Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease

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Abstract

Background/Aims: No information is yet available about the influence of alcohol abuse on the translocation of larger molecules (Mr>1200) through the intestinal mucosa in man. The present study aimed to determine the intestinal permeability to macromolecules in patients with chronic alcohol abuse and mild to more advanced stages of liver disease, and to measure the concentration of endotoxins in the plasma, as these compounds derive from the intestinal flora and are suspected to contribute to the development of alcoholic liver disease (ALD).

Methods: The permeability to polyethylene glycol Mr 400, Mr 1500, Mr 4000, and Mr 10 000 and endotoxin plasma concentrations were measured in 54 patients with alcoholic liver disease, 19 of them with cirrhosis, and in 30 non-alcoholic healthy controls.

Results: Permeability to polyethylene glycol Mr 400 was found to be unchanged in patients with ALD in comparison to healthy controls, whereas polyethylene glycol Mr 1500 and Mr 4000 were recovered in about twice as high concentrations in the urine of ALD patients (p<0.01). Polyethylene glycol Mr 10 000 was detected significantly less frequently in urine from healthy controls (0/30) than in urine of patients with alcoholic liver disease (20/54, p<0.01). Endotoxin concentrations in the plasma of alcoholics were increased more than 5-fold compared to healthy controls (p<0.01).

Conclusions: The results of this study indicate that alcohol abuse impairs the function of the intestinal barrier, which might enhance the translocation of bacterial toxins, thereby contributing to inflammatory processes in alcoholic liver disease.

Section snippets

Materials and Methods

Eighty-four subjects participated in the study. Fifty-four patients were chronic alcohol abusers and all of them had consumed more than 60 g alcohol per day over a period of at least 3 years. Patients with alcohol abuse were divided into three groups (ALD1–ALD3) according to the presence or absence of moderate or advanced liver disease (Table 1). ALD3 consisted of 19 individuals with alcohol-induced liver cirrhosis documented either by liver biopsy or by meeting the following criteria: the

Results

In healthy controls, the percentage of the applied PEG recovered in urine molecules was closely associated to its molecular mass. The average percentage of excretion decreased from 35.2±2.5% for PEG Mr 400 to 0.98±0.18% for PEG Mr 1500 and 0.038±0.009% for PEG Mr 4000, respectively (Fig. 1). Hence, raising the molecular mass 2–4-fold resulted in a decline of the relative permeability of at least one order of magnitude for the molecular mass range between Mr 400 and Mr 4000. In all controls and

Discussion

The choice of an appropriate permeability marker to investigate gut permeability has been the subject of a widespread debate. Some authors have pointed out the striking effect of the shape and size of the molecule being used as a permeability probe (19), but the discussion remained limited to molecules with a molecular mass below Mr 1200. The use of such markers with a low molecular mass in patients with Crohn's disease, for example, resulted in non-uniform study results 20., 21., 22., pointing

Acknowledgements

The authors wish to express their gratitude to the patient volunteers. Further, the authors are indebted to Mrs. S. Kühnle for her help in development of the analysis procedure.

This study was supported by the Robert-Bosch Foundation, Grants F 1/2 - 92/93. Further generous financial support was granted by Hoffmann-La Roche, Grenzach, Germany. The kits for endotoxin measurements were a kind gift from Chromogenix, Mölndal, Sweden.

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    Dedicated to Dr. Dr. Herbert Falk, Director of the Falk Foundation, on the occasion of his 75th birthday.

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