Alcoholic liver disease. Treatment strategies for the potentially reversible stages

Even modest alcohol ingestion can increase the risk of steatosis, and long-term, excessive consumption can lead to alcoholic hepatitis and eventually cirrhosis. Most patients with clinically significant alcoholic liver disease have histologic findings typical of all three conditions. The only clearly beneficial treatment is abstinence from alcohol. Abstinence in combination with proper nutrition and general supportive care is state of the art. Steatosis is reversible upon withdrawal of alcohol, but alcoholic hepatitis can persist even with abstinence and may progress to cirrhosis. Corticosteroid therapy may reduce short-term mortality rates in patients with moderate or severe alcoholic hepatitis who have hepatic encephalopathy but no evidence of infection or gastrointestinal bleeding. Treatment with colchicine may decrease the risk of cirrhosis; however, once cirrhosis has developed, the liver damage is irreversible. The prognosis is improved with abstinence, but complications (e.g., ascites, gastrointestinal bleeding) often occur. Liver transplantation may be considered in patients with severe complications.     

Molecular biology of prostatic intraepithelial neoplasia

Alcoholic hepatitis is a precirrhotic lesion; it develops in only a minority of chronic alcohol abusers even after decades of abuse. The clinical spectrum of disease varies from asymptomatic hepatomegaly to florid hepatocellular failure with gastrointestinal bleeding and hepatic encephalopathy. Corresponding variation is observed both in morbidity and mortality. The majority of individuals with mild to moderate alcoholic hepatitis improve significantly following abstinence from alcohol and the provision of a diet sufficient to meet their nutritional requirements; their long-term outcome is determined largely by their ability to maintain abstinence from alcohol. Individuals with severe alcoholic hepatitis require intensive nutritional support and vigorous management of the complications of their liver injury; their outcome is generally poor. A small, carefully selected subgroup of these very sick patients may benefit, at least in the short-term, from treatment with corticosteroids; the place of orthotopic hepatic transplantation, in this patient group, is still the subject of debate. No other treatment modalities have been shown to confer benefit consistently. A number of new therapeutic approaches have been proposed and need to be explored.     

Angiosarcoma of the bladder: a review

BACKGROUND/AIMS: Correlations between serum levels of soluble tumor necrosis factor receptors p55 (TNFsRp55) and Child Pugh index have previously been reported in alcoholic patients with cirrhosis. We have undertaken this study to improve understanding of the role of tumor necrosis factor soluble receptors (TNFsRs) in alcoholic liver disease. METHODS: One hundred and two patients with alcoholic liver disease of various severity (23 pure steatosis, 22 fibrosis, seven acute alcoholic hepatitis without cirrhosis, 12 cirrhosis without acute alcoholic hepatitis, 14 cirrhosis with mild acute alcoholic hepatitis and 24 cirrhosis with severe acute alcoholic hepatitis) were studied. Blood was collected on EDTA and plasma was tested for TNFsR concentrations using ELISA assays. RESULTS: Plasma levels of TNFsRp55 and p75 increased progressively with the severity of liver disease, reaching a maximum in cirrhotic patients with severe acute alcoholic hepatitis. Plasma levels of TNFsRp55 in patients with fibrosis and of TNFsRp75 in patients with acute alcoholic hepatitis without cirrhosis were already higher than in healthy controls. In cirrhotic patients with or without acute alcoholic hepatitis TNFsRp55 and p75 were significantly increased compared with controls. In cirrhotic patients, plasma levels of TNFsRp55 correlated positively with all parameters of liver injury, whereas the TNFsRp75/ TNFsRp55 ratio correlated negatively. In cirrhotic patients with severe acute alcoholic hepatitis, the TNFsRp75/TNFsRp55 ratio was significantly lower than in all other groups. In cirrhotic patients with severe acute alcoholic hepatitis treated by prednisolone, the decrease in TNFsRp55 plasma levels between day 1 and day 15 was significantly more important in patients still alive at 2 months than in patients who died within 2 months. CONCLUSIONS: These results show that the expression of TNF-soluble receptors (TNFsRs) participates in the early phases of the alcoholic liver disease and that the TNFsRp75/TNFsRp55 ratio and plasma levels of TNFsRp55 may help to determine the diagnosis and the prognosis of severe acute alcoholic hepatitis in cirrhotics.     

Effect of the type of beverage and meat consumed by alcoholics with alcoholic liver disease

We analyzed meat products and alcoholic beverage preference in patients with the three stages of alcoholic liver disease (ALD) compared with controls using diet history data. Daily consumption of total alcohol, types of alcoholic beverages, and types of meat and meat products in grams was obtained by dietary history taken from patients with biopsy proven stage of ALD. A strong association was found between the ALD subjects and total alcohol and beer consumption. There was a significant increase in the consumption of total pig products, pork, and offal in the ALD groups compared with controls. There was a significant positive correlation between beer consumption and pork in alcoholic hepatitis, total pork products in alcoholic hepatitis, and cirrhosis and offal in alcoholic hepatitis and cirrhosis. There was no correlation with the fatty liver stage of ALD. The strongest correlation was between beer and total pig products in the alcoholic hepatitis group. Wine consumption was negatively correlated with the consumption of pig products and beer in the alcoholic cirrhosis group. In conclusion, the association of total pig product consumption with cirrhosis mortality in various countries was validated by personal diet history data obtained from ALD patients in a tested clinical microcosm. The results suggest that this association may be modified by the type of alcoholic beverage that is preferentially consumed.     

Alcoholic hepatitis

Alcoholic hepatitis is the precursor of cirrhosis. Susceptibility is independent of amount and duration of ethanol intake or of diet. Centrilobular hyalin, the key morphologic abnormality, sensitizes lymphocytes to secrete factors which may account (in part) for necrosis, liver cell destruction, increased collagen synthesis and development of cirrhosis. Diagnosis may be facilitated by detection of alcoholic hyalin antigen (AHAg) and antibody (AHAb) in serum of patients with alcoholic hepatitis. Treatment requires abstinence. Steroids have not reduced mortality rates. Measures to improve immunologic reactivity may be helpful. Persons unable to abstain should be enrolled in a surveillance group.     

Experimental, clinical, and metabolic results of side-to-side portacaval shunt for intractable cirrhotic ascites

BACKGROUND: Intractable ascites, refractory to medical therapy, occurs in approximately 10 percent of patients with ascites from cirrhosis and is almost always fatal. Sinusoidal hypertension resulting from hepatic venous outflow obstruction plays a primary role in the pathogenesis of cirrhotic ascites and provides the rationale for decompression of the liver by side-to-side portacaval shunt in treatment of intractable ascites. This report presents the experimental basis for the use of side-to-side shunt and long-term results of a prospective study in 34 selected patients with intractable cirrhotic ascites. STUDY DESIGN: In the experimental studies, hepatic venous outflow obstruction and massive ascites were produced in dogs by ligation of the hepatic veins, and the effect of portacaval shunts on ascites, thoracic duct lymph flow, and aldosterone secretion were measured. In the clinical study, 34 carefully selected patients with cirrhosis (91 percent alcoholic) and truly intractable ascites (failure of medical therapy for 5 to 24 months) underwent side-to-side portacaval shunt. The effects on ascites, survival, metabolic abnormalities, and quality of life were studied prospectively during follow-up that was longer than 5 years in all but two patients. Quantitative Child's risk classes in percent of patients were A in 0, B in 68, and C in 32. RESULTS: In the experimental studies, side-to-side portacaval shunt permanently relieved severe ascites, reduced the 13-fold increase in thoracic duct lymph flow rate to almost normal, and abolished the aldosterone hypersecretory response to minimal hepatic venous outflow obstruction. End-to-side portacaval shunt was much less effective. In the clinical study, side-to-side portacaval shunt reduced mean portal vein-inferior vena cava pressure gradient from 282 mm saline to 4 mm and permanently relieved all patients of ascites without subsequent requirement of diuretic therapy. Two patients who died of hepatoma, and one who died of heart failure developed terminal ascites. Thirty-day mortality rate was 6 percent, and long-term survival rates at 5, 10, and 15 years were 75 percent, 74 percent, and 73 percent. In metabolic studies, side-to-side shunt produced marked diuresis and natriuresis and abolished hypersecretion of aldosterone. Quality of life was generally improved as a result of a low incidence of recurrent portal-systemic encephalopathy (6 percent), abstinence from alcohol in 91 percent, improvement in liver function in 81 percent, and improvement in Child's risk class. The portacaval anastomosis remained permanently patent in every patient. CONCLUSIONS: Side-to-side portacaval shunt is very effective treatment of intractable ascites from cirrhosis. Our results are attributable to careful selection of patients, an organized system of care, and a program of rigorous, lifelong follow-up that emphasizes abstinence from alcohol and dietary protein restriction.     

Clinical significance of hepatitis GB virus C infection in alcoholic liver disease

Recently, hepatitis GB virus C (HGBV-C) has been recovered from patients with non-A-E hepatitis. However, it has been unclear whether HGBV-C may be related to the development of alcoholic liver disease (ALD) or not. In this study, we determined HGBV-C RNA in sera from alcoholic patients without markers for hepatitis C and B viruses to evaluate the role of HGBV-C in ALD. Serum samples were obtained from 68 patients with ALD and 40 nonalcoholic patients with chronic type C liver disease. HGBV-C RNA was detected in only 3 of 68 (4.4%) patients with ALD, in 2 of 27 patients with hepatic fibrosis, and in 1 of 5 patients with chronic hepatitis. There was no HGBV-C RNA in sera from patients with fatty liver, alcoholic hepatitis, or cirrhosis. Serum levels of AST, ALT, and gamma-glutamyltranspeptidase in alcoholic patients with, as well as without, HGBV-C RNA decreased to normal levels after abstinence. In addition, an inflammatory change was not observed in liver biopsy specimens obtained from two HGBV-C-positive patients with alcoholic hepatic fibrosis. Our results clearly suggest that the prevalence of HGBV-C infection in patients with ALD is rare and that HGBV-C may not play an important role in the development of liver disease in alcoholics.     

Prognosis of chronic hepatitis C: results of a large, prospective cohort study

The prognosis of chronic hepatitis C virus (HCV) infection is still ill-defined. The present study prospectively evaluated mortality and complications in a large cohort of patients with chronic hepatitis C. The study included 838 anti-HCV and HCV-RNA-positive patients who were followed for 50.2 +/- 26.9 months (mean +/- SD; range, 6-122 months) in a prospective protocol. During follow-up, 62 patients died (31 from liver disease and 31 from other causes), and 12 patients needed liver transplantation. When compared with a matched general population, hepatitis C increased mortality mainly when cirrhosis was present and in patients who were less than 50 years old at study entry. During follow-up, a further 30 patients developed nonlethal complications of cirrhosis. By multivariate regression, survival was decreased by cirrhosis, long disease duration, history of intravenous drug abuse, and excessive alcohol consumption, whereas interferon therapy improved survival. Alanine transaminase (ALT), bilirubin, sex, and genotype had no effect on survival. The risk of hepatocellular carcinoma (HCC) (n = 17) was increased by cirrhosis and to a lesser degree by long disease duration and high bilirubin, whereas interferon therapy, genotype, and other factors had no effect. Chronic hepatitis C is a disease with considerable mortality and morbidity when cirrhosis is present at diagnosis. Patients who acquire the infection early in life have a markedly increased mortality even when cirrhosis is absent at diagnosis. The age at diagnosis therefore should play a major role in therapeutic considerations. The present data also suggest that interferon therapy has a long-term clinical benefit, although it did not reduce the risk of liver cancer.     

Vasodilatory effects of propylthiouracil in patients with alcoholic cirrhosis

BACKGROUND/AIMS: An experimental study has shown that propylthiouracil increases portal blood flow in normal rats. Whether propylthiouracil has a similar effect in patients with alcoholic cirrhosis remains to be demonstrated. The aim of this study was to evaluate the effects of oral propylthiouracil (300 mg) on systemic and portal hemodynamics in patients with alcoholic cirrhosis. METHODS: Plasma propylthiouracil levels were also measured by high performance liquid chromatography in five patients with alcoholic cirrhosis. In eight patients with cirrhosis, mean arterial pressure, cardiac output and portal blood flow were evaluated before and after placebo and propylthiouracil administration. Hemodynamic measurements were performed by the Doppler technique. The plasma peak level of propylthiouracil was achieved at 1.4 +/- 0.1 h in patients with alcoholic cirrhosis. This time was chosen to express hemodynamic changes. RESULTS: Propylthiouracil administration caused a significant increase in portal blood flow (+16.5%, p < 0.05) in patients with alcoholic cirrhosis. This effect was associated with a mild and significant rise in cardiac output (from 5.8 +/- 0.2 to 6.1 +/- 0.3 l/min, p < 0.05) and a decrease in peripheral vascular resistance (from 1171 +/- 69 to 1070 +/- 67 dyn . s-1 . cm-5, p < 0.01). A significant correlation was observed between changes in portal blood flow and peripheral vascular resistance (r = 0.79, p < 0.05). No significant changes were observed after placebo. CONCLUSIONS: Our findings show that propylthiouracil has a vasodilatory effect in patients with alcoholic cirrhosis. We postulate that this effect could be the mechanism by which propylthiouracil decreases hypermetabolic state, and increases oxygen delivery to the liver, in patients with alcoholic liver diseases.     

Is there a therapeutic effect of cures undergone by patients with chronic liver disease? (authors transl)

"Cures" embrace by definition a broad spectrum starting from taking waters in health resorts to hospital treatment in modern rehabilitation centers. The effectiveness of traditional cure procedures is discussed. Effectiveness of drinking cures, baths and mud packs in liver disease has not yet been proven. Controlled trials are necessary. Clinical treatment is indicated in alcoholic liver damage, viral hepatitis with a protracted course, chronic aggressive hepatitis and compensated cirrhosis of the liver; such treatment, however, is questionable in fatty liver and in chronic persistent hepatitis. Data concerning the effectiveness of treatment of chronic liver diseases are given. The following conclusions are drawn: patients with liver disease ought to be hospitalized when undergoing cures, indications have to be precised, collaboration of patients has to be stimulated, hospital discipline has to be tight, therapy of alcoholism has to include several psychosocial aspects, treatment after leaving hospital has to be improved.     

Different functional effect of Ro 15-4513 and Ro 19-4603 on synaptic responses of Purkinje cells in the rat cerebellar slice

The Sugiura operation has been reported to have low operative mortality, rebleeding, and encephalopathy rates when carried out in a predominantly nonalcoholic Japanese population with good liver function. A literature review of reports of the Sugiura procedure outside Japan reveals a high complication and mortality rate when it is used as an emergency procedure in patients with advanced liver disease, especially in those with alcoholic cirrhosis. Uncontrolled studies report results that differ little from the Japanese series when the operation is confined to good-risk patients in the elective situation. Our experience with the Sugiura operation supports its role in these circumstances, especially in patients with portal vein thrombosis and normal liver function. The only good prospective controlled trial has been carried out in patients with schistosomiasis and suggests that the Sugiura operation is far superior to total shunt and may have a slight advantage over the Warren shunt because of its low incidence of postoperative encephalopathy. More controlled trials are required to establish its role in good- to moderate-risk patients with alcoholic cirrhosis.     

Fifth-year hemodynamic performance of the prima stentless aortic valve

In patients infected with the hepatitis C virus (HCV), 20% to 30% will progress to cirrhosis in over two to three decades. Viral and host factors that are important in the clinical and histologic progression of HCV infection are not entirely certain. It has been suggested that liver disease is worse in alcoholics infected with HCV. In the present retrospective study, we examined the effect of moderate alcohol intake on the histologic and clinical progression of HCV infection and assessed whether other variables such as gender, length of exposure, mode of exposure, HCV RNA levels, and ferritin levels also independently impacted disease progression. Liver biopsies were analyzed for the degree of fibrosis, presence of cirrhosis, and histologic activity by using the Histologic Activity Index of Knodell. Patients were divided into two groups based on whether their alcohol intake was significant or not significant. Significant alcohol intake was defined as > 40 g alcohol/day in women and > 60 g of alcohol/day in men for > 5 years. Groups were further divided based on the decades of exposure to HCV. There was no difference in the age or length of exposure to HCV in the alcohol and the alcohol-free group. HCV RNA serum levels, ferritin levels, and viral genotypes were similar in both groups. There was a two- to threefold greater risk of liver cirrhosis and decompensated liver disease in the alcohol group. Also, the rate to which subjects developed cirrhosis was faster in the alcohol group with 58% being cirrhotic by the second decade as opposed to 10% being cirrhotic in the nonalcohol group by the second decade. The histologic and clinical acceleration of liver disease was independent of the mode of exposure or sex. In summary, alcohol intake is an independent risk factor in the clinical and histologic progression of HCV infection.     

A model to examine the validity of the 6-month abstinence criterion for liver transplantation

Six months of abstinence from alcohol is a commonly used criterion for liver transplantation eligibility for patients with alcoholic cirrhosis. There is limited evidence to document the validity of this criterion with regard to risk of alcoholism relapse. Ninety-one patients with alcoholic cirrhosis were interviewed for relapse risk using the High Risk Alcoholism Relapse (HRAR) Scale. The HRAR model can be used to predict relapse risk independent of duration of sobriety and therefore can be used to examine the validity of the 6 months of abstinence criteria in this clinical population. The two methods demonstrated poor to fair agreement. Agreement was highest with a cutoff allowing a 5% 6-month relapse risk when 79% agreement (c = 0.56) was demonstrated between the two methods. Using the 6-month abstinence criterion alone disallows a significant number of candidates who have a low relapse risk based on their HRAR score. The validity of the 6-month abstinence criterion is supported somewhat by comparison with the HRAR model. However, use of the 6-month abstinence criterion alone forces a significant number of patients with a low relapse risk by HRAR to wait for transplant listing. A relapse risk model based on an estimate of alcoholism severity in addition to duration of sobriety may more accurately select patients who are most likely to benefit from liver transplantation.     

Diagnostic value of the study of caffeine elimination in chronic liver diseases

Data from the past few years have shown that as caffeine metabolizes solely in the liver, caffeine elimination can serve as a liver function test. We have collected data by monitoring 40 persons with liver diseases (11 chronic alcoholic hepatitis, 24 liver cirrhosis, 5 non-cirrhotic liver disease). Eight subjects served as controls. The patients with liver cirrhosis were classified according to the Child--Pugh scoring system. To determine caffeine elimination blood samples were collected before and at 3, 6, 9 and 12 hours after oral administration of 0.2 g caffeine. Fasting serum caffeine concentration and concentration 12 hours after administration, serum clearance, half life, peak concentration and volume of distribution have been compared. The respective values measured in patients with non-cirrhotic liver diseases did not differ significantly from the controls. The disappearance of caffeine was significantly decreased in cirrhotics. Our results demonstrated a good correlation between impairment of caffeine elimination and assessment of severity of liver disease by the Child--Pugh classification. Measuring serum levels in samples taken 12 hours after caffeine administration is a simple and useful method in the diagnosis of liver diseases at cirrhotic stage.     

Effect of insulin versus sulfonylurea therapy on cardiovascular risk factors and fibrinolysis in type II diabetes

1. The synthesis and release of nitric oxide may play a role in the pathogenesis of peripheral vasodilatation and hyperdynamic circulation observed in liver cirrhosis. In this work, we analysed the synthesis of nitric oxide by the lympho-mononuclear cells of peripheral blood from patients with chronic alcoholic and non-alcoholic liver disease and we identified the isoform of nitric oxide synthase involved in the increased nitric oxide synthesis. 2. Patients were classified following clinical and histological criteria in non-alcoholic cirrhotic, alcoholic cirrhotic and non-cirrhotic chronic liver disease. We studied clinical and analytical characteristics, haemodynamic parameters and endotoxin levels in these patients. 3. Cirrhotic patients showed an increase of cardiac output and a decrease of peripheral vascular resistance. These patients had higher levels of plasma endotoxin than those observed in the control group. N omega-Nitro-L-arginine methyl ester (L-NAME)-inhibitable nitrite production from mononuclear lymphocyte cells was higher in patients than in the control group, the highest levels being in non-alcoholic cirrhotic patients, and the lowest levels in patients with non-cirrhotic alcoholic liver disease. 4. Immunocytochemistry studies revealed a positive immunoreactivity for the inducible isoform of nitric oxide synthase in lympho-mononuclear cells that was more evident in non-alcoholic than in alcoholic cirrhotic patients. By Northern blot, inducible nitric oxide synthase mRNA expression was observed only in lymphomononuclear cells from non-alcoholic cirrhotic patients. 5. Our patients show a correlation between nitric oxide synthesis, endotoxin levels and haemodynamic parameters. 6. These findings indicate that lympho-mononuclear cell stimulation may play a role in elevated nitric oxide production in hepatic cirrhosis. Thus, this increased nitric oxide synthesis could be implicated in the pathogenesis of the haemodynamic disturbances frequently found in cirrhotic patients. This increase seems to be induced, at least in part, by activation of an inducible isoform of nitric oxide synthase.     

Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease

Formalin-fixed sections from the brains of 36 patients (30 alcoholic and 6 nonalcoholic) with autopsy-proven cirrhosis who died while in a hepatic coma were stained with hematoxylin and eosin, and examined for the presence of diencephalic, cerebellar, pontine, and basal ganglia lesions. Significant neuropathology was identified in 23 of 36 cases consisting of mammillary body and thalamic lesions characteristic of Wernicke encephalopathy (WE) (9 cases, all alcoholic patients) and cerebellar degeneration (20 cases, 17 alcoholic and 3 nonalcoholic patients). Clinical diagnosis of WE had been entertained during life in only 2 of these patients. All cases, alcoholic and nonalcoholic, manifested mild to severe Alzheimer's type II astrocytosis. No cases of central pontine myelinolysis nor acquired (non-Wilsonian) hepatocerebral degeneration were found. These findings show that the brains of a high proportion of cirrhotic patients with end-stage liver disease manifest concomitant unsuspected diencephalic and cerebellar pathology. The high incidence of WE underscores the need for early sustained treatment of alcoholic cirrhotic patients with vitamin B1. Evaluation of the neurological sequelae of liver transplantation, particularly of alcoholic patients with end-stage liver disease, may require a careful neurological and radiological assessment both before and after surgery.     

Evidence for a tyrosine kinase-dependent activation of the adenylyl Cyclase/PKA cascade downstream from the G-protein-linked endothelin ETA receptor in vascular smooth muscle

Body retinoids are stored in the lipid droplets of hepatic stellate (Ito) cells. In chronic liver disease, the stellate cells differentiate into myofibroblast-like cells, a process whereby they lose their retinoid-containing lipid droplets. We studied the relation between liver retinoid content, the number of lipid droplets per stellate cell, and the number of stellate cells per mm2 in human alcoholic liver disease. Semithin sections of liver biopsies from normal subjects and patients with early (steatosis, inflammation, and mild fibrosis) and late (cirrhosis and cirrhosis with acute alcoholic hepatitis) alcoholic liver disease were morphometrically evaluated. Liver retinoid content was determined by HPLC. In normal patients, liver retinoid content was 901 +/- 213 IU/g of liver (mean +/- SEM). There was a decrease in liver retinoid content in early alcoholic liver disease (409 +/- 50 IU/g) and a further reduction in cirrhosis (153 +/- 50 IU/g). In patients with acute alcoholic hepatitis, retinoid content was strikingly low (5.2 +/- 1.8 IU/g). There was a progressive decrease in the number of stellate cells per mm2 associated with progressive liver damage. We found a fair correlation between the number of stellate cells per mm2 and liver retinoid content in all patient groups (overall correlation: 0.71). In normal subjects, the mean number of lipid droplets per stellate cell was 7.4 +/- 0.7. In patients with early alcoholic liver disease and in patients with alcoholic cirrhosis, this value was increased to 13.6 +/- 0.8 and 10.4 +/- 2.0, respectively. In patients with acute alcoholic hepatitis, only a few lipid droplets were present (4.2 +/- 0.5). There was a good correlation between liver retinoid content and mean number of lipid droplets in normal patients (r = 0.58). In alcoholic cirrhosis, however, correlation was poor (r = 0.34). In early alcoholic liver disease, the correlation was absent (r = 0.004). In conclusion, the major finding of our study is that the correlation between the mean number of lipid droplets per stellate cell and liver retinoid content varies according to the hepatic pathology considered. Marked lipid droplet accumulation occurs in stellate cells in early alcoholic liver disease and, to a lesser extent, in alcoholic cirrhosis, but there is no correlation between the mean number of lipid droplets per stellate cell and liver retinoid content. Therefore, not retinoids but probably lipids are responsible for the accumulation of lipid droplets. We also find that there is a fair correlation between the number of stellate cells per mm2 and liver retinoid content in all patient groups. Finally, we confirm the decrease in hepatic retinoid content that occurs in alcoholic liver disease in humans, even at the early stages of the disease.     

Alcohol use following liver transplantation for alcoholic cirrhosis

Due to the significant increase in the number of patients with alcoholic liver cirrhosis being referred for liver transplantation, studies to determine recidivism rates and influential factors affecting those rates have become increasingly crucial. Between 12/85 and 12/91, 67 patients diagnosed with alcohol related end-stage liver disease underwent orthotopic liver transplantation at Baylor University Medical Center. A 3-8 year follow-up study was conducted wherein surviving patients were contacted by phone to evaluate subsequent alcohol consumption following transplantation (with the exception of two patients whose primary physicians were contacted). Of the 67 patients transplanted, 18 had expired, 7 were alive but unavailable, and 1 had been lost to follow-up. Of the remaining 41 patients interviewed, 21 had remained abstinent, while the other 20 had returned to some form of drinking. Of patients with less than 6 months of pretransplant abstinence, only 30% remained abstinent, while the other 70% had resumed drinking. Regarding patients with at least 6 months of pretransplant abstinence, 58% had remained abstinent, while the other 42% had resumed drinking. In both groups, nearly 1/3 of those who had admitted to posttransplant drinking reported themselves as again abstinent and recommitted to sobriety when interviewed. In conclusion, 49% of patients interviewed had resumed some type of drinking following transplantation-- however, this appears not to have affected compliance or survival potential. Only 2 (4.8%) of the 41 patients interviewed had returned to excessive drinking. Thus, our findings support the use of orthotopic liver transplantation for patients with alcohol related end-stage liver disease.     

Carbohydrate-deficient transferrin: diagnostic efficiency among patients with end-stage liver disease before and after liver transplantation

We tested the diagnostic validity of carbohydrate-deficient transferrin (CDT) as an indicator for relapse into elevated alcohol consumption among patients who were examined under follow-up treatment before (n = 147) and after (n = 102) orthotopic liver transplantation (OLT) in the outpatient-department of the University Hospital Department of Surgery in Hamburg-Eppendorf. CDT measurements were performed with two commercial kits in parallel (CDTect-RIA and CDT%-RIA). Short-term parameters of alcohol consumption (ethanol, methanol) indicated relapses into elevated alcohol consumption in 11.4% of the evaluated patients with alcoholic liver disease (ALD) before transplantation. Before OLT, median CDT values were determined to be elevated among patients with alcoholic as well as nonalcoholic end-stage liver diseases (NALD). Among patients with ALD, we found elevated CDT medians even in those who were successfully scheduled for OLT after long-term evidence of abstinence proved by biochemical short-term parameters and psychological tests. Both CDTect and CDT% assays had comparable low specificities in selected patient groups before transplantation. CDT% and CDTect were negatively correlated with the albumin level. Before the study ended, CDT was no longer implemented in the evaluation of whether an OLT should be administered. This was due to inconsistent results of CDT in ALD as well as NALD. After OLT, patients with ALD, as well as NALD, had statistically significant lower CDT medians than before OLT, which ranged within reference levels. We determined, according to CDT, elevated alcohol consumption subsequent to OLT in 4 of 13 patients with ALD who underwent transplantation during the study (median observation period: 10 months). CDT does not appear to be useful in evaluating patients before OLT. With regained specificity and high sensitivity in patients after OLT, CDT could be recommended as a standard instrument for quality control in patients with ALD after liver transplantation.     

Blunted thrombopoietin response to interferon alfa-induced thrombocytopenia during treatment for hepatitis C

Thrombocytopenia is common in advanced-stage liver disease and is partly caused by inadequate thrombopoietin (TPO) production in the failing liver. Treatment of chronic hepatitis C with interferon alfa (IFN-) often induces thrombocytopenia, sometimes even leading to discontinuation of treatment. TPO regulation in response to IFN--induced thrombocytopenia was studied in patients with chronic hepatitis C with and without cirrhosis (Child A). An in vitro culture system with HepG2 cells was used to demonstrate any direct effects of IFN- on TPO mRNA expression, TPO synthesis, or TPO secretion from liver cells. Thrombocyte count was lower (U test: P < .05) in patients with hepatitis C cirrhosis compared with patients with chronic hepatitis C without cirrhosis before IFN therapy, and decreased in both patient groups (Wilcoxon matched-pairs test: P < . 05) on IFN therapy, the median decrease in both groups being comparable (noncirrhotic patients, 35%; cirrhotic patients, 32%; U test: P = .57). TPO levels rose in noncirrhotic patients (Wilcoxon matched-pairs test: P < .05), but not in patients with cirrhosis (noncirrhotic patients' median increase: 43% vs. cirrhotic patients' median decrease: 5%; U test: P < .001). Even in patients without cirrhosis, the increase in TPO levels was relatively small for the decrease in platelet count. No effect of IFN- could be demonstrated on TPO mRNA expression in vitro, but TPO secretion from liver cells was significantly reduced. Lower platelet counts but similar TPO levels in patients with chronic hepatitis C and cirrhosis compared with noncirrhotic patients and a moderate increase in TPO levels in noncirrhotic patients with a missing increase in cirrhotic patients during IFN--induced thrombocytopenia provide further evidence for an impairment of TPO production in patients with cirrhosis and during IFN therapy. Recombinant human TPO could be of value in patients developing severe thrombocytopenia under IFN- therapy.