[Physiopathological bases for the treatment of acute alcoholic hepatitis].
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Acute Disease↗
Biomedical subjects
J Caballería
Publications and source records attributed to J Caballería.
Hepatocyte growth factor induces MAT2A expression and histone acetylation in rat hepatocytes: role in liver regeneration.
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Acetylation↗
Hepatic familial amyloidosis caused by a new mutation in the apolipoprotein AI gene: clinical and pathological features.
OBJECTIVE: Recently, we reported a nondescribed deletion/insertion mutation in the apolipoprotein AI gene as the cause of hereditary amyloidosis with hepatic presentation. We describe the clinical and pathological features of this type of amyloidosis in one affected family. METHODS: Demographic, clinical, and biochemical data were obtained from 33 members of the family in whom the apolipoprotein AI gene was studied. Diagnosis was based on the detection of the apolipoprotein AI gene mutation, scintigraphy using radioionated serum amyloid P component, and histological and immunohistochemical studies. RESULTS: Eight members with the mutation had hepatic involvement. Six patients were practically asymptomatic, presented with an elevation of alkaline phosphatase and gamma-glutamyl transpeptidase, and remained stable during follow-up (7.6 +/- 4.9 yr). One patient had jaundice, developed ascites and encephalopathy, and died of hepatorenal syndrome a few months after diagnosis. Jaundice and portal hypertension appeared in the remaining patient, who died 4 yr later. CONCLUSION: This form of familial amyloidosis is characterized by elevation in serum alkaline phosphatase and gamma-glutamyl transpeptidase secondary to amyloid deposits in the portal tracts. Patients remain stable and asymptomatic for many years, but portal hypertension and liver failure can develop later in life and lead to death. Thus, patients should be observed regularly and liver transplantation should be indicated when progression is detected.
Adult↗
Hyperhomocysteinemia in liver cirrhosis: mechanisms and role in vascular and hepatic fibrosis.
Numerous clinical and epidemiological studies have identified elevated homocysteine levels in plasma as a risk factor for atherosclerotic vascular disease and thromboembolism. Hyperhomocysteinemia may develop as a consequence of defects in homocysteine-metabolizing genes; nutritional conditions leading to vitamin B(6), B(12), or folate deficiencies; or chronic alcohol consumption. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver. Impaired liver function leads to altered methionine and homocysteine metabolism; however, the molecular basis for such alterations is not completely understood. In addition, the mechanisms behind homocysteine-induced cellular toxicity are not fully defined. In the present work, we have examined the expression of the main enzymes involved in methionine and homocysteine metabolism, along with the plasma levels of methionine and homocysteine, in the liver of 26 cirrhotic patients and 10 control subjects. To gain more insight into the cellular effects of elevated homocysteine levels, we have searched for changes in gene expression induced by this amino acid in cultured human vascular smooth muscle cells. We have observed a marked reduction in the expression of the main genes involved in homocysteine metabolism in liver cirrhosis. In addition, we have identified the tissue inhibitor of metalloproteinases-1 and alpha1(I)procollagen to be upregulated in vascular smooth muscle cells and liver stellate cells exposed to pathological concentrations of homocysteine. Taken together, our observations suggest (1) impaired liver function could be a novel determinant in the development of hyperhomocysteinemia and (2) a role for elevated homocysteine levels in the development of liver fibrosis.
Arteriosclerosis↗
[Prevalence and factors associated to the presence of fatty liver in apparently healthy adult men].
BACKGROUND: Alcohol intake in one of the factors associated with fatty liver, although its contribution as well as other factors have not been completely established. Therefore the aim of this study was to assess the prevalence and associated factors for fatty liver diagnosed by ultrasonography. SUBJECTS AND METHODS: 1,801 presumably healthy male workers (age range 18-60 years). A complete physical and laboratory investigations, including HBsAg and anti-HCV antibodies, a detailed interview on alcohol intake, and an abdominal ultrasound examination were performed in all cases. Diagnosis of fatty liver was based on defined ultrasonographic criteria. RESULTS: Eighty eight cases were excluded because of the HBsAg or anti-HCV positivity or incomplete ultrasonography. Among the remaining 1,713 cases, 236 (13.8%; 12.2-15.4) had fatty liver. Logistic regression analysis disclosed age (RR: 1.04; CI 95%; 1.03-1.05), ethanol intake > 40 g/d (2.19; 1.81-2.65), gamma-glutamyl-transferase > 40 U/l (3.51; 2.95-4.18), body mass index > 30 (3.87; 3.22-4.66) and glycemia > 120 mg/dl (2.69; 1.85-3.90) as the risk factors for fatty liver. Fatty liver was present in 8.8% of cases who did not have obesity, diabetes or hypercholesterolemia. When the subjects with obesity, hyperglycemia or hypercholesterolemia were excluded, regression analysis confirmed age, ethanol intake and gamma-glutamyl-transferase as independent factors associated with fatty liver. CONCLUSIONS: Age, alcohol intake, obesity, and increased serum levels of glucose, cholesterol and gammaglutamyl transferase are the main factors associated with fatty liver in presumably healthy adult men.
Adolescent↗
Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma.
BACKGROUND/AIMS: It has been known for at least 50 years that alterations in methionine metabolism occur in human liver cirrhosis. However, the molecular basis of this alteration is not completely understood. In order to gain more insight into the mechanisms behind this condition, mRNA levels of methionine adenosyltransferase (MAT1A), glycine methyltransferase (GNMT), methionine synthase (MS), betaine homocysteine methyltransferase (BHMT) and cystathionine beta-synthase (CBS) were examined in 26 cirrhotic livers, five hepatocellular carcinoma (HCC) tissues and ten control livers. METHODS: The expression of the above-mentioned genes was determined by quantitative RT-PCR analysis. Methylation of MAT1A promoter was assessed by methylation-sensitive restriction enzyme digestion of genomic DNA. RESULTS: When compared to normal livers MAT1A, GNMT, BHMT, CBS and MS mRNA contents were significantly reduced in liver cirrhosis. Interestingly, MAT1A promoter was hypermethylated in the cirrhotic liver. HCC tissues also showed decreased mRNA levels of these enzymes. CONCLUSIONS: These findings establish that the abundance of the mRNA of the main genes involved in methionine metabolism is markedly reduced in human cirrhosis and HCC. Hypermethylation of MAT1A promoter could participate in its reduced expression in cirrhosis. These observations help to explain the hypermethioninemia, hyperhomocysteinemia and reduced hepatic glutathione content observed in cirrhosis.
Carcinoma, Hepatocellular↗
Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.
Steroids are recommended in severe alcohol-induced hepatitis, but some data suggest that artificial nutrition could also be effective. We conducted a randomized trial comparing the short- and long-term effects of total enteral nutrition or steroids in these patients. A total of 71 patients (80% cirrhotic) were randomized to receive 40 mg/d prednisolone (n = 36) or enteral tube feeding (2,000 kcal/d) for 28 days (n = 35), and were followed for 1 year or until death. Side effects of treatment occurred in 5 patients on steroids and 10 on enteral nutrition (not significant). Eight enterally fed patients were prematurely withdrawn from the trial. Mortality during treatment was similar in both groups (9 of 36 vs. 11 of 35, intention-to-treat) but occurred earlier with enteral feeding (median 7 vs. 23 days; P =.025). Mortality during follow-up was higher with steroids (10 of 27 vs. 2 of 24 intention-to-treat; P =. 04). Seven steroid patients died within the first 1.5 months of follow-up. In contrast to total enteral nutrition (TEN), infections accounted for 9 of 10 follow-up deaths in the steroid group. In conclusion, enteral feeding does not seem to be worse than steroids in the short-term treatment of severe alcohol-induced hepatitis, although death occurs earlier with enteral nutrition. However, steroid therapy is associated with a higher mortality rate in the immediate weeks after treatment, mainly because of infections. A possible synergistic effect of both treatments should be investigated.
Adrenal Cortex Hormones↗
Liver-specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation.
Methionine adenosyltransferase (MAT) is the enzyme that catalyzes the synthesis of S-adenosylmethionine (AdoMet), the main donor of methyl groups in the cell. In mammals MAT is the product of two genes, MAT1A and MAT2A. MAT1A is expressed only in the mature liver whereas fetal hepatocytes, extrahepatic tissues and liver cancer cells express MAT2A. The mechanisms behind the tissue and differentiation state specific MAT1A expression are not known. In the present work we examined MAT1A promoter methylation status by means of methylation sensitive restriction enzyme analysis. Our data indicate that MAT1A promoter is hypomethylated in liver and hypermethylated in kidney and fetal rat hepatocytes, indicating that this modification is tissue specific and developmentally regulated. Immunoprecipitation of mononucleosomes from liver and kidney tissues with antibodies mainly specific to acetylated histone H4 and subsequent Southern blot analysis with a MAT1A promoter probe demonstrated that MAT1A expression is linked to elevated levels of chromatin acetylation. Early changes in MAT1A methylation are already observed in the precancerous cirrhotic livers from rats, which show reduced MAT1A expression. Human hepatoma cell lines in which MAT1A is not expressed were also hypermethylated at this locus. Finally we demonstrate that MAT1A expression is reactivated in the human hepatoma cell line HepG2 treated with 5-aza-2'-deoxycytidine or the histone deacetylase inhibitor trichostatin, suggesting a role for DNA hypermethylation and histone deacetylation in MAT1A silencing.
Acetylation↗
S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.
BACKGROUND/AIM: The efficacy of S-adenosylmethionine (AdoMet) in the treatment of liver cell injury has been demonstrated in several experimental models. The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis. METHODS: A randomized, double-blind trial was performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of the diagnosis was available in 84% of the cases. Seventy-five patients were in Child class A, 40 in class B, and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo. RESULTS: At inclusion into the trial no significant differences were observed between the two groups with respect to sex, age, previous episodes of major complications of cirrhosis, Child classification and liver function tests. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the AdoMet group, although the difference was not statistically significant (p = 0.077). When patients in Child C class were excluded from the analysis, the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the two groups in the 2-year survival curves (defined as the time to death or liver transplantation) were also statistically significant (p = 0.046). CONCLUSIONS: The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.
Double-Blind Method↗
Synthesis and degradation of collagen in pancreatic fibrogenesis.
The mechanism of fibrogenesis in the pancreas is not well known. We analyzed the role of prolylhydroxylase and collagenase activities in the development of fibrosis in chronic alcoholic pancreatitis (CAP). Nineteen patients with CAP and 11 controls (organ donors) with normal pancreatic histology were included in the study. Pancreatic tissue was obtained from all subjects to measure (a) area of fibrosis (histomorphometric method); (b) prolylhydroxylase activity (PHase), which reflects the intracellular synthesis of collagen (Hutton's method); and (c) collagenase activity, which reflects the degradation of collagen (collagenase assay system, 3H). The percentage of the fibrosis area in relation to the total area of pancreatic tissue was significantly higher in CAP than in the control group (70.6+/-20.2% vs. 4.6+/-1.8%; p<0.001). Mean pancreatic PHase activity was also significantly higher in CAP than in the control group (775+/-258 cpm/mg protein/h vs. 405+/-151 cpm/mg protein/h; p<0.001). The collagenase activity was significantly lower in CAP than in the control group (8.7+/-3.5 cpm/cpm added/mg protein vs. 18.0+/-3.9 cpm/cpm added/mg protein; p<0.001). A significant correlation was observed between percentage fibrosis evaluated histomorphometrically and PHase activity in all patients (r = 0.72; p<0.001), and between PHase and collagenase activities in controls (r = 0.70; p = 0.024), but not in CAP. Pancreatic tissue in CAP has an increased fibrogenic activity and an impaired collagen-degradation capacity. These findings might explain the excessive development of fibrosis in CAP.
Collagen↗
Hepatic fibrogenic activity in chronic alcoholic pancreatitis.
The prevalence and the mechanisms of hepatic fibrosis in chronic alcoholic pancreatitis remain uncertain. The aim of this study was to investigate the fibrogenic activity of the liver in patients with chronic pancreatitis and its relation with either the alcohol or cholestasis. Liver biopsies were obtained from 16 patients with chronic pancreatitis at the time of surgery and from 10 organ donors. Samples were processed for histologic examination to assess the presence and extent of fibrosis, inflammatory reactions, and cholestasis- and alcohol-related lesions. In other samples, the collagen content was measured by morphometry, and prolylhydroxylase activity was determined. Liver-function tests, ultrasonography, and endoscopic retrograde cholangiopancreatography were performed before surgery in all the patients. Of patients with chronic pancreatitis, 75% had significantly greater hepatic fibrosis and prolylhydroxylase activity than the control group. Moreover, prolylhydroxylase activity in patients with chronic pancreatitis was higher in those with cholestasis or partial obstruction of the common bile duct than in those without cholestasis or partial obstruction of the common bile duct. Both the fibrogenic activity and the collagen content in the livers of patients with chronic alcoholic pancreatitis are significantly increased, even in those without histologic lesions, and these alterations may be secondary to a partial occlusion of the common bile duct.
Adolescent↗
Metadoxine accelerates fatty liver recovery in alcoholic patients: results of a randomized double-blind, placebo-control trial. Spanish Group for the Study of Alcoholic Fatty Liver.
BACKGROUND/AIMS: Our aim was to investigate the effectiveness of metadoxine (pyridoxol L, 2 pyrrolidone-5-carboxylate) in the treatment of alcoholic fatty liver. METHODS: A double-blind randomized multicenter trial involving 136 chronic active alcoholic patients diagnosed with fatty liver by clinical, biochemical and ultrasonographic criteria was performed. Patients were treated with 1500 mg/day of metadoxine (n = 69) or placebo (n = 67) for 3 months. Patients were clinically and biochemically evaluated every month. Ultrasonography was performed before and after treatment. RESULTS: At the end of the study there was a significant improvement in the liver function tests in both groups. However, the changes were more rapid and greater in patients treated with metadoxine, in whom significant changes in serum levels of bilirubin, aminotransferases and gammaglutamyl transpeptidase were already observed after 1 month of treatment, and normalization of these parameters was observed at the end. After treatment, the percentage of patients with ultrasonographic signs of steatosis was significantly lower in the metadoxine group (28% vs 70%, p < 0.01) and the degree of steatosis was also lower in this group. Sixteen patients treated with metadoxine and 15 with placebo continued drinking. Alcohol intake was lower than initially, and similar in both groups. In the metadoxine group, the biochemical changes were similar in both the abstinent and the nonabstinent patients. In contrast, in the placebo group the improvement in the liver function tests was significantly higher in abstinents. Among patients who continued drinking, the prevalence (45% vs 92%, p < 0.05) and the degree of steatosis were also significantly lower in patients treated with metadoxine. CONCLUSIONS: In patients with alcoholic fatty liver, metadoxine accelerates the normalization of liver function tests and the ultrasonographic changes, even in those who do not completely abstain from alcohol intake. Thus, metadoxine could be useful in the treatment of the early stages of alcoholic liver disease.
Adult↗
Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial.
BACKGROUND/AIMS: Silymarin has protective effects in different experimental conditions, but its efficacy in human liver cirrhosis has not been completely established. Therefore, this study was carried out to determine the effect of silymarin in alcoholics with liver cirrhosis with respect to survival and clinical and laboratory changes. METHODS: From February 1986 to June 1989, we enrolled 200 alcoholics with histologically or laparoscopically proven liver cirrhosis in a randomized, double-blind multicenter trial comparing 450 mg of silymarin (150 mg/ three times per day) with placebo. The primary outcome was time to death, and the secondary outcome was the progression of liver failure. Additional analyses were also performed in 75 patients in whom anti-hepatitis C virus antibodies were measured after completion of the trial. RESULTS: One hundred and three patients were assigned to receive silymarin and 97 to receive placebo. The two groups were well matched for demographic and baseline clinical and laboratory features. A 2-year study period was completed in 125 patients (57 receiving silymarin and 68 receiving placebo). Twenty-nine patients (15 receiving silymarin, and 14 receiving placebo) died during the trial. Survival was similar in patients receiving silymarin or placebo. The effect of silymarin on survival was not influenced by sex, the persistence of alcohol intake, the severity of liver dysfunction or by the presence of alcoholic hepatitis in the liver biopsy. Silymarin did not have any significant effect on the course of the disease. No relevant side-effects were observed in any group. CONCLUSIONS: The results of this study indicate that silymarin has no effect on survival and the clinical course in alcoholics with liver cirrhosis.
Adult↗
Effects of ethanol consumption on hepatic hemodynamics in patients with alcoholic cirrhosis.
BACKGROUND & AIMS: Increased portal blood flow represents a compensatory mechanism preventing hepatic hypoxia after ethanol consumption. In addition, alcohol increases hepatic vascular resistance. Thus, ethanol consumption, by increasing hepatic vascular resistance and portal flow, may worsen portal hypertension in patients with cirrhosis. The aim of this study was to investigate the effects of ethanol consumption on hepatic hemodynamics in patients with alcohol-induced cirrhosis. METHODS: Measurements of hepatic venous pressure gradient (HVPG), azygos blood flow, hepatic blood flow, heart rate, and arterial pressure were obtained in 16 patients with alcohol-induced cirrhosis and portal hypertension before and after random administration of a noncaloric fruit drink (250 mL, n = 7) or of an identical beverage plus 0.5 g/kg of ethanol (n = 9). RESULTS: Vehicle caused no effects. By contrast, ethanol increased HVPG (P < 0.0001). The increase in HVPG was maximum at 15 minutes and remained significant at 45 minutes (P < 0.05 vs. vehicle). Ethanol increased azygos blood flow (P < 0.05) without changes in hepatic blood flow. Heart rate and arterial pressure slightly increased. CONCLUSIONS: Oral ethanol consumption increases portal pressure and portocollateral blood flow in patients with alcohol-induced cirrhosis. These findings suggest that even moderate alcohol consumption worsens the portal-hypertensive syndrome and, therefore, may increase the risk of variceal bleeding in patients with alcohol-induced cirrhosis.
Adult↗
Carbohydrate-deficient transferrin as a marker of alcohol consumption in male patients with liver disease.
Carbohydrate-deficient transferrin (CDT) has been proposed as a marker of alcohol abuse. However, its value in patients with associated liver disease is still controversial. The aim of the study was to investigate the usefulness of CDT as a marker of alcohol consumption in patients with liver disease. We measured serum levels of CDT and those of commonly used hematological and biochemical markers, mean corpuscular volume (MCV), transaminases (AST and ALT), and gamma-glutamyltransferase in 179 male subjects divided into four groups: 45 active drinkers (13 with normal liver, 21 with fibrosteatosis, and 11 with liver cirrhosis), 45 abstinent chronic alcoholics (18 with and 27 without liver disease), 58 patients with nonalcoholic liver disease, and 31 healthy controls. Serum CDT in active alcoholics was 37.5 +/- 3.6 units/liter, being significantly higher than that of abstinent alcoholics (20.3 +/- 1.5 units/liter), patients with nonalcoholic liver disease (18.1 +/- 1.1 units/liter), and controls (13.1 +/- 0.8 units/liter). Contrary to the other markers, no significant differences were observed in CDT values in relation with the presence and severity of liver disease in either the active drinkers or in the abstinent alcoholics. The sensitivity and specificity of CDT as a marker of alcoholism in the series as a whole was 64% and 82%, respectively, similar to the best conventional marker, MCV (64 and 82%). In patients with liver disease, CDT maintained good sensitivity (72%) and specificity (83%). Receiver operating characteristic analysis confirmed that CDT had a similar diagnostic value to that of MCV, but better than gamma-glutamyl-transferase and transaminases for the detection of alcohol abusers. The good diagnostic efficacy of CDT remained unchanged when analyzing only patients with liver disease. We conclude that serum CDT is a good marker of alcoholism and is less influenced than the currently used biochemical markers for associated liver disease. Thus, CDT is an effective laboratory test to detect alcohol abuse regardless of the presence of alcoholic liver disease.
Adult↗
Plexiform neurofibromatosis and angiosarcoma of the liver in von Recklinghausen disease.
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Adult↗
[Class I and II histocompatibility antigens and severity of the alcoholic liver lesion].
The association between the class I and class II histocompatibility antigens (HLA) and the severity of alcoholic liver disease was studied in 102 alcoholic patients (64 males and 38 females) with liver disease. According to histologic diagnosis 41 patients had a mild hepatic lesion (12 with minimum changes, 15 with steatosis and 14 with fibrosis) and 61 patients had severe hepatic lesion (13 with alcoholic hepatitis, 35 with cirrhosis and 13 with cirrhosis and alcoholic hepatitis). No differences were found between the two groups in regards to sex, quantity and length of alcohol consumption, although the patients with mild hepatic lesion were younger than those with severe hepatic lesion (41.2 +/- 8.2 and 47.8 +/- 11.6 years, respectively). The prevalence of the A30, B16, B47, Bw56, Cw1, Cw5 and Cw7 antigens was higher in the alcoholics than in the controls, although only the A30 (12.7% vs. 4.4%, p < 0.04) and the Bw56 antigens (3.9% vs 0.1%, p < 0.001) remained significant when the p value was corrected by the number of antigens studied. These differences were due to a greater prevalence of the A30 antigens (17.0% vs. 4.4%, p < 0.001), B16 (24.3% vs. 7.5%, p < 0.01) and Bw56 (7.3% vs 0.1%, p < 0.001) in patients with mild hepatic lesion versus the controls. In contrast, these antigens were present in similar numbers in patients with severe hepatic lesion and in the controls. On the other hand, no differences were observed regarding the prevalence of the class II HLA antigens between the alcoholics and the controls, or between the two alcoholic groups. These data suggest that the alcoholics with A30, B16 and Bw56 antigens are less susceptible to developing severe liver disease.
Adult↗
Zinc administration improves gastric alcohol dehydrogenase activity and first-pass metabolism of ethanol in alcohol-fed rats.
The effects of zinc on first-pass metabolism (FPM) of ethanol and gastric and hepatic alcohol dehydrogenase (ADH) activities have been investigated in two groups of male Wistar rats fed a liquid ethanol diet with normal zinc content (7.6 mg/liter), or zinc supplemented (76 mg/liter), for 21 days, and in two pair-fed groups receiving the same diets without ethanol. Alcoholic rats with normal dietary zinc had lower FPM (1.64 +/- 0.25 vs. 2.43 +/- 0.20 mM x hr, p < 0.05) and gastric ADH activity (184 +/- 7 vs. 335 +/- 41 micromol/min/mg protein, p < 0.01) than control rats. Zinc supplementation did not produce any change in FPM or in gastric ADH activity in control rats. By contrast, in alcoholic rats, the zinc supplement increased gastric ADH activity (247 +/- 31 vs. 184 +/- 7 micromol/min/mg protein, p < 0.05) and decreased the areas under the curve of blood ethanol concentrations after the intragastric administration of 0.25 g/kg of body weight of ethanol (0.78 +/- 0.07 vs. 1.71 +/- 0.24 mM x hr, p < 0.05), thereby increasing the FPM. In conclusion, in alcohol-fed rats, the administration of zinc supplements restores gastric ADH activity and improves the FPM of ethanol. These effects may be one of the mechanisms in which zinc has a beneficial role in preventing the development of alcoholic hepatic lesions.
Alcohol Dehydrogenase↗