propylthiouracil and Liver-Diseases--Alcoholic

Randomised clinical trials have addressed the question whether propylthiouracil has any beneficial effects in patients with alcoholic liver disease.. To assess the beneficial and harmful effects of propylthiouracil for patients with alcoholic liver disease.. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (April 2011), The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (April 2011), MEDLINE (1948 to April 2011), EMBASE (1980 to April 2011), and Science Citation Index Expanded (1900 to April 2011). These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted.. Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included irrespective of blinding, publication status, or language. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention.. All analyses were performed according to the intention-to-treat method in RevMan Analyses. The risk of bias of the randomised clinical trials was evaluated by bias risk domains such as generation of allocation sequence, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, academic bias, and source of funding.. Combining the results of six randomised clinical trials with high risk of bias which included 710 patients demonstrated no significant effects of propylthiouracil versus placebo on all-cause mortality (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30), liver-related mortality (RR 0.90, 95% CI 0.58 to 1.40), or complications of the liver disease. Although propylthiouracil was not associated with a significant increased risk of non-serious adverse events, there were occasional instances of serious adverse events such as leukopenia and generalised bullous eruption.. We could not demonstrate any significant beneficial effect of propylthiouracil on all-cause mortality, liver-related mortality, liver complications, or liver histology of patients with alcoholic liver disease. Propylthiouracil was associated with adverse events. Confidence intervals were wide. Thus, the risk of random errors and systematic errors was high. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.

Topics: Antimetabolites; Cause of Death; Humans; Liver Diseases, Alcoholic; Propylthiouracil; Randomized Controlled Trials as Topic; Treatment Outcome

Severe alcoholic steatohepatitis (ASH) is the major complication of advanced alcoholic liver disease (ALD) and has a high mortality even when treated with corticosteroids. Despite the importance of reactive oxygen species in the pathophysiology of ALD and ASH, antioxidants provide no benefit in the treatment of patients with ASH. Proinflammatory cytokines are important in the pathophysiology of ALD and might mediate most of the inflammatory aspects of these disorders. New treatment modalities in ASH might involve antagonism of proinflammatory cytokines such as tumor necrosis factor (TNF) by specific antibodies or other TNF-interfering treatment strategies. Propylthiouracil and S-adenosyl methionine may be beneficial to patients with alcoholic cirrhosis, but both require further randomized, controlled trials before their use can be recommended.Liver transplantation is an effective therapy for patients with advanced alcoholic cirrhosis who have not recovered after a period of abstinence.

Topics: Adrenal Cortex Hormones; Antioxidants; Colchicine; Dietary Supplements; Humans; Liver Diseases, Alcoholic; Liver Transplantation; Pentoxifylline; Prognosis; Propylthiouracil; Temperance; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Randomised clinical trials have addressed the question whether propylthiouracil has any beneficial effects in patients with alcoholic liver disease.. To assess the beneficial and harmful of propylthiouracil for patients with alcoholic liver disease.. The Cochrane Hepato-Biliary Group Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (1980 to May 2005), and The Web of Science (May 2005) were searched. These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted.. Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included irrespective of blinding, publication status, or language. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention.. All analyses were performed according to the intention-to-treat method in RevMan Analyses. The methodological quality of the randomised clinical trials was evaluated by components (generation of the allocation sequence; allocation concealment; double blinding; follow-up).. Combining the results of six randomised clinical trials including 710 patients demonstrated no significant effects of propylthiouracil versus placebo on all-cause mortality (relative risks (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30), liver-related mortality (RR 0.80, 95% CI 0.50 to 1.29), complications of the liver disease, or liver histology. Propylthiouracil was associated with a non-significant increased risk of non-serious adverse events and with the seldom occurrence of serious adverse events (leukopenia).. We could not demonstrate any significant beneficial effect of propylthiouracil on all-cause mortality, liver-related mortality, liver complications, and liver histology of patients with alcoholic liver disease. Propylthiouracil was associated with adverse events. Confidence intervals were wide. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.

Topics: Antimetabolites; Humans; Liver Diseases, Alcoholic; Propylthiouracil; Randomized Controlled Trials as Topic; Treatment Outcome

Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. Interactions between acetaldehyde, reactive oxygen and nitrogen species, inflammatory mediators and genetic factors appear to play prominent roles in the development of ALD. The cornerstone of therapy for ALD is lifestyle modification, including drinking and smoking cessation and losing weight, if appropriate. Nutrition intervention has been shown to play a positive role on both an inpatient and outpatient basis. Corticosteroids are effective in selected patients with alcoholic hepatitis and pentoxifylline appears to be a promising anti-inflammatory therapy. Some complementary and alternative medicine agents, such as milk thistle and S-adenosylmethionine, may be effective in alcoholic cirrhosis. Treatment of the complications of ALD can improve quality of life and, in some cases, decrease short-term mortality.

Topics: Animals; Antimetabolites; Antioxidants; Colchicine; Cytokines; Ethanol; Humans; Inflammation Mediators; Life Style; Liver Diseases, Alcoholic; Liver Transplantation; Nitric Oxide; Nutrition Therapy; Oxidative Stress; Pentoxifylline; Phosphodiesterase Inhibitors; Polymorphism, Genetic; Propylthiouracil; Risk Factors

Alcohol is the most common cause of liver disease in the Western world today. Randomised clinical trials have addressed the question whether propylthiouracil has any efficacy in patients with alcoholic liver disease.. The objectives were to assess the efficacy of propylthiouracil on mortality, clinical symptoms and complications, liver biochemistry, and liver histology in patients with alcoholic liver disease. Adverse events were also analysed.. The Cochrane Hepato-Biliary Group Controlled Trials Register (searched July 2001), The Cochrane Controlled Trials Register (Cochrane Library Issue 3, 2001), MEDLINE (January 1966 to July 2001), EMBASE (January 1985 to July 2001) were searched. These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted.. Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention. The trials could be double-blind, single-blind, or unblinded. The trials could be unpublished or published as an article, an abstract, or a letter and no language limitations were applied.. All analyses were performed according to the intention-to-treat method. The statistical package (RevMan and MetaView) provided by the Cochrane Collaboration was used. The methodological quality of the randomised clinical trials was evaluated by components of quality and the Jadad-scale.. Combining the results of six randomised clinical trials including 710 patients demonstrated no significant effects of propylthiouracil versus placebo on mortality (Peto odds ratio (OR) 0.91, 95% confidence interval (CI) 0.59 to 1.40), liver related mortality (OR 0.78, 95% CI 0.45 to 1.33), complications of the liver disease (OR 1.14, 95% CI 0.58 to 2.24), or liver histology. Propylthiouracil was associated with a non significant trend towards an increased risk of non-serious adverse events (OR 1.49, 95% CI 0.74 to 2.99) and with the seldom occurrence of serious adverse events (leukopenia).. This systematic review could not demonstrate any significant efficacy of propylthiouracil on any clinically important outcomes (mortality, liver related mortality, liver complications, and liver histology) of patients with alcoholic liver disease and propylthiouracil was associated with adverse events. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.

Topics: Antimetabolites; Humans; Liver Diseases, Alcoholic; Propylthiouracil; Randomized Controlled Trials as Topic

The etiology and the pathogenesis of different forms of hepatotoxicity are discussed; case reports are included to illustrate the importance of history-taking and examination of liver tissue in establishing a specific diagnosis. The role of alcohol as a hepatotoxin as well as an enzyme-inducing agent is stressed. Genetic factors have been identified that may determine susceptibility to alcoholism and the hepatotoxic effects of alcohol and other compounds. Some cases of drug-induced cholestasis may be explained by disturbances in the known pathways of bile acid uptake, transport, and excretion. The importance of small duct destruction in patients with progressive drug-induced cholestasis is discussed. Finally, the potential hepatic complications of some nonprescription remedies used by adherents of "alternative medicine" are described, emphasizing the relevance of thorough etiological inquiry in all patients presenting with hepatic dysfunction.

Topics: Acetaminophen; Acetylcysteine; Adenoma, Liver Cell; Adult; Amoxicillin; Anabolic Agents; Beverages; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Contraceptives, Oral; Female; Humans; Isoniazid; Liver Diseases; Liver Diseases, Alcoholic; Liver Neoplasms; Male; Nonprescription Drugs; Propylthiouracil; Rifampin

The therapy of alcohol-related liver disease remains relatively unsatisfactory despite years of research designed to understand the pathogenesis of alcoholic liver injury and the processes involved in recovery from alcohol-related liver injury. Drugs such as the corticosteroids and colchicine appear to have a place in the management of some patients with alcohol-related liver disease but their use is not widespread in clinical practice. Liver transplantation has become an increasingly used therapy in patients with advanced liver disease but the enthusiasm of the early 1990s is now being replaced by a more cautious approach, particularly to those who have not abstained from alcohol for a significant period prior to transplant assessment. The brightest area in any discussion of treatment approaches to alcoholic liver disease is that of predicting the future. A number of agents designed to modify the inflammatory response and the endotoxaemia associated with significant alcoholic liver injury may be more beneficial than current drugs used for severe alcoholic hepatitis or cirrhosis. As in all discussions of alcohol-related liver disease and its management, it is important to highlight the need to exclude other forms of liver injury in patients who drink heavily as those diseases respond more to specific therapies than does alcoholic liver disease. The underlying therapy for all patients with alcoholic liver disease is abstinence from alcohol and the importance of encouraging patients to cease their damaging intake of alcohol can not be overemphasised.

Topics: Adrenal Cortex Hormones; Colchicine; Hepatitis, Alcoholic; Humans; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Liver Transplantation; Nutritional Support; Penicillamine; Propylthiouracil

Topics: Adrenal Cortex Hormones; Amino Acids; Anabolic Agents; Colchicine; Humans; Liver Diseases, Alcoholic; Liver Transplantation; Prognosis; Propylthiouracil

The treatment of alcoholic liver disease at present consists of abstinence from alcohol, bed rest, and dietary intake or administration of adequate amounts of calories and protein. Besides corticosteroids, which have been shown to improve hospital survival in severely ill patients with alcoholic hepatitis and liver transplantation in advanced cirrhosis, no successful specific therapy is available for alcoholic liver disease. Potential new therapeutic approaches include: (1) Treatment with specific dietary supplements such as polyunsaturated lecithin, which in baboons prevented the progression of the early stages of pericentral and interstitial fibrosis to septal fibrosis and cirrhosis; (2) antagonists to cytokines or antibodies to cytokine receptors for cytokines that have been shown to enhance hepatocellular necrosis or fibrosis; (3) substances that block pathways of oxygen radical formation or increase their metabolism or binding to form nonharmful compounds; (4) inhibition of collagen synthesis by proline analogues that increase intracellular collagen degradation or increase in collagen degradation by stimulation of collagenase or by insertion of exogenous DNA encoding amino or carboxyterminal peptides of procollagen into hepatocytes; and (5) stimulation of hepatic regeneration and recovery from alcohol-inducer liver injury.

Topics: Adrenal Cortex Hormones; Anabolic Agents; Diet Therapy; Enteral Nutrition; Female; Humans; Liver Diseases, Alcoholic; Liver Transplantation; Male; Parenteral Nutrition; Penicillamine; Propylthiouracil

Propylthiouracil (Propycil Thyreostat) is presently being used in hyperthyroidism, thyroidectomy, and other diseases affecting thyroid gland metabolism. Canadian clinicians have published interesting reports showing that propylthiouracil can be used to successfully treat alcohol-induced liver damage. In two clinical trials (approximately 340 patients) it was shown that long-term treatment with propylthiouracil was associated with a significantly more favorable prognosis in cirrhosis of the liver and with a reduction in mortality. Preclinical studies suggest that alcohol abuse leads to a hypermetabolic status of the liver, which is similar to hyperthyroidism. The results of these studies suggest a rationale for the use of propylthiouracil in alcohol-induced liver cirrhosis.

Topics: Energy Metabolism; Humans; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Propylthiouracil

Aggressive management to prevent alcoholic cirrhosis should include the use of biopsy results to diagnose and to monitor alcoholic liver disease. Guidelines for the interpretation of the liver biopsy are highlighted. The diagnosis, course, and treatment of alcoholic hepatitis and cirrhosis are presented in detail.

Topics: Adrenal Cortex Hormones; Biopsy; Colchicine; Diagnosis, Differential; Fatty Liver, Alcoholic; Glucagon; Hemosiderosis; Humans; Insulin; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Diseases, Alcoholic; Porphyrias; Propylthiouracil

In conclusion, the studies presented suggest that two factors commonly occurring in the alcoholic, namely, an increased rate of ethanol metabolism and hepatomegaly, may have important pathogenic implications in alcoholic liver disease. An increased rate of ethanol metabolism is linked to a greater oxygen demand, thus resulting in greater susceptibility to hypoxia in Zone 3 of the liver acinus, a factor which might be responsible for hepatocellular necrosis in alcoholic hepatitis. Propylthiouracil has been shown to have a protective effect against hypoxic necrosis in alcohol-fed animals and has been found to be most effective in accelerating the rate of recovery of alcoholics with active liver disease. On the other hand, hepatocyte expansion in hepatomegaly, in the face of a semi-rigid liver capsule, leads to constriction of extracellular volume and to an increase in intrahepatic and portal pressure. The latter, in turn, could produce a variety of haemodynamic alterations as those found in the alcoholic. To what extent the mechanisms described are responsible for or might add to the myriad of other disturbances observed in alcoholic disease should be further analysed.

Topics: Animals; Collagen; Hemodynamics; Humans; Liver; Liver Diseases, Alcoholic; Oxygen Consumption; Propylthiouracil

Although propylthiouracil has previously been shown to reduce the risk of mortality in alcoholic liver disease by 60%, generalized use of propylthiouracil for this condition has not occurred. Additional data are therefore presented on four aspects to provide a better assessment of its therapeutic effectiveness. First, the characteristics and the prognosis of dropouts were virtually identical in both the drug and placebo groups. Also the methodology and analysis employed, were designed to control for dropouts, thus providing an accurate interpretation of the outcome. Secondly, since 97% of the patients continued to drink, abstinence was not a precondition for the beneficial effect of propylthiouracil. However, the beneficial effect was observed most clearly in those patients who continued to drink at lower levels, whereas lower level drinking per se did not afford protection in placebo patients. Thirdly, serious side effects or clinical hypothyroidism occurred extremely rarely in these patients, many of whom have now received propylthiouracil for over 4 years. Fourthly, we discuss why the outcome in long-term clinical trials in alcoholic liver disease cannot be compared with effects observed in clinical trials lasting only a few weeks. Journal of Hepatology.

Topics: Clinical Trials as Topic; Female; Follow-Up Studies; Humans; Hypothyroidism; Liver Diseases, Alcoholic; Male; Middle Aged; Patient Compliance; Propylthiouracil; Time Factors

Topics: Clinical Trials as Topic; Double-Blind Method; Humans; Liver Diseases, Alcoholic; Propylthiouracil; Random Allocation

Topics: Female; Humans; Liver Diseases, Alcoholic; Male; Middle Aged; Propylthiouracil; Time Factors

Topics: Clinical Trials as Topic; Humans; Liver Diseases, Alcoholic; Propylthiouracil

Propylthiouracil has been shown experimentally to protect against alcohol-induced hepatocellular necrosis in hypoxic conditions. An earlier, short-term study of patients with alcoholism and liver disease indicated clinical improvement with propylthiouracil, but the effect on mortality could not be assessed. In the present study, we investigated the effect of propylthiouracil on mortality in patients with alcoholic liver disease in a long-term, double-blind, randomized clinical trial involving 310 compliant patients who received propylthiouracil (n = 157) or placebo (n = 153) for a maximum of two years. There were no differences between the two groups in demographic and clinical characteristics and biopsy-confirmed diagnoses at randomization, or in daily urinary alcohol levels during the study. The cumulative dropout rate over two years was not significantly different (propylthiouracil group, 0.68; placebo group, 0.60). The group receiving propylthiouracil (300 mg per day) had a cumulative mortality rate half that in the group receiving placebo (0.13 vs. 0.25 [P less than 0.05] in the total sample, and 0.25 vs. 0.55 [P less than 0.03] in a subgroup of severely ill patients [propylthiouracil group, n = 56; placebo group, n = 41]). Proportional-hazards stepwise regression analyses indicated that only propylthiouracil treatment, prothrombin time, hemoglobin levels, and mean daily urinary alcohol levels significantly affected mortality. The hazards ratio for the complete group indicated that mortality in the propylthiouracil group was 0.38 (95 percent confidence interval, 0.20 to 0.83) that of the placebo group. Protection by propylthiouracil was not observed in patients with high morning urinary alcohol levels. No clinically important side effects of propylthiouracil were observed at the dose used. We conclude that the administration of propylthiouracil can reduce mortality due to alcoholic liver disease.

Topics: Alcohol Drinking; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Liver Diseases, Alcoholic; Male; Middle Aged; Patient Compliance; Propylthiouracil; Random Allocation; Regression Analysis; Thyroid Gland

The effect of propylthiouracil (PTU; 300 mg/day) on alcoholic liver disease was evaluated in 133 patients in a short-term randomized double-blind trial. Severity of the disease was assessed by a composite clinical and laboratory index (CCLI). A normalization rate (NR) representing the rate of improvement in CCLI was calculated. Patients with alcoholic hepatitis, with and without cirrhosis, showed a significantly higher NR on PTU (43.6 +/- 4.6) than on placebo (19.8 +/- 3.3; P less than 0.001). A similar effect was observed in patients with abnormal prothrombin (no biopsy): NR was 32.9 +/- 6.9 on PTU and 2.6 +/- 3.7 on placebo (P less than 0.005). The effect of PTU on each clinical and laboratory component of the CCLI was also compared in these two groups. In 38 patients with alcoholic hepatitis and in 25 with abnormal prothrombin, those on PTU showed a greater improvement in 15 of 15 items (P less than 0.001) and 14 of 15 (P less than 0.01), respectively. When patients were divided according to the severity of the disease into those in the lower and upper halves of the CCLI range (81 and 52 patients, respectively), PTU was shown to have a significant effect only in the latter: The NR was 41.4 +/- 3.8 on PTU and 22.5 +/- 4.2 on placebo (P less than 0.005). PTU was ineffective in patients with inactive cirrhosis.

Topics: Double-Blind Method; Drug Evaluation; Fatty Liver, Alcoholic; Hepatitis, Alcoholic; Humans; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Liver Function Tests; Placebos; Propylthiouracil; Prothrombin Time; Time Factors

The relationship between alcoholic liver disease and circulating thyroid hormones was investigated in 124 hospitalized patients treated with placebo or propylthiouracil (PTU) for a maximum of 46 days in a double-blind study. Serum triiodothyronine (T3) levels on admission were significantly (P less than 10(-6) and inversely correlated with the severity of alcoholic liver disease. After hospitalization, changes in T3-levels in patients with low admission T3 significantly correlated (P less than 0.001) with the degree of spontaneous improvement of liver function (placebo group). Treatment with 300 mg of PTU daily (Orrego et al. Gastroenterology 76:105--115, 1979) markedly increased the rate of improvement in severely ill patients with low T3 on admission. In this group, serum T3-levels were also increased after PTU, but this increase did not correlate with the change in the patient's condition. It is suggested that the known inhibitory effect of PTU on peripheral deiodination of T4 to T3 is marked by a more marked improvement in liver function in this group. PTU treatment in this group reduced the free T4-index and increased TSH levels markedly (16%; P less than 0.02) toward levels found in hypothyroidism. PTU did not improve the condition of mildly ill patients with normal admission T3-levels, nor did it alter free T4-index or serum TSH levels in these patients. Serum T3-levels provide a sensitive indicator of the severity of alcoholic liver disease and of its response to conventional treatment. Serum T3-levels also distinguish between a group of patients, in whom low-dose PTU administration results in a beneficial effect, and another group, in whom no therapeutic effect of PTU is observed.

Topics: Humans; Liver Diseases, Alcoholic; Placebos; Prognosis; Propylthiouracil; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

The present study was performed in order to discern the effects of propylthiouracil (PTU) on ethanol and/or protein deficiency-mediated liver histological changes and liver Fe, Zn, Cu and Mn alterations in male adult Wistar rats. The study was performed on 64 animals divided into eight groups, fed with the Leiber-DeCarli control, 36% ethanol-2% protein- and 36% ethanol-2% protein-containing diets, without and with PTU, respectively. PTU was administered at a concentration of 0.05%, an amount which rendered the animals hypothyroid. Two further groups of 5 animals each, with and without PTU respectively, were allowed to consume the control diet ad libitum. Animals treated with PTU showed significantly less fibrosis, but more fat, than animals without PTU. Liver fibrosis was inversely correlated with liver zinc, liver content of this element being higher in the PTU-treated and the ethanol or protein deficiency groups. PTU also reversed ethanol-mediated hepatocyte ballooning and also led to a reduction in nuclear areas.

Topics: Animals; Cell Nucleus; Cell Size; Copper; Ethanol; Fatty Liver, Alcoholic; Iron; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Male; Manganese; Propylthiouracil; Protein-Energy Malnutrition; Rats; Rats, Wistar; Zinc

Topics: Humans; Liver; Liver Diseases, Alcoholic; Oxygen Consumption; Propylthiouracil

Topics: Adrenal Cortex Hormones; Anabolic Agents; Colchicine; Combined Modality Therapy; Female; Humans; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Male; Propylthiouracil; Testosterone

The concept of a hypermetabolic state to explain metabolic tolerance to ethanol grew from the recognition that the rate of alcohol metabolism is, in general, limited by the rate at which mitochondria can reoxidize reducing equivalents and thus by the rate at which oxygen can be consumed by the liver. This relationship appears to be most important in conditions in which the alcohol dehydrogenase (ADH)/QO2 ratio is high and is not in conflict with observations suggesting that ADH can, under certain conditions, constitute a rate-determining step for ethanol metabolism in rodents. Liver preparations from animals fed alcohol chronically, in which an increase in ethanol metabolism is shown, consume oxygen at higher rates. This effect, concerning which there is discrepancy among investigators, depends on the type of preparation. Thyroid hormones play a permissive role in the development of the hypermetabolic state, while increased circulating levels of these hormones are not required. Antithyroid drugs inhibit both metabolic tolerance in vivo and the hypermetabolic state. While the hypermetabolic state requires an increased ATP utilization in the form of an adenosine triphosphatase, or an inhibition of ATP synthesis, the different mechanisms proposed for such an effect do not quantitatively account for the increases in oxygen consumption. In humans and animals chronically exposed to ethanol, but withdrawn, oxygen tensions in blood leaving the liver are significantly reduced. In some situations, low oxygen tensions in zone 3 of the hepatic acinus can reach critical hypoxic levels and may lead to cell necrosis. Studies in which the effectiveness of propylthiouracil is tested in human alcoholic hepatitis are discussed.

Topics: Adenosine Triphosphate; Alcohol Dehydrogenase; Alcohol Oxidoreductases; Alcoholism; Animals; Energy Metabolism; Ethanol; Humans; Liver; Liver Circulation; Liver Diseases, Alcoholic; NAD; Oxygen Consumption; Papio; Propylthiouracil; Rats; Sodium-Potassium-Exchanging ATPase; Thyroid Hormones

Alcoholism is a major health problem, and one of its primary manifestations is alcoholic liver disease. The mechanisms responsible for the various forms of alcoholic liver disease--fatty liver, alcoholic hepatitis, and cirrhosis--are at present poorly understood. Knowledge of these mechanisms is needed to provide a sound framework for the therapy and prevention of liver disease due to alcohol and for the identification of those individuals most susceptible to develop liver disease from alcohol abuse. These experiments were designed specifically to evaluate the postulate that ethanol-induced pericentral liver damage results from an accentuated gradient of decreasing oxygen tension leading to pericentral hypoxia. Microlight guides were used to detect NADH fluorescence, and miniature oxygen electrodes were employed to measure oxygen tensions from periportal and pericentral regions of the liver lobule from the perfused rat liver. With both techniques, ethanol treatment increased the hepatic oxygen gradient. This increase was blocked by the antithyroid drug propylthiouracil. Thus, these experiments provide evidence in support of the hypothesis that pericentral hypoxia is involved in the mechanism of ethanol-induced liver injury. Furthermore, low-flow hypoxia was shown to cause blebs in the pericentral region of the liver lobule in as little as 15 min. This surface blebbing could represent the mechanism for the well-known release of enzymes by impaired hepatic tissues.

Topics: Acetaldehyde; Alcohol Dehydrogenase; Alcohol Oxidoreductases; Alcoholism; Animals; Humans; L-Lactate Dehydrogenase; Liver; Liver Circulation; Liver Diseases, Alcoholic; Microscopy, Electron, Scanning; NAD; Oxygen Consumption; Propylthiouracil; Rats

Centrilobular hypoxia has been postulated as a mechanism for the development of hepatocellular necrosis and fibrosis in alcoholic liver disease. Chronic ethanol ingestion in rodents results in increased hepatic oxygen consumption and in a steeper fall in oxygen tension between the periportal and the pericentral area of the lobule, rendering the pericentral area susceptible to hypoxia. Hepatocellular necrosis occurs when ethanol-fed animals are exposed to low atmospheric oxygen. In man, the existence of a hypermetabolic state is more tenuous, but suggested by an increased rate of ethanol elimination after chronic ethanol consumption that has been linked to increased oxygen consumption in animals. Also, decreases in hepatic blood flow and hepatic vein oxygen tension were found in alcoholics with histological evidence of liver-cell necrosis as compared to those without necrosis. It is postulated that in man, reduction in the availability of oxygen to the liver may be caused by miscellaneous conditions such as anemia, respiratory depression or infection, cigarette-smoking, or reduction of hepatic blood flow, but the contribution of one or more of these factors remains to be proven. Trials of the effect of propylthiouracil (PTU) on alcoholic hepatitis are based on the effect of this drug in decreasing the ethanol-induced hypermetabolic state and in preventing hepatocellular necrosis in animals exposed to low atmospheric oxygen. A tentative conclusion of the two small trials that have been completed is that PTU may be beneficial in moderately ill patients with a low mortality, but not useful in severely ill patients with a high mortality.

Topics: Alcohol Dehydrogenase; Alcohol Oxidoreductases; Animals; Energy Metabolism; Hepatitis, Alcoholic; Humans; Liver; Liver Circulation; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; NAD; Oxygen Consumption; Propylthiouracil; Rats; Thyroid Hormones

Topics: Adult; Aged; Animals; Female; Half-Life; Humans; Kinetics; Liver Diseases, Alcoholic; Male; Middle Aged; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroidectomy; Time Factors

Topics: Adrenal Cortex Hormones; Ethanol; Fatty Liver, Alcoholic; Humans; Liver Diseases, Alcoholic; Propylthiouracil