propylthiouracil and Liver-Cirrhosis--Alcoholic

The aim of this review was to determine the benefits and adverse effects of propylthiouracil for patients with alcoholic liver disease.. Systematic Cochrane Review of randomised clinical trials. The Cochrane Hepato-Biliary Controlled Clinical Trials Register, The Cochrane Library, MEDLINE, and full text searches were combined. All analyses were performed according to the intention-to-treat method. Only 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.. Six randomised clinical trials randomising 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, CI 0.45 to 1.33), complications to the liver disease (OR 1.14, CI 0.58 to 2.24), and liver histology. Propylthiouracil was associated with a nonsignificant trend toward an increased risk of nonserious adverse events (OR 1.49, CI 0.74 to 2.99) and with the rare occurrence of serious adverse events (leukopenia).. This systematic review could not demonstrate any significant effect of propylthiouracil on any clinically important outcomes (mortality, liver-related mortality, liver complications and liver histology) of patients with alcoholic liver disease.

Topics: Antithyroid Agents; Hepatic Encephalopathy; Humans; Liver Cirrhosis, Alcoholic; Propylthiouracil; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Survival Rate; Treatment Outcome

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

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

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

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

Topics: Animals; Ethanol; Humans; Hyperthyroidism; Hypothalamo-Hypophyseal System; Liver; Liver Cirrhosis, Alcoholic; Propylthiouracil; Rats; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Adrenal Cortex Hormones; Azathioprine; Chronic Disease; Colchicine; Hepatitis; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Penicillamine; Propylthiouracil; Vidarabine

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.. 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.. 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.. 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.

Topics: Female; Hemodynamics; Humans; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Osmolar Concentration; Portal System; Propylthiouracil; Splanchnic Circulation; Vasodilator Agents

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 cause of the cycle of urinary alcohol levels (UALs) in rats fed ethanol continually at a fixed rate is unknown. Rats were fed ethanol intragastrically at a constant dose for 2 mo, and daily body temperatures and UALs were recorded. Body temperature cycled inversely to UAL, suggesting that the rate of metabolism could be mechanistically involved in the rate of ethanol elimination during the cycle. To document this, whole body O(2) consumption rate was monitored daily during the cycle. The rate of O(2) consumption correlated positively with the change in body temperature and negatively with the change in UAL. Since the metabolic rate responds to changes in body temperature, thyroid hormone levels were measured during the UAL cycle. T(4) levels correlated positively with the O(2) consumption rate and negatively with the UALs. In a second experiment using propylthiouracil treatment, UALs did not cycle and a fall in body temperature failed to stimulate an increase in the rate of ethanol elimination. Consequently, rats died of overdose. Likewise, in a third experiment using rats with severed pituitary stalks, UALs failed to cycle and rats died of overdose. From these observations it was concluded that the UAL cycle depends on an intact hypothalamic-pituitary-thyroid axis response to the ethanol-induced drop in body temperature by increasing the rate of ethanol elimination.

Topics: Alanine Transaminase; Animals; Antimetabolites; Body Temperature; Central Nervous System Depressants; Endotoxins; Enteral Nutrition; Ethanol; Hypothalamo-Hypophyseal System; Interleukin-1; Liver; Liver Cirrhosis, Alcoholic; Male; Organ Size; Oxygen Consumption; Propylthiouracil; Rats; Rats, Wistar; Thyroid Gland; Thyrotropin; Thyroxine; Tumor Necrosis Factor-alpha

The antithyroid drug propylthiouracil has been suggested for the treatment of alcoholic liver disease. Its beneficial effects could be due to either a decrease in hepatic oxygen consumption or an increase in hepatic blood flow. The aim of this study was to test these two hypotheses in patients with proven alcoholic cirrhosis.. The pharmacokinetic parameters after intravenous administration of 300 mg of propylthiouracyl were first determined in four patients. Then, the effects on systemic and splanchnic hemodynamics, and oxygen content were measured 45 and 90 min after the intravenous administration of 300 mg (n=6) or 600 mg (n=6) of propylthiouracil.. Systemic hemodynamics (heart rate, arterial pressure, cardiac output and systemic vascular resistance) and splanchnic hemodynamics (hepatic venous pressure gradient, hepatic and azygos blood flows) were not modified 45 and 90 min after the administration of 300 mg or 600 mg of propylthiouracil. Moreover, neither oxygen content in the radial artery, pulmonary artery or hepatic vein, nor systemic oxygen uptake was modified after propylthiouracyl administration. The absence of effect of propylthiouracyl administration was also confirmed in patients with cirrhosis with proven acute alcoholic hepatitis (n=7).. In patients with alcoholic cirrhosis, acute administration of propylthiouracyl has no effect on systemic and splanchnic hemodynamics or on oxygen contents. The presence of acute alcoholic hepatitis does not modify these results.

Topics: Adult; Antimetabolites; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Infusions, Intravenous; Liver; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Oxygen Consumption; Propylthiouracil; Spectrophotometry; Splanchnic Circulation; Treatment Outcome

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

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