Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values=0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.

Patients with cirrhosis and ascites have false values of bone density: implications for the diagnosis of osteoporosis.

UNLABELLED: The effect of ascites on bone densitometry has been assessed in 25 patients with advanced cirrhosis, and it was concluded that ascites over 4 l causes inaccuracy of BMD measurements, particularly at the lumbar spine. This fact must be considered when assessing bone mass in patients with decompensated cirrhosis. INTRODUCTION: Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DXA) is the best procedure for assessment of osteoporosis and fracture risk, but BMD values at the central skeleton may be influenced by changes in soft tissues. Therefore, we have studied the effect of ascites on BMD. METHODS: BMD was measured by DXA at the lumbar spine, femoral neck and total hip, just before and shortly after therapeutic paracentesis in 25 patients with advanced liver cirrhosis. Changes in BMD, lean and fat mass, abdominal diameter and weight, as well as the amount of removed ascites were measured. RESULTS: The amount of drained ascites was 6.6 ± 0.5 l (range: 3.0 to 12.7 l). After paracentesis, BMD increased at the lumbar spine (from 0.944 ± 0.035 to 0.997 ± 0.038 g/cm(2), p < 0.001) and at the total hip (from 0.913 ± 0.036 to 0.926 ± 0.036 g/cm(2), p < 0.01). Patients with a volume of drained ascites higher than 4 l showed a significant increase in lumbar BMD (7.0%), compared with patients with a lower amount (1.5%) (p < 0.03). The decrease in total soft tissue mass correlated with the amount of removed ascites (r = 0.951, p < 0.001). Diagnosis of osteoporosis or osteopenia changed after paracentesis in 12% of patients. CONCLUSION: Ascites over 4 l causes inaccuracy of BMD measurements, particularly at the lumbar spine. This fact must be considered when assessing bone mass in patients with advanced cirrhosis.

Estrategias de mejora del tratamiento de la enfermedad hepática por depósito de grasa / No disponible

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Patología orgánica / Somatic pathology

El consumo crónico de alcohol se acompaña de un amplio espectro de trastornos orgánicos, derivados de la acción directa de la oxidación del alcohol y de la producción de acetaldehído, o bien de las deficiencias nutricionales asociadas. La enfermedad hepática alcohólica es una de las alteraciones más frecuentes en los alcohólicos crónicos y se caracteriza por presentar desde lesiones leves como esteatosis hasta una cirrosis hepática. También son importantes las alteraciones neurológicas, de patogenia menos clara, pero relacionadas con la acción directa del alcohol y las deficiencias nutricionales. Asimismo, es frecuente que el alcohólico crónico tenga manifestaciones del tracto gastrointestinal y páncreas, asi como trastornos hematológicos, metabólicos y endocrinos. El alcoholismo crónico también se asocia a osteoporosis y osteopenia, al desarrollo de ciertos tipos de cáncer y a la fetopatía alcohólica (AU)

Chronic alcohol intake results in a wide spectrum of organic disturbances derived from the alcohol oxidation and the subsequent generation of acetaldehyde, as well as from the nutritional deficiencies associated with alcohol intake. Alcoholic liver disease is the most prevalent organic abnormality observed in chronic alcoholic, ranging from fatty liver to established cirrhosis. Neurologic diseases are also frequent. Its pathogenesis is less clear, but it probably results from the direct toxic effect of alcohol as well as nutritional deficiencies. Moreover, alcoholic patients also may experience other diseases of the gastrointestinal tract and pancreas, as well as hematological, metabolic and endocrine disturbances. Chronic alcoholism is also associated with osteopenia and osteoporosis, the development of cancer and the fetal alcoholic syndrome (AU)

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.

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.

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.

S-adenosylmethionine prevents hepatic tocopherol depletion in carbon tetrachloride-injured rats.

In various experimental models, S-adenosylmethionine (SAMe) has been shown to reduce liver injury by preventing depletion of glutathione, one of the antioxidant systems that plays a critical role in defence against oxidative stress. On the other hand, alpha-tocopherol may be decreased in liver diseases, and treatment with this vitamin reduces liver injury in CCl(4)-treated rats. Since there is a close relationship among the different antioxidant systems (mainly glutathione, alpha-tocopherol and ascorbic acid), we have assessed whether, as well as restoring hepatic glutathione content, SAMe has any effect on liver alpha-tocopherol and ascorbic acid levels in CCl(4)-injured rats. Four groups of seven male Wistar rats treated for 9 weeks were studied: rats induced to cirrhosis with CCl(4), rats induced to cirrhosis plus SAMe administration (10 mg x kg(-1) x day(-1)) and their respective controls. Liver samples were obtained for measuring levels of glutathione, alpha-tocopherol, ascorbic acid and thiobarbituric acid-reactive substances (TBARS), and hydroxyproline concentration as an index of collagen content. The hydroxyproline content was higher in CCl(4)-injured rats than in the control group (4.4+/-1.8 and 1.1+/-0.3 micromol/g respectively; P<0.05). In CCl(4)-injured rats, SAMe administration decreased collagen content (2.7+/-1.0 microl/g; P<0.05) and TBARS, and corrected glutathione depletion. alpha-Tocopherol was significantly lower in CCl(4)-injured rats than in controls (17.3+/-4.9 and 23.0+/-4.0 micromol/g respectively; P<0.05). By contrast, alpha-tocopherol levels were similar (23.8+/-5.1 micromol/g) in CCl(4)-injured rats receiving SAMe and in controls. In CCl(4)-injured rats, liver ascorbic acid was decreased in comparison with controls (4.9+/-1.8 and 8.2+/-1.0 micromol/g respectively; P<0.05), levels which were not replenished by SAMe (4.6+/-0.4 micromol/g). In conclusion, SAMe not only decreases fibrosis and protects against hepatic glutathione depletion, but has a further antioxidant effect of preventing alpha-tocopherol depletion in CCl(4)-injured rats.

[Prevalence and factors associated to the presence of fatty liver in apparently healthy adult men]. / Prevalencia y factores asociados a la presencia de esteatosis hepática en varones adultos aparentemente sanos.

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.

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.

Enhanced DNA binding and activation of transcription factors NF-kappa B and AP-1 by acetaldehyde in HEPG2 cells.

Because transcription factors NF-kappaB and activator protein-1 (AP-1) are known to regulate gene expression, we have analyzed the role of acetaldehyde in the activation of NF-kappaB and AP-1 in HepG2 cells. Binding activity and transactivation of NF-kappaB and AP-1 were determined by gel retardation assays and transfection of a luciferase reporter construct controlled by kappaB and AP-1 binding sites, respectively. Acetaldehyde enhanced the DNA binding of NF-kappaB and AP-1 by 1 and 4 h, respectively, increasing the kappaB- and AP-1-dependent luciferase expression. Supershift assays revealed the presence of NF-kappaB heterodimers p65/p50 and p50/p52, whereas nuclear c-Jun levels correlated with the DNA binding of AP-1. The enhanced binding of NF-kappaB to DNA by acetaldehyde in intact cells was accompanied by the proteolytic degradation of IkappaB-alpha. However, the addition of acetaldehyde to cytostolic extracts from untreated Hep G2 cells did not affect the DNA binding of AP-1 but activated the NF-kappaB heterodimer p65/p50 in the absence of IkappaB-alpha degradation. Preincubation of HepG2 cells with protein kinase C inhibitors abolished the enhanced DNA binding of NF-kappaB and AP-1 caused by acetaldehyde. Hence, these findings uncover a previously unrecognized role for acetaldehyde in the activation of NF-kappaB and AP-1, which may be of relevance in the alcohol-induced liver disease.

Enfermedad hepática alcohólica

Las enfermedades hepáticas asociadas al consumo crónico de alcohol son muy frecuentes y representan, junto con las hepatopatías de origen vírico, la gran mayoría de las enfermedades hepáticas. Los problemas médicos derivados del consumo excesivo de alcohol constituyen uno de los problemas sanitarios más importantes de nuestro país, de manera que un porcentaje elevado de consultas a nivel de Atención Primaria y de ingresos hospitalarios se deben a patología relacionada con el consumo de alcohol. La asociación entre el consumo crónico de alcohol y el desarrollo de enfermedades hepáticas es conocido desde la antigüedad, aunque hasta hace poco tiempo se consideraba que la enfermedad hepática era consecuencia de las deficiencias nutricionales que suelen asociarse al alcoholismo más que debida al efecto tóxico directo del alcohol.En la actualidad existen suficientes datos epidemiológicos, clínicos y experimentales que permiten afirmar que aunque existan otros factores que pueden contribuir a sus efectos tóxicos, el consumo crónico de alcohol es el responsable del desarrollo de la lesión hepática. Además, el consumo abusivo de alcohol también se asocia con otras enfermedades orgánicas, trastornos psíquicos y problemas sociales. Por todo ello, el alcoholismo representa un problema sanitario de primera magnitud en todos los países del mundo, problema todavía más trascendental por cuanto el consumo y los problemas médicos asociados van en aumento en todos los países (AU)

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.

Differential role of ethanol and acetaldehyde in the induction of oxidative stress in HEP G2 cells: effect on transcription factors AP-1 and NF-kappaB.

The oxidative metabolism of ethanol by the cytochrome P450 2E1 (CYP2E1) has been recognized to contribute to the ethanol-induced deleterious effects through the induction of oxidative stress. This study compared the effect of ethanol and acetaldehyde in the induction of oxidative stress and activation of transcription factors nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1) in HepG2 cells, which do not express CYP2E1, and HepG2 cells transfected with CYP2E1 (E47 cells). Neither ethanol (80 mmol/L) nor acetaldehyde (25-200 micromol/L) caused oxidative stress in HepG2 cells, an effect that was independent of blocking reduced glutathione (GSH) synthesis with buthionine-L-sulfoximine (BSO). However, BSO preincubation caused an overproduction of peroxides and activation of NF-kappaB and AP-1 in E47 cells even in the absence of ethanol. Furthermore, the incubation of E47 cells with ethanol (80 mmol/L for up to 5 days) depleted cellular GSH stores in both cytosol and mitochondria, reflecting the induction of oxidative stress. Ethanol activated NF-kappaB and AP-1 in E47 cells, an effect that was prevented by 4-methylpyrazole, potentiated by cyanamide, and attenuated by trolox C. Interestingly, however, despite the inability of acetaldehyde to induce oxidative stress in HepG2, acetaldehyde activated NF-kappaB and AP-1; in contrast, ethanol failed to activate these transcription factors in HepG2. Thus, our findings indicate that activation of NF-kappaB and AP-1 by ethanol and acetaldehyde occurs through distinct mechanisms. CYP2E1 is indispensable in the induction of oxidative stress from ethanol, whereas the activation of NF-kappaB and AP-1 by acetaldehyde is independent of oxidative stress.

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.

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.

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.

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.