propylthiouracil and Hepatitis--Alcoholic

Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality. Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. Several clinical scoring systems have been derived to predict the clinical outcomes of patients with AH; such as Child-Turcotte-Pugh score, the Maddrey discriminant function, the Lille Model, the model for end stage liver disease scores, and the Glasgow alcoholic hepatitis score. At present, Corticosteroids or pentoxifylline are the current pharmacologic treatment options; though the outcomes from the therapies are poor. Liver transplantation as the treatment of alcoholic hepatitis remains controversial, and in an era of organ shortage current guidelines do not recommend transplantation as the treatment option. Because of the limitations in the therapeutic options, it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.

Topics: Acetylcysteine; Adrenal Cortex Hormones; Alcoholism; End Stage Liver Disease; Enteral Nutrition; Hepatitis, Alcoholic; Humans; Immunity, Innate; Inflammation; Liver Transplantation; Pentoxifylline; Propylthiouracil; S-Adenosylmethionine; Treatment Outcome

Alcoholic hepatitis is a common disease with an overall 1-year mortality of 20%. Although the classical treatment for alcoholic hepatitis is abstinence, in some individuals abstinence alone is inadequate to promote survival and recovery. This is particularly true of patients with severe alcoholic hepatitis, who are identified by jaundice, coagulopathy and neutrophilia. Within the last two decades, several agents have been examined as treatments for alcoholic hepatitis and cirrhosis. They have targeted several key processes in the pathophysiology of alcoholic liver disease, including hypermetabolism, inflammation, cytokine dysregulation and oxidant stress. The compounds that offer the greatest survival benefit to patients with severe alcoholic hepatitis are corticosteroids. Several groups have reported excellent results with corticosteroids, but positive results are not uniform, and there remains some controversy over their efficacy. Even if corticosteroids are beneficial for alcoholic hepatitis, they are not recommended for all patients at risk. Consequently, other agents are being tested that have broader applicability to individuals with contraindications to steroids. In this regard, pentoxifylline shows some promise, as does enteral feeding with medium chain triglycerides. Independent efforts are also being directed toward treatment of chronic alcoholic liver disease and alcoholic cirrhosis. Anti-oxidants have received the greatest attention; drugs such as S-adenosyl-methionine may be of benefit. This and others are under active study.

Topics: Adrenal Cortex Hormones; Antimetabolites; Antioxidants; Colchicine; Hepatitis, Alcoholic; Humans; Liver Transplantation; Pentoxifylline; Propylthiouracil

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: Alcoholism; Anabolic Agents; Colchicine; Enteral Nutrition; Ethanol; Female; Food, Formulated; Glucagon; Hepatitis, Alcoholic; Humans; Insulin; Liver; Male; Methylprednisolone; Nutrition Disorders; Prednisone; Propylthiouracil

Topics: Adrenal Cortex Hormones; Anabolic Agents; Clinical Trials as Topic; Colchicine; Enteral Nutrition; Female; Glucagon; Hepatitis, Alcoholic; Humans; Insulin; Male; Parenteral Nutrition; Propylthiouracil

The poor prognosis of severe acute alcoholic hepatitis has stimulated interest in specific forms of treatment aimed at reducing the short term mortality as well as preventing progression to cirrhosis. Several controlled trials of steroid therapy have suggested an improvement in short-term survival, but the benefit seems to apply to highly selected cases only. Treatment with propylthiouracil and insulin and glucagon infusions has also shown promising results in controlled studies but there is still no general agreement on their value. Despite recent interest in the use of colchicine to prevent progression of cirrhosis in chronic liver disease of other aetiologies, its role in alcoholic liver disease is not yet clear. In end-stage alcoholic cirrhosis, excellent results are now being achieved with liver transplantation, although this is limited to patients who are not alcohol dependent and in whom there is no alcohol-induced extrahepatic disease.

Topics: Amino Acids; Anabolic Agents; Colchicine; Combined Modality Therapy; Hepatic Encephalopathy; Hepatitis, Alcoholic; Humans; Liver Cirrhosis, Alcoholic; Liver Transplantation; Prednisolone; Propylthiouracil

Alcoholic hepatitis is a necrotizing, often inflammatory, process that is an important precursor to the development of cirrhosis. Acetaldehyde, which is derived from alcohol by the action of alcohol dehydrogenase, is apparently the most important factor leading to alcohol-induced liver injury. Other factors of importance in determining the appearance and rate of progression of liver diseases in patients who are chronic alcoholics include sex, nutritional status, and various immunologic reactions. In addition, there is an incompletely understood genetic predisposition to the development of alcoholic hepatitis. Several histologic features found in patients with alcoholic hepatitis have been evaluated in efforts to determine which are of prognostic value. The predominance of the alcohol-induced injury in zone III of the hepatic lobule; deposition of collagen, IgA, and fibronectin in the space of Disse; defenestration of endothelial cells; and transformation of lipocytes and myofibroblasts to fibroblasts have been investigated. Prolongation of the prothrombin time and marked elevation of serum bilirubin levels are indicators of a subgroup of patients with alcoholic hepatitis who have a poor prognosis, especially if there is also evidence of hepatic encephalopathy. Supportive care and abstinence from alcohol are the foundations of therapy. Corticosteroid therapy appears to decrease the number of early deaths in patients with severe alcoholic hepatitis. Other experimental approaches to therapy include the use of propylthiouracil, anabolic-androgenic steroids, and insulin and glucagon.

Topics: Acetaldehyde; Adrenal Cortex Hormones; Anabolic Agents; Glucagon; Hepatitis, Alcoholic; Humans; Insulin; Liver; Liver Function Tests; Propylthiouracil

Topics: Adult; Biopsy; Female; Food, Formulated; Hepatitis, Alcoholic; Humans; Liver; Oxandrolone; Parenteral Nutrition; Prednisolone; Propylthiouracil

Topics: Adrenal Cortex Hormones; Amino Acids; Anabolic Agents; Collagen; Endothelium; Fibroblasts; Glucagon; Hepatitis, Alcoholic; Humans; Inclusion Bodies; Insulin; Liver; Prognosis; Propylthiouracil

Alcoholic hepatitis is defined by histological findings, i.e. Mallory bodies, necrosis and polynuclear infiltration. It may be accompanied by steatosis and more or less advanced fibrosis. The clinical picture is variable, ranging from a total absence of symptoms to high fever, jaundice and encephalopathy. Laboratory findings reveal high polynuclear white cell counts, SGOT (but not SGPT) and glutamate dehydrogenase levels. The prognosis varies according to the series studied. The pathogenesis is unclear but cellular and humoral immunity mechanisms may play a role. Therapeutic possibilities are limited, corticosteroids only being useful in very serious cases. Alcoholic hepatitis is not a nosological entity but an acute inflammatory reaction of the liver due to cell necrosis caused by alcohol, and can therefore occur at any stage of alcoholic liver.

Topics: Adult; Aspartate Aminotransferases; Fatty Liver; gamma-Glutamyltransferase; Hepatitis, Alcoholic; Humans; Liver Cirrhosis; Male; Nutrition Disorders; Propylthiouracil; T-Lymphocytes

Topics: Acute Disease; Clinical Trials as Topic; Hepatitis, Alcoholic; Humans; Propylthiouracil

Sixty-seven patients entered a double-blind, controlled trial to evaluate the efficacy of propylthiouracil treatment in severe alcoholic hepatitis. Twenty-three percent (7 of 31) given propylthiouracil and 19% (7 of 36) given placebo died during the 6-wk study. Propylthiouracil treatment did not reduce the frequency and incidence of complications in alcoholic hepatitis, but induced hypothyroidism in 4 patients. Treatment produced no beneficial effect on any of the hepatic biochemical tests. We were unable to show any beneficial effect of propylthiouracil treatment on morbidity and mortality in patients with severe acute alcoholic hepatitis.

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Female; Hepatitis, Alcoholic; Humans; Hypothyroidism; Male; Propylthiouracil; Random Allocation

Topics: Animals; Ethanol; Hepatitis, Alcoholic; Humans; Liver; Propylthiouracil; Rats; 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 basic therapeutic principle in alcoholic liver diseases in general and in alcoholic hepatitis in particular is the consequent withdrawal of alcohol intake. Basic therapy of more complicated causes includes well balanced nutrition and symptomatic treatment according to the known principles of hepatology and intensive care medicine. Infusions with glucose-glucagon-insulin, or the administration of silymarin, and in individual cases of glucocorticoids seems to be justified as additional treatment. The therapy with S-adenosyl-L-methionine is promising, but clear evidence of the therapeutic effect has to be supplied by clinical studies. Liver transplantation should be taken into consideration in prognostically infaust cases.

Topics: Combined Modality Therapy; Glucocorticoids; Hepatitis, Alcoholic; Humans; Liver Transplantation; Parenteral Nutrition, Total; Propylthiouracil; S-Adenosylmethionine; Silymarin

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Anabolic Agents; Diagnosis, Differential; Female; Hepatitis, Alcoholic; Humans; Male; Middle Aged; Prognosis; Propylthiouracil

This report touched three aspects of drug therapy in alcoholics. The first topic consisted of a comparison between the effects of disulfiram treatment with the consequences of inborn deficiency of aldehyde dehydrogenase isozyme I; the comparison generated some concepts which might be subject to observational verification. The second topic was the citation of studies which suggest a selective decrease of the appetite for alcohol by drugs classified as serotonin uptake blockers. Finally, I cited the presently revealed success of propylthiouracil treatment of alcoholics suffering from liver damage, a success measured not only in laboratory terms but in terms of patient survival.

Topics: Alcoholism; Aversive Therapy; Disulfiram; Hepatitis, Alcoholic; Humans; Propylthiouracil; Serotonin Antagonists

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: Ethanol; Hepatitis, Alcoholic; Humans; Propylthiouracil

Topics: Hepatitis, Alcoholic; Humans; Propylthiouracil

Topics: Animals; Hepatitis, Alcoholic; Humans; Liver; Liver Function Tests; Propylthiouracil