Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis.

Plasma tumor necrosis factor alpha (TNF alpha), interleukin 1 alpha (IL-1 alpha), and interleukin 1 beta (IL-1 beta) were measured in plasma samples obtained from 23 patients with severe alcoholic hepatitis on admission and after 30 days of hospitalization. Over a 2-year follow-up period, 14 patients died at a mean time of 8 months following discharge. The presence of elevated plasma TNF alpha either at admission or discharge from the hospital was associated with death in 82% (14/17) of patients. By contrast absence of elevated plasma TNF alpha was associated with survival in 100% (6/6). The difference in survival with and without detectable plasma TNF alpha was significant at p = 0.0022. Plasma TNF alpha was not elevated in alcoholic patients without clinically apparent liver disease, with alcoholic cirrhosis, or in nonalcoholic healthy controls. Plasma IL-1 alpha was also significantly increased in alcoholic hepatitis whereas IL-1 beta was not. Neither IL-1 alpha nor beta was correlated with outcome in the alcoholic hepatitis group. It is concluded that the presence of elevated plasma TNF alpha is a significant predictor of decreased long-term survival in patients with severe alcoholic hepatitis.

Relationship of endocrine status on the stimulatory effect of ethanol on hepatic very low density lipoprotein synthesis.

The normal stimulatory effect of an acute oral dose of ethanol on hepatic very low density lipoprotein synthetic rate is abolished in thyroidectomized rats but not in adrenalectomized rats. This lack of stimulation by ethanol can be explained in part by the decreased rate of hepatic fatty acid esterification to neutral lipids in thyroidectomized animals.

The metabolism of acetone in rat.

Intraperitoneal injection of 5 mumol of acetone/g, body weight, into 3 rats previously fed 1% acetone (v/v) in their drinking water resulted in the appearance in blood serum of 16 +/- 2 nmol of 1,2-propanediol/ml and 8 +/- 1 nmol of 2,3-butanediol/ml. No detectable 1,2-propanediol or 2,3-butanediol was found in the serum of animals after acetone or saline injection without prior addition of acetone to drinking water or in the serum of animals injected with saline after having been maintained on drinking water containing 1% acetone. These data suggest that acetone both acts to induce a critical enzyme or enzymes and serves as a precursor for the production of 1,2-propanediol. It is also clear from these data that chronic acetone feeding plays a role in 2,3-butanediol production in the rat. Microsomes isolated from the liver of animals maintained on drinking water supplemented with 1% acetone contained two previously unreported enzymatic activities, acetone monooxygenase which converts acetone to acetol and acetol monooxygenase which converts acetol to methylglyoxal. Both activities require O2 and NADPH. Prior treatment with acetone increased serum D-lactate from 9 nmol/ml +/- 9 nmol/ml in control animals to 77 +/- 36 nmol/ml in acetone-fed animals after injection with 5 mumol of acetone/g, body weight. This is consistent with methylglyoxal being a by-product of acetone metabolism. Two pathways for the conversion of acetone to glucose are proposed, the methylglyoxal and the propanediol pathways. The methylglyoxal pathway is responsible for the conversion of acetone to acetol, acetol to methylglyoxal, and the subsequent conversion of methylglyoxal to glucose. The propanediol pathway involves the conversion of acetol to L-1,2-propanediol by an as yet unknown process. L-1,2-Propanediol is converted to L-lactaldehyde by alcohol dehydrogenase, and L-lactaldehyde is converted to L-lactic acid by aldehyde dehydrogenase. Expression of these metabolic pathways in rat appears to be dependent on the induction of acetone monooxygenase and acetol monooxygenase by acetone.

2,3-butanediol: an unusual metabolite in the serum of severely alcoholic men during acute intoxication.

In a controlled experiment 15 (79%) of 19 severely alcoholic men but only 1 of 22 controls had a serum concentration of greater than or equal to 5 mumol/l 2,3-butanediol after ingestion of distilled spirits. Another diol, 1,2-propanediol, was found in a concentration of greater than or equal to 5 mumol/l in all patients' specimens after drinking; but it was also present in lower concentrations in the reference specimens of most of the patients. These data are consistent with the experimental evidence that ethanol can be metabolised in rats to produce 2,3-butanediol and with the epidemiological hypothesis that severely alcoholic men metabolise ethanol by a different pathway than do control subjects.

Electron-capture, capillary column gas chromatographic determination of low-molecular-weight diols in serum.

Research on alcoholism has revealed that concentrations of 1,2-propanediol, d,1-2,3-butanediol and meso-2,3-butanediol may be greater in the serum of chronic alcoholics than in the serum of social drinkers and nondrinkers. In connection with one of these studies, we developed methodology to determine these diols at the micromolar levels in 500 serum samples. The procedure consisted primarily of extraction of the serum with acetonitrile containing internal standard. The extract was then concentrated to dryness and reacted with p-bromophenylboric acid. The reaction mixture was injected into a gas chromatograph fitted with a capillary column and an electron-capture detector. The total coefficients of variation were best for 1,2-propanediol, 6.82 and 10.00%, and worst for d,1-2,3-butanediol, 13.64 and 19.22%. The observed means for the analytes were all within 10% of the spiked level.

Alcohol and very low density lipoprotein synthesis and secretion by isolated hepatocytes.

Labeled leucine can be used to measure accurately the rate of both total and secretory protein synthesis by isolated hepatocytes if at least 1 mM leucine is added to the incubation medium, even in the presence of 50 mM ethanol. Using this technique it was found that ethanol caused a significant inhibition of very low density lipoprotein (VLDL) as well as total protein synthetic rates in hepatocytes from both fed and fasted rats. In contrast, a single acute oral dose of ethanol to fasted rats caused within 4 hr a threefold stimulation in the rate of VLDL synthesis without affecting the total protein synthetic rate in the hepatocyte system.

The presence of 2,3-butanediol in the blood of chronic alcoholics admitted to an alcohol treatment center.

Fifty-one of sixty-three unselected alcoholic subjects had 2,3-butanediol in their blood in concentrations ranging from 0.011 to 0.775 mM upon admission to an alcohol detoxification center. The concentration of 2,3-butanediol was below the detection limit of 0.01 mM in twelve non-alcoholic controls. Eighteen hours after admission, second blood samples showed no ethanol in all eleven subjects tested. 2,3-Butanediol levels declined in all of the patients and became undetectable in eight.