastroduodenal and intestinal permeability in alcoholics with and without chronic liver disease and in nonalcoholic subjects with chronic liver disease. Methods: Gastroduodenal permeability was assessed by measurement of urinary excretion of sucrose after oral administration. Intestinal permeability was assessed by measurement of urinary lactulose and mannitol after oral administration of these sugars. Results: Alcoholics with no liver disease showed a small but significant increase in sucrose excretion. Alcoholics with chronic liver disease demonstrated a marked and highly significant increase in urinary sucrose excretion relative to the controls, to the alcoholics with no liver disease, and to the nonalcoholics with liver disease. Alcoholics with chronic liver disease demonstrated a marked and highly significant increase in both lactulose absorption and in the urinary lactulose/mannitol ratio (alcoholics 0.703 vs controls 0.019,   p = 0.01  ). In contrast, alcoholics with no liver disease and nonalcoholics with liver disease showed normal lactulose absorption and normal lactulose/mannitol ratio. Conclusion: Because only the alcoholics with chronic liver disease had increased intestinal permeability, we conclude that a "leaky" gut may be a necessary cofactor for the development of chronic liver injury in heavy drinkers.     

Drug-induced liver diseases

About 1000 drugs produced world-wide may lead to clinically relevant hepatotoxic reactions which are unpredictable at normal doses and occur at various frequencies. Among these are well established therapeutic drugs which have been in use for years or decades as well as newly introduced drugs, the number of which is steadily increasing. For the development of drug-induced liver disease, various pathogenetic mechanisms, many risk factors and variable latency periods are known. The histological picture may imitate practically all known non-toxic liver diseases from which toxic liver disease needs to be differentiated. Patients under drug therapy require regular medical follow-up with regard to the development of toxic liver disease since the prognosis is only good with early recognition and immediate withdrawal of the alleged drug. Specific therapeutic modalities to prevent toxic liver disease are limited to paracetamol overdosage which is treated by the application of N-acetylcysteine. For other drug-induced liver diseases characterised by a prolonged course, therapy with ursodeoxycholic acid or steroids may be helpful. When fulminant drug-induced liver failure occurs, liver transplantation is the therapy of choice with a better prognosis than a conventional therapy. Despite this therapeutic option more than 40 different drugs are known to have caused lethal forms of toxic liver disease. Physicians have therefore to be alert to early recognize drug-induced liver disease and to withdraw the drug at first suspicion of the diagnosis.     

Characteristics of chronic hepatitis B patients who underwent liver biopsies

Summary. Significant liver disease has been reported in chronic hepatitis B patients with normal alanine aminotransferase (ALT) but most studies performed biopsies on selected patients only. The aims of this study were to determine the rate of liver biopsy, characteristics of patients who underwent a biopsy and factors associated with significant liver disease in a cohort of such patients. Records of patients with chronic hepatitis B during a 10‐year period were reviewed. Significant liver disease was defined as Knodell HAI ≥ 7 and/or Ishak fibrosis ≥ 3. Of 743 patients, 55.7% were Asian, 56.4% were men, and the mean age was 43.1 years. One hundred and ninety‐three (26%) had undergone a biopsy. Biopsied patients were more likely to be men, HBeAg positive, and had lower platelet and higher alkaline phosphatase, bilirubin, ALT and hepatitis B virus (HBV) DNA. Significant liver disease was observed in 20% of patients who had normal ALT at presentation, 14% of those with normal ALT at the time of biopsy and in none of the patients with persistently normal ALT. Patients with normal ALT who were biopsied had higher HBV DNA and higher ALT than those not biopsied. Multivariate analysis showed that low albumin at the time of biopsy and HBV DNA >5 log₁₀ copies/mL were predictors of significant liver disease. Significant liver disease is rare in patients with chronic HBV and persistently normal ALT and liver histology of chronic HBV infected patients with normal ALT cannot be generalized to other patients with normal ALT that were not biopsied.     

New insights into the coagulopathy of liver disease and liver transplantation

INTRODUCTION The liver plays several key roles in blood coagulation being involved in both primary and secondary hemostasis[1]. It is the site of synthesis of all coagulation factors and their inhibitors except for von Willebrand factor (vWf)[2]. Liver da…     

Expression of factor VII in the liver of patients with liver disease: correlations with the disease severity and impairment in the hemostasis.

Factor VII (FVII) plasma levels in patients with liver disease may be below the normal range. However, no data are available on FVII expression in liver biopsies from patients with liver diseases other than cirrhosis. We have analyzed the expression of FVII by in situ hybridization in liver biopsies from 50 patients in comparison with the procoagulant activity of FVII, and with the plasma levels as activated FVII (FVIIa) and FVII antigen. The level of FVIIa was significantly lower in stage 4 liver fibrosis patients than in the remaining ones (P < 0.05). The percentage of hepatocytes expressing FVII was significantly lower in stage 4 liver fibrosis patients (4.1+/-1.3%) than in stage 3 (22.7+/-6.1%), stage 2 (31.5+/-6.1%), stage 1 (43.7+/-8.2%) and stage 0 patients (63.8+/-4.4%) (P < 0.001). These percentages correlated inversely in a statistically significant way with the histological activity index and the liver function tests. We have demonstrated that the FVIIa plasma levels in patients with chronic liver disease other than cirrhosis may be below the normal range in the absence of blood coagulation impairment. The percentage of hepatocytes expressing FVII decreases as the severity of liver damage increases.     

Fatty liver disease in morbid obesity

About 90 per cent of morbidly obese patients show histological abnormalities of the liver. One third of patients have fatty change involving more than 50 per cent of hepatocytes. Fatty liver disease can be divided into four histological groups: Fatty liver, fatty hepatitis, fatty liver with portal fibrosis, and cirrhosis. Most patients show only fatty change. Alcohol, drugs, diabetes, poor nutrition, and weight-reducing surgery contribute to progressive liver damage, but morbid obesity alone may lead to severe disease showing all the features of alcoholic hepatitis and may end in cirrhosis and liver failure. The accumulation of fat alone is unlikely to be the stimulus to inflammation and fibrosis. Only one fifth of patients have complaints that arise from the liver. The development of severe fatty liver disease may also be asymptomatic and rarely shows the florid picture associated with alcoholic hepatitis. There is poor correlation of liver function test results with morphology in obesity. ALT levels exceeding twice the normal limit have some predictive value for histological grades of severity, but they are present in few patients. Pericentral and pericellular fibrosis in prebypass liver biopsies may be an important prognostic lesion for the development of fatty hepatitis and cirrhosis. In contrast with the frequent progression to massive fatty change, inflammation and fibrosis after bypass surgery, weight loss by low-calorie dieting, or starvation is accompanied by improvement in fatty change and return of liver function tests to normal.     

Reduced leucocyte zinc in liver disease.

The zinc content of peripheral blood leucocytes has been measured in normal controls and in three groups of patients with liver disease. A significant reduction in leucocyte zinc, but not erythrocyte zinc, was observed in patients with primary biliary cirrhosis, alcoholic cirrhosis, and active chronic hepatitis. It is suggested that the nucleated tissues of some patients with liver disease are therefore zinc deficient, and that leucocyte zinc may prove of value in the assessment of the zinc status of such patients.     

Surgery for adult polycystic liver disease

Adult polycystic liver disease, commonly associated with polycystic kidney disease, can result in massive hepatomegaly and debilitating symptoms. Surgical intervention for symptomatic polycystic liver disease, such as cyst fenestration or liver resection has been associated with significant morbidity and inconsistent long-term palliation. However, selected patients with severe symptoms benefit from liver resection and extensive fenestration with acceptable morbidity and mortality. Total hepatectomy and orthotopic liver transplantation may be considered for patients with severe adult polycystic liver disease.     

Antipyrine clearance per unit volume liver: an assessment of hepatic function in chronic liver disease.

Liver size has been estimated clinically and by a non-invasive ultrasound technique in 16 normal subjects, 16 patients with cirrhosis, 10 patients with chronic biliary obstruction, and three patients with primary hepatoma. Antipyrine disposition was also measured in each subject. Hepatomegaly was not clinically detectable until there was approximately a 20% increase in liver size. Additional increases in size correlated significantly with clinical estimates of hepatomegaly. Antipyrine clearance had a three-fold range in normal subjects. Its mean value was significantly reduced in each subgroup of patients with liver disease. However, 48% of patients with liver disease had values within the normal range. In normal subjects there was a significant correlation between antipyrine clearance and liver volume. Thus, intersubject variation in clearance normalised for liver volume was less than clearance alone. Antipyrine clearance normalised for liver volume in patients with liver disease was significantly lower than in normal subjects and there was no overlap with normal subjects. In conclusion, assessment of drug metabolising efficiency per unit volume of liver increased the discrimination in differentiating subjects with normal from abnormal livers.     

Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease

S-Adenosyl-L-methionine (SAMe) is a physiologic precursor of thiols and sulfurated compounds, which are known to be decreased in patients with liver disease. The effect of its administration on the hepatic glutathione content of liver patients was investigated. Four groups of subjects were selected: a) 9 patients with alcoholic liver disease treated with SAMe (1.2 g/day orally for 6 months); b) 7 patients with non-alcoholic liver disease treated as above; c) 8 placebo-treated patients with alcoholic liver disease; and d) 15 normal subjects as a control group. Total and oxidized glutathione were assayed by high-performance liquid chromatography of liver biopsy specimens before and after the treatment period. In all patients pre-treatment hepatic glutathione was significantly decreased as compared with controls. SAMe therapy resulted in a significant increase of hepatic glutathione levels both in patients with alcoholic and in those with non-alcoholic liver diseases as compared with placebo-treated patients. SAMe may therefore exert an important role in reversing hepatic glutathione depletion in patients with liver disease.     

Acid-base disturbances in liver disease

There are several important associations between the liver and acid-base balance. First, primarily because of its metabolism of certain cationic amino acids and organic acid anions, particularly lactate, the liver has a surprisingly important influence on normal acid-base homeostasis. Second, in the presence of the necessary pathogenic milieu, the liver may produce a life-threatening number of hydrogen ions. Examples include accelerated ketogenesis during insulinopenic states, or lactate production during severe hepatic parenchymal hypoxia. Third, patients with various types of liver disease, both acute and chronic, often develop complicating acid-base disturbances. In addition, liver disease may predispose the patient to a particular acid-base disorder such as phenformin-induced lactic acidosis. Finally, the acid-base disturbance may be a complication of therapy, as when diuretic therapy directed at ascites results in metabolic alkalosis.     

Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes

To clarify the pathogenetic role of acetaldehyde in the development of alcoholic liver disease, genotyping of aldehyde dehydrogenase-2 genes was performed and the clinical features of the alcoholic liver disease patients with different genotypes were compared. Genotyping of aldehyde dehydrogenase-2 was performed in 47 patients with alcoholic liver disease using the polymerase chain reaction and slot-blot hybridization. Of the 47 patients with alcoholic liver disease, 40 were homozygous for the normal aldehyde dehydrogenase-2 gene and the remaining seven cases were heterozygous for the normal and mutant aldehyde dehydrogenase-2 genes. No homozygote was found for the mutant aldehyde dehydrogenase-2 genes. Daily alcohol intake was less than 100 gm in all heterozygotes without relation to the type of alcoholic liver disease. On the other hand, all but four patients homozygotic for the normal aldehyde dehydrogenase-2 gene drank more than 100 gm alcohol/day. The mean daily alcohol intake in the heterozygotes was significantly lower than that in the normal homozygotes. The incidence of alcoholic fibrosis tended to be lower in the heterozygotes than in the normal homozygotes (14.2% vs. 52.5%). On the other hand, the incidence of alcoholic hepatitis and/or cirrhosis tended to be higher in the heterozygotes than in the normal homozygotes. These results indicate that alcoholic liver disease develops even with moderate amounts of alcohol intake in heterozygotes of the aldehyde dehydrogenase-2 genes, in which acetaldehyde metabolism in the liver is impaired and liver damage in the heterozygotes is more severe than that in the normal homozygotes, suggesting that habitual drinkers who are heterozygotes of the aldehyde dehydrogenase-2 genes may be at high risk for alcoholic liver disease.     

Hepatic aldehyde dehydrogenase activity in liver diseases, with particular emphasis on alcoholic liver disease

Hepatic aldehyde dehydrogenase isozyme activity was measured in 51 patients with various types of liver diseases, including 24 patients with alcoholic liver disease, to elucidate the relationship between hepatic aldehyde dehydrogenase activity and liver disease, especially alcoholic liver disease. The levels of low-Km and total aldehyde dehydrogenase activity in the liver decreased both in alcoholic and nonalcoholic liver disease patients, who showed an isoelectric focusing pattern of the usual type. There was no significant difference in the aldehyde dehydrogenase activity between alcoholic and nonalcoholic liver disease. In alcoholic liver disease, the decrease in the activity was significantly correlated with the progression of liver histology. The activity in liver cirrhosis was significantly lower than that in the other types of alcoholic liver disease. In nonalcoholic liver disease patients, the unusual type of hepatic aldehyde dehydrogenase activity observed was not different from the unusual type observed in nonhepatobiliary disease patients. These results indicate that the reduction of hepatic low-Km aldehyde dehydrogenase activity is a change that occurs subsequent to liver damage. Genetic abnormality in aldehyde dehydrogenase may not be important in the pathogenesis of alcoholic liver injury.