David W. Crabb

Rate-determining factors for ethanol metabolism in fasted and castrated male rats.

The effects of castration and fasting upon the alcohol elimination rate, liver alcohol dehydrogenase (LADH) maximum activity (Vmax), and hepatic concentrations of ethanol, acetaldehyde, and free NADH during ethanol oxidation were examined in male Wistar rats. Castration increased the Vmax of LADH and, to a lesser extent, the alcohol elimination rate in vivo. On the other hand, fasting reduced the Vmax of LADH and the alcohol elimination rate in sham-operated and castrated rats but it did not nullify the effect of castration. Castration produced small but significant changes in the hepatic concentrations of ethanol, acetaldehyde and free NADH in fed rats during ethanol oxidation. Fasting also caused significant increases in the concentration of free NADH during alcohol oxidation in both the sham-operated and castrated groups. The ratio of the steady-state velocities of LADH in situ to the maximum velocities of LADH (v/Vmax) under the different experimental conditions was calculated by using the steady-state rate equation for the enzyme mechanism of rat LADH and its kinetic constants. The calculated v/Vmax ratios were 50-62%, indicating that LADH activity was limited to about the same extent by its substrates and products under these conditions and that the changes in alcohol elimination rates produced by fasting and castration mainly reflected changes in the Vmax of LADH. The calculated steady-state velocities in situ (v) were 14-28% lower than the measured rates of alcohol elimination in vivo. The extent of agreement is probably acceptable in view of the assumptions needed to determine the free NADH concentration in liver and the existence of non-LADH-related processes for alcohol elimination in vivo.

Molecular and Genetic Approaches to Understanding Alcohol-Seeking Behavior

In alcoholism research, two fundamental and related questions are: “why do people drink?” and“why do some people drink too much despite having experienced negative consequences?” Drinking normally occurs in a social setting. Environmental factors and how individuals react to them can therefore have powerful influences on drinking behavior. On the other hand, the neuropsychopharmacological actions of ethanol and how different individuals react to these effects can be important biological determinants. Ethanol’s action is biphasic, that is, it can be reinforcing or rewarding at low concentrations, but aversive at high concentrations (Pohorecky, 1977). Perception by the individual of the reinforcing actions of ethanol might be expected to maintain alcohol-seeking behavior, whereas aversive effects would be expected to extinguish it. The disorder alcoholism can be defined in experimentally approachable terms as a state of abnormally intense alcohol-seeking behavior that over time leads to the alcohol dependence syndrome (Edwards and Gross, 1976). Identification of both the environmental and the biological variables that promote and maintain high alcohol-seeking or alcohol self-administration behavior is key to our understanding of this disorder.

The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis

Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH, and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate AH (MAH) (n = 18) or severe AH (SAH) (n = 19). These data were compared with heavy drinking controls (HDCs) without obvious liver disease (n = 19) and non–alcohol‐consuming controls (NACs, n = 20). The data were related to endotoxin levels and markers of monocyte activation. Linear discriminant analysis effect size (LEfSe) analysis, inferred metagenomics, and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (P < 0.01) and SAH (P < 0.001) subjects. Compared with NACs, the relative abundance of phylum Bacteroidetes was significantly decreased in HDCs, MAH, and SAH (P < 0.001). In contrast, all alcohol‐consuming groups had enrichment with Fusobacteria; this was greatest for HDCs and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (P = 0.01). Compared with alcohol‐consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Furthermore, both HDCs and SAH showed activation of a type III secretion system that has been linked to gram‐negative bacterial virulence. Metagenomics in SAH versus NACs predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram‐positive bacterial growth and biofilm production, respectively. Conclusion: Heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions. (Hepatology 2018;67:1284‐1302).

Acute Alcoholic Hepatitis: Natural History and Predictors of Mortality Using a Multicenter Prospective Study

Objective To examine the natural history of acute alcoholic hepatitis (AH) and identify predictors of mortality for AH using data from a prospective multicenter observational study.Objective To examine the natural history of acute alcoholic hepatitis (AH) and identify predictors of mortality for AH using data from a prospective multicenter observational study. Participants and Methods We analyzed data from 164 patients with AH and 131 heavy-drinking controls with no liver disease. Participants underwent clinical/laboratory assessment at baseline and 6 and 12 months after enrollment. Multivariable analyses were conducted to identify variables associated with mortality and examine the association between coffee drinking and risk of AH. Results Thirty-six patients with AH died during follow-up, with estimated 30-day, 90-day, 180-day, and 1-year survival of 0.91 (95% CI, 0.87-0.96), 0.85 (95% CI, 0.80-0.91), 0.80 (95% CI, 0.74-0.87), and 0.75 (95% CI, 0.68-0.83), respectively. In the multivariable analysis, higher serum bilirubin level (hazard ratio [HR]=1.059; 95% CI, 1.022-1.089), lower hemoglobin level (HR=1.263; 95% CI, 1.012-1.575), and lower platelet count (HR=1.006; 95% CI, 1.001-1.012) were independently associated with mortality in AH. Compared with controls, fewer patients with AH regularly consumed coffee (20% vs 44%; P<.001), and this association between regular coffee drinking and lower risk of AH persisted after controlling for relevant covariates (odds ratio=0.26; 95% CI, 0.15-0.46). Time-dependent receiver operating characteristic curve analysis revealed that Model for End-Stage Liver Disease; Maddrey Discriminant Function; age, serum bilirubin, international normalized ratio, and serum creatinine; and Child-Pugh scores all provided similar discrimination performance at 30 days (area under the curve=0.73-0.77). Conclusion Alcoholic hepatitis remains highly fatal, with 1-year mortality of 25%. Regular coffee consumption was associated with lower risk of AH in heavy drinkers.