Splenic function in alcoholic liver disease.

Splenic function was assessed in 42 patients with alcoholic liver disease by counting the percentage of erythrocytes with indentations or pits, seen by differential interference contrast microscopy. These pits represent cellular debris normally removed by the spleen. The findings were compared with 42 age and sex matched controls. Mean (SEM) pitted red cell counts in the patients was 2.7 (0.4)% and in the controls 0.7 (0.07)% (p < 0.001). In all of the eight reformed drinkers (five with biopsy proven cirrhosis), cell counts were normal. Six patients with alcoholic liver disease had had serious infections within the past year. Of these, one had had a recent pneumococcal pneumonia and another of the patients died from overwhelming pneumococcal septicaemia. Both of these patients had evidence of functional hyposplenism as judged by high pitted erythrocyte counts. A total of 18 patients were considered to have pitted red cell counts above the normal, and 11 of these had proven cirrhosis and/or gross ascites. This study is the first to show the presence of functional hyposplenism in alcoholic liver disease and provides further evidence of the predisposition that these patients have to infection. At present, it is unclear whether the hyposplenism is a direct toxic effect of alcohol or the result of cirrhosis; further studies are warranted.     

Splanchnic and renal extraction of circulating hyaluronan in patients with alcoholic liver disease

Splanchnic and renal extraction of hyaluronan was determined in patients with alcoholic cirrhosis (n = 9), non-cirrhotic alcoholic liver disease (n = 5), and controls without liver disease (n = 19) in the supine fasting condition. Arterial plasma concentration of hyaluronan was significantly increased in patients with cirrhosis (mean 480 micrograms/l) as compared to non-cirrhotic patients (29 micrograms/l, P less than 0.001) and controls (25 micrograms/l, P less than 0.001), whereas no difference was present between the two last-mentioned groups. In patients with liver disease, circulating hyaluronan was inversely correlated to indocyanine green clearance (r = -0.85, P less than 0.001) and to galactose elimination capacity (r = -0.62, P less than 0.02), but positively correlated to portal pressure (determined as wedged-to-free hepatic vein pressure) (r = 0.92, P less than 0.001). Splanchnic extraction ratio (arterio-hepatic venous extraction ratio) had a mean value of 0.14 in patients with cirrhosis as compared to 0.36 in non-cirrhotic patients (P less than 0.05) and 0.34 in controls (P less than 0.025). Splanchnic hyaluronan extraction was not correlated to liver function tests or portal pressure. In patients with alcoholic liver disease no significant renal hyaluronan extraction was found as compared to an extraction ratio of 0.17 in controls (P less than 0.05). Our results suggest that the increased level of circulating endogenous hyaluronan found in patients with cirrhosis is caused by a combination of increased supply to and decreased extraction from plasma.     

Characteristics of serum IgA and liver IgA deposits in alcoholic liver disease

Patients with alcoholic liver disease frequently reveal an increase in IgA serum concentration and IgA deposits in a continuous pattern along hepatic sinusoids. We investigated whether the hepatic IgA deposits are a passive reflection of changes in concentration or composition of IgA in the circulation, or represent a distinct effect of alcohol on the liver. Forty-one patients with alcoholic liver disease (daily alcohol intake at least 50 gm for more than five consecutive years) were compared with 41 patients with nonalcoholic liver disease. Patients in both groups were matched for serum IgA and histopathological changes in the liver biopsy. IgA deposits in the liver were found in 78% of the alcoholic patients and in 12% of the nonalcoholic patients. The presence of deposits was not related to histopathological changes in the liver or to the serum IgA concentration. In serum IgA subclass distribution, alcoholic patients differed from nonalcoholic patients by a slight but significant shift to IgA2; in contrast, the hepatic IgA deposits in alcoholic patients were almost of the IgA1 subclass. Serum secretory component (which is an equivalent of serum secretory IgA) was elevated in both alcoholic and nonalcoholic patients; patients with a liver biopsy revealing hepatitis showed the highest level. In contrast, the hepatic deposits did not contain secretory component. We conclude that the continuous deposits of IgA along liver sinusoids are not a passive reflection of changes in concentration or composition of circulating IgA, but may represent a distinct effect of alcohol on the liver related to the role of this organ in IgA metabolism.     

T and B cell function in alcoholic liver disease

Increased in vivo synthesis of immunoglobulin in patients with alcoholic liver damage has been attributed to direct activation of B cells, although other defects of lymphocyte function have been identified suggesting a more generalised defect. In the present study we have investigated the role of T cell regulation of immunoglobulin production in alcoholic liver disease analysed according to the presence or absence of alcoholic hepatitis. Spontaneous production of IgG and IgA was elevated and co-culture experiments confirmed hyper-reactivity of B cells, but also suggested impaired T cell function. Suppressor cell activity for IgG and IgA was impaired. Similarly, the response to pokeweed mitogen for IgG and IgA was defective, although this was more marked for secretion than for proliferation suggesting an associated T helper defect. No differences in the immunological abnormalities were identified between those with alcoholic hepatitis and those with other alcoholic liver diseases. This study demonstrates a broad defect of T cells and a hyper-reactivity of B cells in patients with alcoholic liver disease, irrespective of the severity of hepatic inflammation.     

Microheterogeneity of serum glycoproteins in alcoholic liver disease]

It has been reported that microheterogeneity (M-HT) of serum glycoproteins including transferrin is found in alcoholic liver disease (ALD). In the present study, M-HT of serum glycoproteins in ALD patients was analyzed using the Western blotting technique after isoelectric focusing. M-HT was found in serum alpha 1-antitrypsin, alpha 2-macroglobulin, ceruloplasmin, alpha 1-acid glycoprotein and hemopexin as well as transferrin, but not in serum prealbumin. M-HT disappeared following treatment with sialidase in one group of glycoproteins, but not in another group of glycoproteins. In hemopexin, M-HT was recognized only after treatment with sialidase. These results suggest that mechanisms of the appearance of M-HT of serum glycoproteins in ALD may differ. One mechanism is the interference of glycosylation of glycoproteins in the Golgi apparatus, and another is the decrease of asialo-protein receptors in hepatocytes.     

Long-term survival and predictors of relapse and survival after liver transplantation for alcoholic liver disease

Objective: Studies of predictive factors of alcohol recidivism and survival post-LT are not up-to-date. With evolving LT activity and with longer-term outcomes becoming increasingly available, re-evaluating post-LT outcomes is imperative. We analyzed recent data on survival, alcohol recurrence and predictive factors.

Methods: We compared long-term survival among 159 consecutive ALD patients transplanted 2003–2016 with 159 propensity-score matched controls transplanted for non-ALD. Alcohol ‘slips’ (occasional lapse) and relapse to moderate or harmful drinking were assessed from medical records and structured forms filled in by home-district physicians, and analyzed by competing-risk and multivariate Cox regression analyses.

Results: Patient and graft survival at 10 years were 75 and 69% in the ALD group and 65 and 63% in the control group (p=.06 and .36). In ALD patients, the 10-year cumulative rate of alcohol slip was 52% and of relapse, 37%. Duration of pre-LT abstinence (HR 0.97, 95% CI 0.94–0.99) and a history of prior alcohol relapses (HR 3.05, 95% CI 1.41–6.60) were significant predictors of relapse, but failed to predict death/graft loss. Patients with <6 months abstinence relapsed sooner than those with 7–24 months abstinence, but 10-year relapse rates were similar (40–50%). Ten-year relapse rate with 2–5-year pre-LT abstinence was 21%, and with >5-year abstinence, 0%. In patients with <6 months pre-LT abstinence, years of heavy drinking, prior addiction treatments, and lack of children predicted inferior survival.

Conclusions: Although 37% of our ALD patients relapsed to drinking by 10 years post-LT, 14-year survival was not significantly different from survival in non-ALD patients. Short duration of pre-LT abstinence and prior relapses predicted post-LT relapse.     

瘦素与酒精性肝病肝纤维化的关系

研究瘦素与酒精性肝病 (ALD)肝纤维化发生发展的关系。用ELISA法检测 6 0例ALD患者血清瘦素水平 ,16例健康人作为对照组 ,同步检测了ALD患者的血清肝纤维化指标HA、LN、PC -Ⅲ及TGFβ1,对血清瘦素与肝纤维化指标、肝组织纤维化分期间的关系进行了分析。ALD患者的血清瘦素水平明显高于对照组 ,在单纯性脂肪肝 (AFL)、脂肪性肝炎 (AH)、脂肪性肝硬化 (ALC)瘦素水平依次增高 ,差异有显著性。在AH、ALC血清瘦素水平与肝纤维化血清学指标和TGFβ1正相关 ,ALD患者的血清瘦素水平与肝组织纤维化分期密切相关。血清瘦素是ALD患者肝纤维化的始动因子之一     

Clinical significance of serum hyaluronan in patients with chronic viral liver disease

In order to elucidate the clinical significance of serum hyaluronan in chronic viral hepatitis, serum hyaluronan concentrations were measured using a sandwich enzyme binding assay in 115 patients with chronic viral hepatitis. These findings were examined in relation to the results of laboratory liver tests, levels of serum markers for fibrosis and liver histological findings. Serum hyaluronan levels increased with the progress of liver disease, particularly in liver cirrhosis. There were no significant differences in serum hyaluronan levels among the cirrhotic patients according to Child's grade. Multivariate analysis showed that the significant independent predictors of serum hyaluronan were serum aspartate aminotransferase (P= 0.020), serum alanine aminotransferase (P= 0.008), serum cholinesterase (P< 0.001), particularly serum type IV collagen 7S domain (P< 0.0001), and the histological degree of liver fibrosis (P< 0.0001). These findings suggest that elevated serum hyaluronan levels are closely related to the severity of liver fibrosis. We assessed the predictive value of serum hyaluronan in differentiating cirrhosis from chronic hepatitis, constructing receiver operating curves; we found that serum hyaluronan was a better test for diagnosing cirrhosis than serum type IV collagen 7S domain and laboratory liver tests.     

Neural networks as predictors of outcomes in alcoholic patients with severe liver disease

We developed and evaluated neural networks as predictors of outcomes in alcoholic patients with severe liver disease using commonly available clinical and laboratory values. Hospital charts of 144 patients were reviewed. Nine variables (five laboratory, four clinical) were recorded along with in-hospital death or survival. Data were organized into separate development and validation sets. Neural network predictions of survival were compared with those of the Maddrey discriminant function and logistic regression models developed on the same data. Model performance was evaluated by comparing areas under receiver-operating characteristic (ROC) curves and the distributions of model scores. Survivors had significantly different laboratory and clinical characteristics, the most important being a higher prothrombin time, lower bilirubin, and lower incidence of encephalopathy. Neural network performance was significantly better than that of the Maddrey score (ROC areas, 81.5% vs. 73.8%; P = .04). The ROC area for neural networks was similar to that of logistic regression (ROC area 78.2%; P = .3), but the neural networks were more successful in classifying patients into low- and high-risk groups (P < .001). A neural network score with laboratory data from hospital-day 7 improved prognostic accuracy further to 84.3%. After adjusting for baseline risk, the neural network change in illness severity was still a significant predictor of mortality (P = .001). Neural networks using clinical and laboratory data showed a high prognostic accuracy for predicting mortality in alcoholic patients with severe liver disease.(Hepatology 1997 Feb;25(2):302-6)     

Immune mechanisms in alcoholic liver disease.

This paper reviews the potential role of immune factors in alcoholic liver diseases. They can either be involved in liver damage and hepatocyte's neurons or in the development of liver fibrosis, or in the sequellae of the disease. Cytokines, as mediators of the relationships between circulating monocytes, Kupffer cells, sinusoidal cells, Ito cells and hepatocytes, seem to play a crucial role in the development of the disease. Studies are now ongoing which try to identify the alcohol-related cofactor which triggers immune activation and the development of liver damage.     

Glycerol clearance in alcoholic liver disease.

Glycerol clearance was studied by a primed dose-constant infusion technique in 14 patients with alcoholic liver disease and six normal control subjects. Fasting blood glycerol concentrations were raised in the alcoholic subjects (0.09 +/- 0.01 vs 0.06 +/- 0.01 mumol/l, p less than 0.05) and glycerol clearance was impaired (24.5 +/- 1.9 vs 37.5 +/- 3.2 ml/kg/min, p less than 0.005). Endogenous production rate of glycerol and distribution space at steady state were similar in alcoholic and control subjects. The metabolic clearance rate of glycerol correlated negatively with basal glycerol concentrations. Thus tissue uptake of glycerol is impaired in liver disease. As glycerol is metabolised primarily in the liver by conversion to glucose, these data suggest a defect of gluconeogenesis in alcoholic liver disease.     

Escherichia coli antibodies in alcoholic liver disease. Correlation to alcohol consumption, alcoholic hepatitis, and serum IgA

In 41 patients with alcoholic liver disease, antibodies to 12 common Escherichia coli O antigens (expressed as number of O antibody reactions with an agglutination titre of greater than or equal to 40) and to immunoglobulins IgG, IgA, and IgM were studied for 8 weeks. In 18 patients (8 with cirrhosis, 10 with fatty liver) who continued drinking during this period no significant changes were found. In 23 patients (11 with cirrhosis, 12 with fatty liver) who stopped or reduced drinking, a significant decrease in the levels of E. coli O antibodies and IgA was found (p less than 0.05 and p less than 0.01, respectively). In these 41 patients and in an additional 43 patients with alcoholic liver disease the amount of E. coli O antibodies was compared with type of histological lesion. The levels of E. coli O antibodies were significantly higher in cirrhosis with alcoholic hepatitis (22 cases) than in cirrhosis without alcoholic hepatitis (17 cases) (p less than 0.05). In these 17 patients antibody levels were significantly higher than in 41 patients with fatty liver without alcoholic hepatitis (p less than 0.02). In all patients a significant correlation between the number of positive reactions to E. coli O antigens and serum IgA concentration was found (p less than 0.01). No microbes were cultured from the liver biopsies, and no E. coli O antigens were demonstrated in the liver tissue by immunohistochemistry. Our results support the hypothesis that the high levels of E. coli O antibodies in alcoholic liver diseases are due to failure of the liver to extract circulating antigens and gut-derived endotoxins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acquired stomatocytosis in alcoholic liver disease.

The occurrence of transient stomatocytosis observed on peripheral blood smears and by scanning electron microscopy, was studied in 100 alcoholic patients admitted to a general medical ward. 15% of the patients manifested marked stomatocytosis, i.e. 10% or more of the cells being stomatocytes and a further 29% had slight stomatocytosis (3--9%). All patients with marked stomatocytosis had a daily average ethanol ingestion of 100 g or more, and had also more pronounced histological and biochemical evidence of alcoholic liver disease than those lacking stomatocytosis. MCV was significantly higher in these patients, but there were no differences in Hb, serum B12, folate, cholesterol or triglyceride levels. The stomatocytosis subsided gradually during 4--6 weeks of abstinence. Triconcave cells (knizocytes) were observed in 2 patients with terminal alcoholic liver disease. Along with an increased MCV, the presence of stomatocytosis may be a useful erythrocyte indicator of alcoholic liver disease.     

Kupffer cells and alcoholic liver disease.

Liver disease is a major cause of illness and death worldwide. A central component in the complex network leading to the development of alcoholic liver disease is the activation of Kupffer cells by endotoxin and other soluble mediators. Alcohol consumption induces a state of "leaky gut increasing plasma and liver endotoxin levels. When Kupffer cells become activated, they interact with a complex of proteins located on the extracellular membrane signaling to produce a wide array of soluble factors, including cytokines, chemokines, growth factors, cyclooxygenase and lipoxygenase metabolites, and reactive oxygen species such as superoxide anion, hydrogen peroxide, and nitric oxide, all of which provide physiologically diverse and pivotal paracrine effects on all other liver cell types and, ultimately, liver injury. Kupffer cells are also central to the liver homeostatic response to injury as upon cellular degenerative changes, they immediately respond to the insult and release mediators to orchestrate inflammatory and reparative responses. Thus, the homeostatic responses are initiated by Kupffer cell-derived mediators at the cellular level and underlie the liver s defense and reparative mechanisms against injury. In order to understand better the role of Kupffer cells in the onset of liver injury, animal models in which Kupffer cells are inactivated, and cell culture settings (e.g. co-cultures) are being used with promising results that advance our understanding of alcoholic liver disease.     

Aminoterminal propeptide of type III procollagen in serum in alcoholic liver disease

An assay of serum antigens related to the aminoterminal propeptide of type III procollagen has been suggested for monitoring fibrotic processes in the liver. These antigens were measured here in 61 alcoholics who were divided into four groups on the basis of liver histology: normal light microscopy, fatty liver, alcoholic cirrhosis with hepatitis, and inactive cirrhosis. All the subjects having alcoholic hepatitis with cirrhosis had elevated values in the assay, whereas some of those with either fatty liver or inactive cirrhosis still had normal values. It was, therefore, not possible on the basis of this method alone to distinguish fatty liver from cirrhosis or alcoholic hepatitis, although very high values were suggestive of alcoholic hepatitis. In a follow-up study, the aminopropeptide value decreased slowly during recovery from alcoholic hepatitis and increased rapidly after a new drinking bout. The antigens detected by the assay are heterogeneous in human serum. The proportions of the three main peptide forms varied during recovery from alcoholic hepatitis, the authentic propeptide being the main one at the acute stage, but almost disappearing later. The usefulness of the assay could probably be improved if distinct assays were available for the different antigen forms.     

Hepatic stellate cells and alcoholic liver disease.

Liver fibrosis represents a significant health problem worldwide for which no effective therapy exists. A great deal of research has been carried out to understand the molecular mechanisms responsible for the development of liver fibrosis. Activated stellate cells are the primary cell type responsible for the production of collagen I, the key protein involved in the development of liver fibrosis. Excessive deposition of collagen I occurs along with impaired extracellular matrix remodeling. Following a fibrogenic stimulus stellate cells transform into an activated collagen type I-producing cell. Numerous changes in gene expression are associated with stellate cell activation, including the induction of several intracellular signaling cascades, which help maintain the activated phenotype and control the fibrogenic and proliferative state of the cell. Activation of stellate cells is mediated by factors released from hepatocytes and Kupffer cells as they produce reactive oxygen species, nitric oxide, cytokines, growth factors, and cyclooxygenase and lipoxygenase metabolites, which provide pivotal paracrine effects in the liver milieu. Inhibition of stellate cell activation, proliferation, and the increased production of extracellular matrix (i.e. collagen type I) are therefore crucial steps for intervention in hepatic fibrogenesis.