Long-term treatment of alcoholic liver disease with propylthiouracil. Part 2: Influence of drop-out rates and of continued alcohol consumption in a clinical trial.

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.

Connective tissue metabolism and alcohol intake in alcoholic liver disease.

We have examined the relationship between blood markers of fibrogenesis and basement membrane formation and alcohol intake in patients with a wide range of clinical and histological severity of alcoholic liver disease (Niemelä et al., 1990). While the patients with a mean of less than 8 mM alcohol in morning urines (mild or moderate drinkers) had a significant (p < 0.00001) decrease in serum aminoterminal propeptide of type III procollagen, type IV collagen and laminin in a period of 27 +/- 1 weeks, the patients with more than 8 mM of urinary alcohol (heavy drinkers) had no improvement. There was also a significant decrease in serum gamma glutamyl transferase activity in the group with lower, but not in that with the higher urinary alcohol concentrations. The Combined Clinical and Laboratory Index (CCLI) decreased in both groups, although the recovery was significantly (p < 0.03) greater in those with the lower urinary alcohol levels (66% +/- 6%) than in the group with a urinary alcohol level of > or = 8 mM (28% +/- 15%). We suggest that connective tissue metabolism in alcoholic liver disease is closely related to alcohol intake and thus affects the prognosis of the alcoholic patient.

Markers of fibrogenesis and basement membrane formation in alcoholic liver disease. Relation to severity, presence of hepatitis, and alcohol intake.

This study investigated the relationships of the serum markers of fibrogenesis and basement membrane formation to the clinical and morphological severity of alcoholic liver disease and to the degree of alcohol abuse. The concentrations of the aminoterminal propeptide of type III collagen, type IV collagen, and laminin were measured from 87 samples representing a wide range of clinical and histological severities of the disease, which were assessed with indices that have been shown to correlate well with the risk of dying within 1 yr. Significant correlations (p less than 0.00001) were found between the markers of connective tissue metabolism and the Combined Clinical and Laboratory Index: (aminoterminal propeptide of type III collagen, rs = 0.82; type IV collagen, rs = 0.82; laminin, rs = 0.81), as well as between these markers and the Combined Morphological Index: (aminoterminal propeptide of type III collagen, rs = 0.70; type IV collagen, rs = 0.68; laminin, rs = 0.64). Whereas the patients with less than 8 mM of alcohol in their morning urine (mild or moderate drinkers) showed a significant (p less than 0.00001) decrease in these markers in a period of 27 +/- 1 wk, the patients with more than 8 mM of urinary alcohol (heavy drinkers) had no improvement. It is proposed that both fibrogenesis and basement membrane formation are associated with disease severity, degree of alcoholic hepatitis, and alcohol intake, which are important determinants of prognosis in alcoholic liver disease.

Accuracy of death certificates in the diagnosis of alcoholic liver cirrhosis.

In 108 patients with alcoholic liver disease who died during a 10-year follow-up, the diagnoses from the liver biopsies were compared with that from the Death Certificates. Data show that the currently used ICD-9 category of cirrhosis with or without mention of alcohol has a 47.2% chance of missing the diagnosis of cirrhosis. On the other hand when the mention of liver disease in the Death Certificate is used for the diagnosis of cirrhosis, the percentage of undiagnosed cirrhosis decreases to 19.4% (p less than 0.0001).

Long-term treatment of alcoholic liver disease with 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.

Ethanol vapor above skin: determination by a gas sensor instrument and relationship with plasma concentration.

Studies with a new instrument show that blood ethanol concentrations in rats and humans can be estimated by measurement of ethanol vapor above the skin. After intravenous bolus administration of ethanol (1 g/kg) to rats a novel device based on the Figaro sensor was placed above the animal's abdomen. Plasma and skin vapor ethanol concentrations, analyzed by gas chromatography and sensor, respectively, declined in parallel (r = 0.96). In healthy human subjects, plasma and skin vapor concentrations, measured on the palm, also declined in parallel after intravenous ethanol infusion (1 hr, 0.5 g/kg), r = 0.99. In 10 alcoholic liver disease outpatients attending clinic in whom plasma ethanol concentrations ranged from 32-304 mg/dl, the correlation of plasma ethanol determined directly by gas chromatography and indirectly by skin vapor analysis was slope = 0.93, intercept = 1.8, r = 0.94. In controlled studies, skin vapor measurements are comparable with breathalyzer determinations; they may be performed in situations where breathalyzer measurements are inconvenient or where continuous monitoring is desirable.