Night Driving (Mesopic) Visual Acuity in Sober Male Alcoholics with and without Liver Disease

Night driving (mesopic) visual acuity and recovery after dazzle has been reported to be reduced in patients with liver disease. Mesopic visual acuity and dazzle recovery were evaluated in 32 patients with alcoholic cirrhosis, 29 alcoholics without liver disease, and 27 age-matched normal controls. All subjects were sober for at least 7 days prior to visual testing, a mean sobriety period of 22 and 39 weeks in alcoholics and cirrhotics, respectively. Serum vitamin A levels and/or dark adaptation were normal in all. Mean best decimal acuities were not significantly different among the groups: alcoholic cirrhotics, 0.32 ± 0.02; alcoholics, 0.32 ± 0.02; and normals, 0.33 ± 0.03 at 2 min. Although cirrhotics had significantly higher SGOT and lower albumin levels than alcoholics, mesopic acuity did not relate to liver blood tests. Decimal acuity following a dazzle stimulus was not significantly worse in cirrhotics and alcoholics compared to normals. Sober patients with alcoholic cirrhosis or a history of alcoholism have no evidence of a static mesopic visual defect and therefore may not have impaired night driving vision.     

Cytokine Storm of COVID-19 and Its Impact on Patients with and without Chronic Liver Disease

The coronavirus pandemic has resulted in increased rates of hepatic decompensation, morbidity and mortality in patients suffering from existing liver disease, and deranged liver biochemistries in those without liver disease. In patients with cirrhosis with coronavirus disease 2019 (COVID-19), new onset organ failures manifesting as acute-on-chronic liver failure have also been reported. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) also directly binds to enterocytes and cholangiocytes via the angiotensin converting enzyme receptor 2, although the lung remains the portal of entry. Superadded with the COVID-19 related bystander hepatitis, a systemic inflammatory response is noted due to unregulated macrophage activation syndrome and cytokine storm. However, the exact definition and diagnostic criteria of the ‘cytokine storm’ in COVID-19 are yet unclear. In addition, inflammatory markers like C-reactive protein, ferritin, D-dimer and procalcitonin are frequently elevated. This in turn leads to disease progression, activation of the coagulation cascade, vascular microthrombi and immune-mediated injury in different organ systems. Deranged liver chemistries are also noted due to the cytokine storm, and synergistic hypoxic or ischemic liver injury, drug-induced liver injury, and use of hepatotoxic antiviral agents all contribute to deranged liver chemistry. Control of an unregulated cytokine storm at an early stage may avert disease morbidity and mortality. Several immunomodulator drugs and repurposed immunosuppressive agents have been used in COVID-19 with varying degrees of success.     

Oxidation Phenotyping in Alcoholics with Liver Disease of Varying Severity

The propensity to develop alcoholic cirrhosis is probably, at least in part, genetically determined. A striking similarity exists histologically between perhexiline and alcohol-related hepatitis and both are potentially precirrhotic lesions. Liver damage due to perhexiline is associated with impaired drug oxidation capacity which is genetically determined and tested by use of debrisoquine. Oxidation phenotyping might be used to predict susceptibility to perhexiline liver damage; it might also predict the potential to develop alcoholic cirrhosis. Oxidation phenotyping was therefore undertaken, using debrisoquine in 100 alcoholic patients, 30 of whom had only fatty liver despite prolonged alcohol abuse, while the remaining 70 had alcoholic hepatitis and/or cirrhosis. One hundred patients with nonalcoholic chronic liver disease served as controls. The number of patients with severely impaired drug oxidation capacity (poor metabolizer phenotype) was similar in the alcoholic group (8%) and the nonalcoholic control group (7%). In particular, the incidence of the poor metabolizer phenotype was similar in alcoholics with severe liver disease (10%) and in those with only fatty change (3%). There appears to be no association between the susceptibility to develop alcoholic cirrhosis and drug oxidizing capacity.     

Alveolar Macrophage Release of Tumor Necrosis Factor-α in Chronic Alcoholics without Liver Disease

Alcohol is an immunosuppressive drug, and chronic abuse has been associated with increased susceptibility to a variety of infections, including bacterial pneumonia and tuberculosis. Alveolar macrophages are the resident phagocytes of the lung and play a central role in lung host defenses against infection ranging from direct antibacterial activity to the release of proinflammatory cytokines such as tumor necrosis factor-α (TNFα). TNFα, in particular, plays a key role in the development of the early inflammatory response. In this study, we investigated the effects of chronic alcohol consumption on alveolar macrophage release of TNFα in vitro. We prospectively studied lipopolysaccharide (LPS)-stimulated release of TNFα from alveolar macrophages obtained from bronchoalveolar lavage fluid (BALF) in 22 alcoholic (18 smokers, 4 nonsmokers) and 7 nondrinking healthy volunteers (3 smokers, 4 nonsmokers). The total number of cells recovered by bronchoalveolar lavage (BAL) and their differential distribution were not significantly different in alcoholics versus controls (43 ± 8 × 10⁶ and 39 ± 13 × 10⁶, respectively). However, the total number of cells recovered from BALF was significantly higher in smokers (51 ± 8 × 10⁶) than in nonsmokers (19 ± 5 × 10⁸). Spontaneous (basal) release of TNFα by alveolar macrophages was the same in alcoholics and controls. In contrast, LPS-stimulated release of TNFα was significantly suppressed in alcoholics compared with that of controls (1343 ± 271 vs. 3806 ± 926 U TNF/ml/10⁶ cells, respectively, p < 0.015). When controlled for smoking, LPS-stimulated TNFα production was suppressed in alcoholic nonsmokers (563 ± 413 U TNF/ml/10⁶) compared with control nonsmokers (5113 ± 1264 U TNF/ml/10⁶). LPS-stimulated TNFα production was also less in control smokers (2063 ± 386 U TNF/ml/10⁶ cells) than in control nonsmokers (5113 ± 1264 U TNF/ml/10⁶ cells). There was no difference in TNFα production between smoking alcoholics and smoking control subjects. We conclude that chronic alcohol consumption significantly suppresses LPS-stimulated alveolar macrophage production of TNFα. This effect is obscured if the subject also smokes. Because TNFα production is an important element in host defense, this may explain, in part, the susceptibility of chronic alcohol abusers to a variety of infections.     

Divergence of Ethanol and Acetaldehyde Kinetics and of the Disulfiram-Alcohol Reaction between Subjects with and without Alcoholic Liver Disease

Despite standardization, marked interindividual variation in the severity of the disulfiram-alcohol reaction (DAR) has been observed. We studied the DAR in 51 consecutive alcoholics with ( n = 16) and without ( n = 35) significant alcoholic liver disease. Clinical signs of the DAR were much weaker in the patients with compared with those patients without liver disease. Because acetaldehyde is thought to be the main cause of the DAR, we studied ethanol and acetaldehyde kinetics in 13 patients (6 females, 7 males) with alcoholic liver disease (documented by biopsy, clinical and/or radiological findings, and by quantitative liver function) [galactose elimination capacity (GEC) 4.2 ± SD 1.0 mg/min/kg; aminopyrine breath test (ABT) 0.14 ± 0.10% dose × kg/mmol CO₂] and 13 age- and sex-matched controls (alcoholics without significant liver disease, GEC 7.1 ± 0.7; ABT 0.81 ± 0.35). Clinical signs of acetaldehyde toxicity during the DAR (flush, nausea, tachycardia, and blood pressure drop) were absent in alcoholic liver disease, but clearly evident in controls. Blood ethanol kinetics were similar in both groups, C_max and area under the concentration-time curve (AUC) being 6.27 ± 1.82 and 368.9 ± 72.9 mmol × min/liter in alcoholic liver disease, and 6.62 ± 1.71 and 377.6 ± 124.5 in controls, respectively. In contrast, there was a strong ( p < 0.001) difference in C_max and AUC of acetaldehyde, respective values being 33.46 ± 21.52 and 1463.8 ± 762.5 μmol × min/liter in alcoholic liver disease, and 110.87 ± 56.00 and 4162.0 ± 2424.6 in controls. We hypothesize that the lack of disulfiram-induced acetaldehyde retention in the alcoholic liver disease group may be due to decreased formation of disulfiram metabolites.     

Alteration of Copolymer-Specific Humoral and Cell Mediated Immune Responses by Ethanol

Excessive alcohol consumption represents a major human health threat. The frequency and severity of infections in alcoholics is often pronounced, suggesting impaired immune function in these patients. The precise effect of ethanol on cells of the immune system is poorly understood. We have previously shown that synthetic copolymers of L-amino acids, GT and GAT, are powerful tools for clarifying the role of regulatory T-cells in both cell-mediated and humoral immunity in inbred mouse strains. We asked whether these same antigens would have application to a murine model of ethanol consumption. In this study, female mice were placed on a nutritionally complete liquid diet containing 35% ethanol-derived calories. As control, mice either were placed on a liquid control diet that isocalorically substitutes sucrose for ethanol or remained on a solid diet consisting of standard laboratory chow and water ad libitum. Our data show that the liquid ethanol diet severely inhibits two measures of cell-mediated immunity, the ability of responder B6 mice to make an anti-GAT delayed hypersensitivity and GAT-specific T-cell proliferative responses as compared with pair-fed liquid control diet or solid diet controls. On the contrary, this liquid ethanol diet does not significantly impair humoral immunity; it allows nonresponder C57BL/6 or C3H/HeN mice to respond in vivo to GT immunization. These findings suggested to us that the effect of ethanol may occur prior to antigenic stimulation, and this was confirmed by in vitro immunization.     

Effect of the Type of Beverage and Meat Consumed by Alcoholics with Alcoholic Liver Disease

We analyzed meat products and alcoholic beverage preference in patients with the three stages of alcoholic liver disease (ALD) compared with controls using diet history data. Daily consumption of total alcohol, types of alcoholic beverages, and types of meat and meat products in grams was obtained by dietary history taken from patients with biopsy proven stage of ALD. A strong association was found between the ALD subjects and total alcohol and beer consumption. There was a significant increase in the consumption of total pig products, pork, and offal in the ALD groups compared with controls. There was a significant positive correlation between beer consumption and pork in alcoholic hepatitis, total pork products in alcoholic hepatitis, and cirrhosis and offal in alcoholic hepatitis and cirrhosis. There was no correlation with the fatty liver stage of ALD. The strongest correlation was between beer and total pig products in the alcoholic hepatitis group. Wine consumption was negatively correlated with the consumption of pig products and beer in the alcoholic cirrhosis group. In conclusion, the association of total pig product consumption with cirrhosis mortality in various countries was validated by personal diet history data obtained from ALD patients in a tested clinical microcosm. The results suggest that this association may be modified by the type of alcoholic beverage that is preferentially consumed.     

Hepatic Saturation Mechanism of Ethanol: Application of Mathematical Models to Ethanol Outflow Profiles in the Perfused Rat Liver

The saturation mechanism of hepatic ethanol (EtOH) elimination was studied in the perfused rat liver. EtOH outflow profiles after the instantaneous administration of 3 (mg/ml) × 0.4 (ml), 12 × 0.1, 24 × 0.1, and 3 × 0.1 mg (as a dose concentration × a volume) through the portal vein were analyzed by the statistical moment analysis and mathematical models (i.e., dispersion models). Results for 3 × 0.1 and 12 × 0.1 mg doses by moment analysis were similar. This demonstrated that the elimination exhibits linear kinetics. Recovery ratio and hepatic volume of distribution for 3 × 0.4 and 24 × 0.1 mg were larger than those for 3 × 0.1 and 12 × 0.1 mg doses and were similar. Kinetics after administration of 3 × 0.4 and 24 × 0.1 mg may be nonlinear. A difference in the relative dispersion ( CV ²) obtained by moment analysis between 3 × 0.4 and 24 × 0.1 mg doses indicated different properties of the nonlinear elimination kinetics. There were no differences in all the parameters in the one-compartment dispersion model between 3 × 0.4 and 24 × 0.1 mg doses. In the two-compartment dispersion model, there were differences in the blood volume ( V _B ) and the forward partition rate constant ( K ₁₂) between 3 × 0.4 and 24 × 0.1 mg ( p < 0.05), whereas the elimination rate constant ( k _e) and the dispersion number values for these doses were similar. These findings demonstrated that there is difference in the no-equilibrium process between 3 × 0.4 and 24 × 0.1 mg doses. Therefore, we suggest that the continuous EtOH input into the liver causes the saturation of enzyme pathways and the change of the nonequilibrium process.     

Prevalence of Markers of Hepatotrophic Viruses in Alcoholics with Symptomatic Liver Cirrhosis or Pancreatitis

The reason why similar amounts of alcohol consumption cause different types of organ damage in alcoholics is obscure. Recent studies indicate that hepatitis B virus infection may influence the development of liver cirrhosis in alcoholics. We investigated the prevalence of markers of viruses known to cause hepatitis (HAV, HBV, EBV, CMV) in two groups of patients, one with alcoholic pancreatitis without known liver cirrhosis and one with alcoholic liver cirrhosis without known pancreatitis. We found signs of past infection with HAV and HBV more often in alcoholics with liver cirrhosis than in patients with alcoholic pancreatitis or in age-matched controls.     

Absorption of a Nutrient Solution in Chronic Alcoholics without Nutrient Deficiencies and Liver Cirrhosis

Duodenal and jejunal absorption of a nutrient solution at two different caloric loads (1.32 and 3.96 kcal/ min = 5.6 and 16.8kJ/min) was compared in chronic alcoholics without malnutrition, liver cirrhosis, obvious small-bowel dysfunction, and exocrine pancreatic insufficiency and in an age-matched control group, by means of the intestinal perfusion technique. In chronic alcoholics duodenal net absorption of water (p < 0.025), sodium (p < 0.02), potassium (p < 0.005), total nitrogen (p < 0.02), carbohydrates (p < 0.05), and lipids (p < 0.05) was lower than in controls when both caloric loads were administered, but jejunal absorption rates were not decreased. Biliopancreatic secretion did not differ between alcoholics and controls. Higher serum protein leakage in alcoholics was indicated by an increased (p < 0.01) duodenal α-antitrypsin clearance under low caloric load infusion. It is concluded that the absorptive function of the duodenum is impaired in alcoholics, whereas the upper jejunum is not affected.     

Adrenocorticotropin Responses Following Administration of Ethanol and Ovine Corticotropin-Releasing Hormone in the Sons of Alcoholics and Control Subjects

Alcoholism is a familial disorder with both genetic and environmental determinants. The sons of alcoholic fathers have been documented to have alterations in several neuroendocrine measures. We investigated the ACTH/cortisol response to ovine corticotropin-releasing hormone (oCRH) and ethanol in men with and without a family history of alcoholism. Men were defined as family history positive (FHP) ( n = 7) if their father was alcoholic; as family history negative (FHN) ( n = 16), if their father was nonalcoholic. Ethanol (0.75 g/kg) or placebo was ingested over 15 min, 1 μg/kg oCRH was administered, and plasma ACTH/cortisol levels were determined at –20, 0, 15, 30, 60, and 90 min after oCRH. Following placebo, FHP men had lower peak ACTH response to oCRH than did FHN men (12 ± 2 vs 20 ± 2 pmol/liter, P = 0.04). In FHN men, plasma ACTH response to oCRH was blunted during the ethanol session compared to the placebo session (13 ± 1 vs 20 ± 2 pmol/liter; P = 0.006). In contrast, FHP men had similar ACTH responses to oCRH during ethanol and placebo sessions. Cortisol responses to oCRH were similar in both groups during both sessions. In summary, FHP and FHN nonalcoholic men had different plasma ACTH responses following the administration of oCRH.     

Defective Calcium Increase and Inositol Phosphate Production in Anti-CD3-Stimulated Lymphocytes of Alcoholics without Progressive Liver Disease

Intracellular free calcium concentration, phosphoinositide turnover, and inositol phosphate production were analyzed in peripheral blood lymphocytes from seven well-nourished alcoholic patients without severe acute or chronic liver disease, before and after stimulation with anti-CD₃ antibody. Seven comparable nondrinkers were studied as controls. A lower increase in intracellular free calcium concentration was detected in alcoholics, after anti-CD₃ stimulation of lymphocytes, than in control subjects. Lymphocyte activation generated inositol phosphates in both controls and alcoholics, but inositol phosphate production was significantly lower in alcoholics. The agreement between these findings indicates that the reduction in inositol phosphates is one of the most important events in the early phases of lymphocyte activation in alcoholics.     

Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications

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