Influence of liver injury and hepatic alcohol dehydrogenase and aldehyde dehydrogenase activity on ethanol metabolism (2023)


Barcelona University. Department of Medicine



The main objectives of the thesis have been: 1) to analyze the hepatic metabolism of ethanol in chronic alcoholics, 2) the production of acetaldehyde, 3) the activity and isoenzymes of alcohol dehydrogenase (ADH) and liver aldehyde dehydrogenase (ALDH), and 4) the relationship of each of these factors with alcoholism and the degree of liver injury.


Hepatic ADH and ALDH have been studied in 84 patients, 60 were alcoholics (5 with normal liver, 9 steatosis, 9 fibrosis, 11 alcoholic hepatitis, 19 alcoholic cirrhosis and 7 cirrhosis and alcoholic hepatitis) and 24 were non-alcoholic liver disease (14 chronic hepatitis and 10 cirrhosis). Furthermore, in 25 of the alcoholics (4 normal liver, 4 steatosis, 4 fibrosis, 7 alcoholic hepatitis and 7 non-alcoholic cirrhosis) and in 6 of the non-alcoholic cirrhotic patients, the hepatic metabolism of ethanol has been studied.


The oxidation capacity of ethanol was higher in alcoholic patients than in non-alcoholic patients, so that in alcoholics the rate of metabolization of ethanol (VME ) was 113+/-16.9 mg/Kg/h and in non-alcoholic patients it was 90.5+/-18.9 mg/Kg/h (P<0.01).

In alcoholic patients the EMV decreased progressively as the severity of the histological lesion increased, being higher in alcoholics with normal liver, steatosis or fibrosis than in patients with alcoholic hepatitis or cirrhosis (121.8+/-17.5 vs 104.9+/-12.4 mg/ Kg/h, P<0.01).

Hepatic metabolism of ethanol was related to the functional state of the liver. A significant linear relationship was observed between EMV and the aminopyrine test (r:0.70, p<0.001), as well as between EMV and intrinsic hepatic clearance of indocyanine green (r:0.76, p<0.01).< br/>
Although ADH and ALDH activities were lower in patients with lower ethanol oxidative capacity, no relationship was observed between VME. and ADH activity (r:0.10, p:NS), high Km ALDH (r:0.21, p:NS) or low Km ALDH (r:0.32, p:NS).


After the ethanol infusion, in 14 of the 25 alcoholic patients, acetaldehyde levels were detected above 0.5 millimeters (sensitivity limit), ranging between 0.7 and 4.7 millimeters. In the 6 non-alcoholic patients, acetaldehyde levels were always undetectable.

When comparing alcoholic patients with and without detectable plasma acetaldehyde after ethanol infusion, no differences were observed between the two groups in the age, duration and intensity of ethanol consumption, liver function parameters, neither hepatic ADH nor ALDH activities. The only difference between these two groups of alcoholic patients was their ability to oxidize ethanol so that the MVE was 120+/-17.4 mg/Kg/h in the patients in whom acetaldehyde was detected and 104+/-11.7 mg/Kg/h in which it was undetectable. In addition, there was a direct linear correlation between VME and the maximum peak of acetaldehyde (r:0.48, p<0.02). In contrast, acetaldehyde levels after ethanol administration did not correlate with ADH activity (r:0.006, p:NS), high Km ALDH (r:0.12, p:NS) or low Km ALDH (r: 0.28, p:NS).


Hepatic ADH activity was significantly different between the histological groups studied (P=4.16, p:0.0007). When analyzing only the different subgroups of alcoholic patients, ADH activity also turned out to be significantly different between them (F: 4.80, p: 0.001). ADH activity decreased progressively as the severity of liver injury increased. Thus, alcoholic patients with normal liver had significantly higher ADH activity than patients with alcoholic hepatitis (p<0.05), alcoholic cirrhosis (p<0.01) or cirrhosis associated with alcoholic hepatitis (p<0.01). In contrast, in non-alcoholic individuals, ADH activity was not related to the degree of histological lesion. The patients with chronic hepatitis presented an activity very similar to that of the patients with cirrhosis of non-alcoholic origin. Hepatic ADH activity correlated with liver function parameters (bilirubin, prothrombin) only in alcoholic patients.

High Km ALDH activity was similar between different histological groups (F=1.89, p :0.08). When comparing the means of the different subgroups of alcoholic and non-alcoholic patients, no significant differences were observed. High-Km ALDH activity did not correlate with liver function parameters.

Mark differences in low-Km ALDH activity were observed between different histological groups (F=5.27, p<0.0001). The activity of this enzyme decreased progressively with increasing severity of liver lesions in both alcoholic and non-alcoholic patients.

In alcoholic patients, significant differences were also observed in the ALDH activity of low Km between the different subgroups (F=3.94, p<0.004). Significant differences were also observed in low-km ALDH activity between the subgroups of patients with normal liver and those with cirrhosis (p<0.05) or cirrhosis associated with alcoholic hepatitis (p<0.01), and between patients with steatosis and those with patients with cirrhosis associated with alcoholic hepatitis (p<0.05). Among non-alcoholics, cirrhosis patients had significantly lower activity than chronic hepatitis patients (p<0.02).

Low Km ALDH activity correlated with function tests hepatica in both alcoholic and non-alcoholic patients.

The relationship observed between decreased ADH and ALDH activities and the degree of liver injury in alcoholic patients suggests that changes in enzyme activities They do not constitute primary anomalies that predispose to alcoholism or the development of liver lesions, but are the consequence of cell lesion.


The phenotypes of the ADH2 locus could be determined in all patients. In six cases of the 84 studied (7.1%) the "atypical" phenotype was observed (band more cathodic than the B1B1 isoenzyme and activity at pH 8.5 > pH 10.5). The prevalence of "atypical" ADH was similar in alcoholic (4/60, 6.7%) and nonalcoholic (2/24, 8.31%) patients.

The "Indianapolis" phenotype was not found in none of the samples studied. The phenotype of the ADH3 locus could be studied in 60 patients, 38 alcoholics and 22 nonalcoholic. The T1T1 phenotype was observed in 16 patients (27%), 39 cases (65%) presented the T1T2 phenotype and 5 cases (81%) the T2T2 phenotype. The observed phenotypic frequency was significantly different from that calculated from the gene frequency according to the law of equilibrium distribution of genotypes. Among alcoholic patients, the phenotypic frequency was significantly different from that calculated according to this law. In contrast, no differences were found between the expected and observed phenotypic frequencies among non-alcoholic individuals.

This imbalance may be due to a greater predisposition to the development of liver lesions in alcoholic patients with the T1T2 phenotype since in alcoholics with normal liver or steatosis the phenotypic frequency of the ADH3 locus followed the genotype equilibrium principle, while in patients with severe liver lesions such as fibrosis, alcoholic hepatitis or cirrhosis the phenotypic frequency was significantly different from that calculated according to the Hardy-Weinberg law, mainly due to an increase in the observed frequency of the T1T2 phenotype compared to the expected one.

The study of the ALDH isoenzymes revealed the band corresponding to ALDH1, in all the samples studied, both from alcoholic and non-alcoholic patients.

The ALDH2 isoenzyme band was undetectable in 17 alcoholics (39.51%) and in two non-alcoholic patients (9.5%), existing between both proportions a statistically significant difference (p<0.02). Among alcoholic individuals, the proportion of patients with an absence of the ALDH2 band was higher as the severity of liver injury increased, suggesting that the lack of ALDH2 detection is probably a consequence of decreased ALDH2 activity. this isoenzyme, which is more marked in alcoholic patients with severe liver lesions such as alcoholic hepatitis or cirrhosis.

The influence of liver injury on the hepatic alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities (total, high-Km and low-Km ALDH) has been investigated in 60 alcoholics -5 normal liver (N), 9 steatosis (S), 9 fibrosis (F), 11 alcoholic hepatitis (AH), 19 cirrhosis (AC) and 7 cirrhosis with alcoholic hepatitis (ACAH)- and 24 non-alcoholics -14 chronic hepatitis (CH) and 10 cirrhosis (NAC)-. ADH and ALDH activities decreased proportionally with the progression of liver disease in alcoholics (ADH: N: 39.9 +/- 9,6; S: 32.6 +/- 6; F: 29.9 +/-4.9; AH: 20.8+/-3.8; AC:15.3+/-2.9; ACAH: 10+/- 2.8. Low-Km ALDH: N: 4.4 +/- 0.9; S: 4.1+/- 0.5; F: 2.3+/- 0.5; AH: 2.4+/- 0.5; AC:1.9 +/- 0.5; ACAH:1.2+/-0.5 mU/mg protein). By contrast, in non-alcoholics, there was a reduction of low-Km ALDH related to the severity of liver injury (CH: 5.3 +/- 0.8: NAC: 2.4 +/- 0.7 mU/mg protein), but not of ADH (CH:36.1+/-14.2; NAC: 36.0 +/- 8.7 mU/mg protein), Atypical ADH was present in 6.6% alcoholics and in 8.3% non-alcoholics. AH patients exhibited the isozyme ALDH II, but isozyme ALDH I was not detected in 39.5% alcoholic patients and in 9.5% of those with non-alcoholic liver disease. These results suggests that the decrease of ADH and ALDH activities in alcoholics are a consequence of liver damage. The diminution of ADH found particularly in alcoholics could be due to the leakage of the enzyme secondary to centrilobular cell necrosis.

In 31 of the patients, 25 alcoholics (4 N, 4 S, 4 F, 7 AH, 7 AC) and 6 non-alcoholics (NAC), the blood ethanol and acetaldehyde concentrations after an intravenous infusion of ethanol were analyzed. In the alcoholics the ethanol metabolic rate (EHR) was significantly higher than in non-alcoholics. A significant positive correlation was observed between EMR and liver function estimated by the aminopyrine breath test (r=0.70, P<0.001). In non-alcoholics acetaldehyde levels were below the detection limits (<0.5 milimicres), in contrast, an elevated blood acetaldehyde was found in 14/15 alcoholics. The clinical characteristics and hepatic ADH and ALDH activities were similar in both groups of alcoholics. The only difference between alcoholics with elevated blood acetaldehyde and those without was EMR (120+/-17.4 vs 104+/-11.7 mg/Kg/h). Furthermore, the peak blood acetaldehyde level correlated positively with EMR. These results suggest that the main reason for blood acetaldehyde elevation in chronic alcoholics is their higher capacity to metabolize ethanol.


Hepatology; Alcohol - Metabolism


616.4 - Pathology of the lymphatic system, haemopoietic (haematopoietic) organs, endocrines

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