Alcohol-associated Cirrhosis Research Articles

Possibilities of essential phospholipids in alcoholic liver disease of terminal stage

Essential phospholipids (Essentiale Forte N, Aventis, France-Germany) in alcohol-associated hepatic cirrhosis improve the subjective state of patients, reduce manifestations of asthenic and dyspeptic syndromes, intensity of jaundice, have a positive effect on biochemical indicators of cytolysis and cholestasis. The conducted clinical study showed effectiveness of use of essential phospholipids as hepatoprotective agents for hepatic diseases of alcoholic etiology.

Infection as a Trigger for Portal Hypertension

Background: Microbial infections are a relevant problem for patients with liver cirrhosis. Different types of bacteria are responsible for different kinds of infections: Escherichia coli and Klebsiella pneumoniae are frequently observed in spontaneous bacterial peritonitis or urinary tract infections, and Streptococcus pneumoniae and Mycoplasma pneumoniae in pulmonary infections. Mortality is up to 4-fold higher in infected patients with liver cirrhosis than in patients without infections. Key Messages: Infections in patients with liver cirrhosis are due to three major reasons: bacterial translocation, immune deficiency and an increased incidence of systemic infections. Nonparenchymal liver cells like Kupffer cells, sinusoidal endothelial cells and hepatic stellate cells are the first liver cells to come into contact with microbial products when systemic infection or bacterial translocation occurs. Kupffer cell (KC) activation by Toll-like receptor (TLR) agonists and endothelial sinusoidal dysfunction have been shown to be important mechanisms increasing portal pressure following intraperitoneal lipopolysaccharide pretreatment in cirrhotic rat livers. Reduced intrahepatic vasodilation and increased intrahepatic vasoconstriction are the relevant pathophysiological pathways. Thromboxane A₂ and leukotriene (LT) C₄/D₄ have been identified as important vasoconstrictors. Accordingly, treatment with montelukast to inhibit the cysteinyl-LT₁ receptor reduced portal pressure in cirrhotic rat livers. Clinical studies have demonstrated that activation of KCs, estimated by the amount of soluble CD163 in the blood, correlates with the risk for variceal bleeding. Additionally, intestinal decontamination with rifaximin in patients with alcohol-associated liver cirrhosis reduced the portal pressure and the risk for variceal bleeding. Conclusions: TLR activation of nonparenchymal liver cells by pathogens results in portal hypertension. This might explain the pathophysiologic correlation between microbial infections and portal hypertension in patients with liver cirrhosis. These findings are the basis for both better risk stratifying and new treatment options, such as specific inhibition of TLR for patients with liver cirrhosis and portal hypertension.

Nonalcoholic Fatty Liver Disease Increases the Risk of Hepatocellular Carcinoma in Patients With Alcohol-Associated Cirrhosis Awaiting Liver Transplants

Many patients with alcohol-associated cirrhosis also have diabetes, obesity, or insulin resistance-mediated steatosis, but little is known about how these disorders affect the severity of liver disease. We analyzed the prevalence and prognostic implications of metabolic risk factors (MRFs) such as overweight, diabetes, dyslipidemia, and hypertension in patients with alcohol-associated cirrhosis awaiting liver transplants. We performed a retrospective study of 110 patients with alcohol-associated cirrhosis (77% male; mean age, 55 y; 71% with >6 mo of abstinence) who received liver transplants at a single center in Paris, France, from 2000 through 2013. We collected data on previous exposure to MRFs, steatosis (>10% in the explant), and histologically confirmed hepatocellular carcinoma (HCC). HCC was detected in explants from 29 patients (26%). Steatosis was detected in explants from 47 patients (70% were abstinent for ≥6 mo); 50% had a history of overweight or type 2 diabetes. Fifty-two patients (47%) had a history of MRFs and therefore were at risk for nonalcoholic fatty liver disease. A higher proportion of patients with MRF had HCC than those without MRF (46% vs 9%; P < .001). A previous history of overweight or type 2 diabetes significantly increased the risk for HCC (odds ratio, 6.23; 95% confidence interval [CI], 2.47-15.76, and odds ratio, 4.63; 95% CI, 1.87-11.47, respectively; P < .001). MRF, but not steatosis, was associated with the development of HCC (odds ratio, 11.76; 95% CI, 2.60-53; P = .001) independent of age, sex, amount of alcohol intake, or severity of liver disease. Patients with alcohol-associated cirrhosis who received transplants frequently also had nonalcoholic fatty liver disease. MRFs, particularly overweight, obesity, and type 2 diabetes, significantly increase the risk of HCC.

Polymorphisms at PRSS1–PRSS2 and CLDN2–MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study

ObjectiveSeveral genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1–PRSS2 (rs10273639; near the...

Ascites Due to Different Hepatic Diseases Known to have Differing Rates of Spontaneous Bacterial Peritonitis Have Unique Cytokine and Growth Factor Levels and Patterns in Ascitic Fluid

Purpose: Individuals with viral and alcohol-associated cirrhosis are known to have high rates of spontaneous bacterial peritonitis. In contrast, individuals with ascites due to liver disease as a result of heart failure or malignancy rarely develop spontaneous bacterial peritonitis (SBP). Hypothesis: Differing patterns and levels of ascitic fluid cyctokine and growth factors exist between those with a high risk and low risk of SBP. Methods: Fifty-seven consecutive patients with ascites requiring a large-volume paracentesis were studied. Their age, gender, and specific underlying disease conditions were recorded after a review of their clinical records. Each underwent a routine assessment prior to their paracentesis, consisting of a complete blood count, complete metabolic profile, and prothrombin time/INR determination. The ascitic fluid was cultured, and a complete cell count and albumin determination was obtained on the fluid. In addition, blood and ascitic fluid was assessed for the levels of IL-1A, IL-1B, IL-2, IL-4, IL-8, IL-10, MCP-1, TNFα, IFNγ, VEGF, and EGF, utilizing the Randox Biochip platforms (Boston, MA). A serum-ascites gradient, for each cytokine and growth factor was calculated. The results are reported as mean values ± SEM between disease groups, with statistical analysis consisting of the student t-test (two tailed) with a p value of 0.05 defining significance. Results: No clinically important demographic or biochemical differences between the 4 groups studied were evident. In contrast, marked difference in the cytokine and growth factors levels and pattern were evident between the four disease groups. Individuals with alcoholic cirrhosis had the highest levels of IL-1A, IL-1B, IL-4, IFNγ. Those with malignant disease had the highest levels of IL-2. Those with HCV-associated cirrhosis had the highest value for IL-6, IL-8, IL-10, MCP-1, and VEGF. Those with cardiac disease had the highest level of TNFα and EGF. The calculated serum-ascites gradients for the cardiac and malignant disease groups had a greater frequency of negative values signifying greater levels of IL-8, IL-10, and MCP-1 in ascites than did those with alcohol or HCV disease. Conclusion: These data document important differences in the cytokine and growth factor levels in plasma, ascitic fluid, and the calculated plasma-ascites fluid gradients in cirrhotics requiring a large volume ascites. These differences may be important in determining the risk for bacterial peritonitis, and suggest that high levels of IL-8, IL-10, and MCP in ascites may contribute to the lower risk for SBP. Obviously, sequential studies to include patients who have or develop SBP are needed to more precisely identify the cytokine and growth factor levels in ascitic patients who are at risk for SBP.

Etiological and clinicopathologic characteristics of intrahepatic cholangiocarcinoma in young patients.

To investigate the prevalence, risk factors, and clinicopathologic characteristics of intrahepatic cholangiocarcinoma (ICC) in young patients. A retrospective analysis was performed in ICC patients referred to the Eastern Hepatobiliary Surgery Hospital in Shanghai, China. Among 317 consecutively enrolled patients, 40 patients were aged <or= 40 years (12.61%). We compared the risk factors and clinicopathologic characteristics of these patients (group I: n = 40) with those aged > 40 years (group II: n = 277). Group I had distinct features compared with group II, including a low frequency of hepatolithiasis (P = 0.000); a high positive rate of serum hepatitis B surface antigen (P = 0.000) and hepatitis B virus (HBV)-associated cirrhosis (P = 0.038); a high frequency of alpha-fetoprotein (> 400 microg/L) (P = 0.011); a low frequency of carbohydrate antigen 19-9 (> 37 U/mL) (P = 0.017); and a high frequency of liver histological inflammation (P = 0.002). Although there was no significant difference between the two groups in regards to hepatic schistosomiasis, alcohol-associated cirrhosis and cirrhosis due to other causes (P > 0.05), they only occurred in the elderly group. The risk factors are significantly different between young and elderly ICC patients. HBV and HBV-associated cirrhosis are the most important risk factors for young ICC patients.

Elevated adiponectin serum levels in patients with chronic alcohol abuse rapidly decline during alcohol withdrawal

Adiponectin is a circulating protein with hepatoprotective effects. To study the relationship of excessive alcohol consumption and serum adiponectin levels (SAL). The SAL were determined in (i) heavy drinkers without advanced liver damage during the course of alcohol withdrawal, (ii) patients with chronic hepatitis C virus (HCV) infection, (iii) patients with alcohol-associated cirrhosis, and (iv) healthy volunteers that consumed excessive amounts of alcohol for only a short period of time. Further, primary human hepatocytes (PHH) and adipocytes were incubated in vitro with alcohol or serum of patients. Patients with chronic alcohol consumption had significantly higher SAL than HCV-patients with comparable degrees of liver damage. In alcoholics, but not in HCV patients, SAL positively correlated with serum levels of aminotransferases. Further, SAL correlated with the amount of alcohol consumption but declined during the course of alcohol abstinence. After short-term excessive alcohol consumption SAL were not elevated in healthy individuals. Adiponectin mRNA was detectable in adipocytes but not in hepatocytes, and alcohol failed to induce adiponectin in both cell types. In contrast, serum of active drinkers induced adiponectin expression in adipocytes while serum from the same individuals collected after alcohol withdrawal had no effect. Alcohol exhibits a specific effect on SAL that is dose and time dependent, and correlates with the degree of hepatic damage. Alcohol does not seem to affect adiponectin expression directly in adipocytes but potentially via mediators systemically released as a result of the chronic alcohol intake.

Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection

Clinical and experimental data suggest that gut-derived endotoxins are an important pathogenic factors for progression of chronic liver disease. Recently, a C-T (-159) polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression and to be associated with advanced alcoholic liver damage. Here, we investigated this polymorphism in patients with less advanced alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) infection. CD14 genotyping was performed by PCR-RFLP analysis in (a) 121 HCV patients, (b) 62 patients with alcohol-associated cirrhosis (Alc-Ci), (c) 118 individuals with heavy alcohol abuse without evidence of advanced liver damage (Alc-w/o Ci), and (d) 247 healthy controls. Furthermore, serum levels of soluble CD14 (sCD14) and transaminases were determined. The TT genotype was significantly more frequent in Alc-Ci compared to Alc-w/o Ci or controls (40.3% vs 23.7% or 24.0%, respectively). In Alc-w/o Ci, serum levels of transaminases did not differ significantly between patients with different CD14 genotypes. In HCV patients, TT-homozygotes had significantly higher sCD14 levels and sCD14 serum levels were significantly higher in patients with advanced fibrosis or cirrhosis. However, no association was found between CD14 genotypes and histological staging or grading. Considering serum transaminases as surrogate markers for alcoholic liver damage, the CD14 polymorphism seems to exhibit different effects during the course of ALD. Differences in genotype distribution between cirrhotic HCV patients and alcoholics and the known functional impact of this polymorphism on CD14 expression levels further indicate differences in the pathophysiological role of CD14 and CD14-mediated lipopolysaccharides signal transduction with regard to the stage as well as the type of the underlying liver disease.

Effect of alcohol use on allograft rejection rates after liver transplantation for alcoholic liver disease.

Alcoholic liver disease is a major cause of liver disease and has become an ever-increasing indication for liver transplantation (LTx). Follow-up studies have reported a higher rate of alcohol recidivism in patients transplanted for alcoholic hepatitis, compared with those transplanted for endstage alcohol-associated cirrhosis. It is assumed widely that recurrent alcohol use is associated with reduced compliance with immune suppression and, as a result, an increased risk of graft rejection and loss. To assess this question, 209 alcoholic patients transplanted for either alcoholic hepatitis with cirrhosis or cirrhosis alone between January 1, 1986 and December 31, 1991 were followed, with a mean follow-up of 4.4 +/- 0.6 years. There were 175 episodes of acute cellular rejection (ACR) that occurred in 137 patients, for an overall rejection rate of 83.7% or at a rate of 1.25 episodes/patient with rejection. The rate of ACR was three times as great in those who remained alcohol-abstinent (2.24 episodes/patient), compared with those who admitted to continued alcohol use (0.75 episodes/patient) (p < 0.01). A total of 33 episodes of chronic rejection occurred in 26 patients, for an overall rate of 12.4%. As was the case for ACR, the chronic rejection rate was greater among those who were continuously alcohol-abstinent, compared with those who intermittently used alcohol after successful LTx. There were no differences in the mean FK 506 or cyclosporin A levels in the groups with and without a rejection episode at the time the rejection episode was documented by liver biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Liver Transplantation on the Hypothalamic‐Pituitary‐Gonadal Axis of Chronic Alcoholic Men with Advanced Liver Disease

The hormones testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) were assayed in blood obtained from men with alcoholic liver disease before and after successful liver transplantation. The frequency and severity of self reported impotence, intercourse, and paternity were assessed before and 18 +/- 3 months post-transplantation. The results obtained were compared with those of age-matched males transplanted within the same month by the same surgical teams for advanced hepatocellular disease other than alcoholism. Little change for any parameter assessed pre- and post-transplantation was noted for the nonalcoholics. In contrast, the FSH, LH, and testosterone levels of the alcoholic men all increased significantly following successful transplantation. These data suggest that the liver disease associated with alcoholism contributes to some of the endocrine effects of alcohol-associated cirrhosis but not all. Because the transplanted alcoholics remain less adequate than controls, it is further suggested that some residual alcohol-induced injury to the hypothalamic-pituitary-gonadal axis persists despite successful liver transplantation.

Vitamin-A reversal of abnormal dark adaptation in cirrhosis. Study of effects on the plasma retinol transport system.

Of 26 patients hospitalized with mild to moderate alcohol-associated cirrhosis, 14 had dark-adaptation abnormalities consistent with marginal vitamin-A status. The response of dark adaptation and the plasma retinol transport proteins, retinol-binding protein and prealbumin, was studied in 12 of these patients after daily oral vitamin-A supplements of 3300 microgram. Vitamin-A supplementation was associated with significant (p less than 0.05-0.005) improvement in dark adaptation and increased plasma concentrations of retinyl esters, retinol, and retinol-binding protein. Thus in patients with cirrhosis and marginal vitamin-A status, supplemental vitamin-A therapy appears to stimulate retinol-binding protein release from the liver. This enhancement of plasma retinol transport and delivery of retinol to peripheral tissues such as the retina is one of several factors that may serve to optimize vitamin-A nutritional status in patients with cirrhosis.

Ultrastructure of Hyaline Cytoplasmic Inclusions in a Human Hepatoma: Relationship to Mallory's Alcoholic Hyalin

Electron microscopic study of hepatoma tissue from a patient with mildly active alcohol-associated cirrhosis has demonstrated the ultrastructural nature of the two forms of hepatoma hyaline inclusions described by Norkin and Campagna-Pinto (Cytoplasmic hyaline inclusions in hepatoma. Arch Pathol 86:25-32, 1968). The reticular form of hepatoma hyalin is identical to alcoholic hyalin of Mallory. The globular deposits of hepatoma hyalin have a fibrillar internal structure also indistinguishable from that of the classical alcoholic hyalin of Mallory, except for closer packing of fibrils. Physical continuity of globular and reticular forms of hepatoma hyalin and a close association of globular hyalin with microbodies is demonstrated.