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I thank Dr. Fujita for raising an important issue of difficulties in measuring endotoxemia. The concern regarding the interfering factors in measuring plasma endotoxin by limulus amebocyte lysate (LAL) assay is well taken. The difficulties in measuring plasma endotoxin are due to the inhibitory factors present in samples, the variability due to the type of lysate used, and variability caused by different standards used this assay. Therefore, it is imperative to improve the LAL assay method to avoid interfering factors. Several approaches have been attempted to minimize the interference by inhibitors. Extraction of endotoxin from the sample,1 treatment of samples with chloroform to remove inhibitors, or dilution of samples to tone down the inhibitory effects2 are some of these approaches.

Endotoxin assay, however, in experimental setups is likely to yield valuable information. As discussed in the review,3 there was a consistent 5-fold to 20-fold increase in endotoxin level following ethanol feeding, despite the variability in the levels of plasma endotoxin measured in different studies. Similarly, a high level of plasma endotoxin was recorded in patients with alcoholic liver disease (ALD) compared to normal subjects when similar extraction methods, lysate, and standards were used. Therefore, comparison of data in different groups within a study is very useful. However, the use of endotoxin values to determine the state of endotoxemia in individual subjects and in diagnostic or prognostic applications in the clinic is still premature. A more controlled and reliable assay needs to be developed for this purpose.

Regarding the anti-endotoxin therapy, the issue is much more complicated. The evidence suggests that intestinal barrier function and endotoxin-mediated liver injury are some of the initial events in the pathogenesis of ALD. Therefore, once endotoxin has triggered the cascade of injurious events in the liver, following it with anti-endotoxin therapy may not be very effective. However, anti-endotoxin therapy may be useful in preventive measures and to attenuate the recurrence of disease.

Finally, Dr. Fujita is right about the view that endotoxemia is not the only culprit in the pathogenesis of ALD. Experimental evidence is clear that ethanol and endotoxin in combination are much more dangerous than each of them alone. Nevertheless, evidence is clear that endotoxemia is one of the major factors that are involved in the pathogenesis of ALD.

References

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  • 1
    Shiomi S, Kuroki T, Ueda T, Takeda T, Nishiguchi S, Nakajima S, et al. Use of immobilized histidine in assay for endotoxin in patients with liver disease. J Gastroenterol 1994; 29: 751755.
  • 2
    Bohrer D, Horner R, Nascimento CDP, Adaime M, Pereira ME, Martins AF, et al. J Pharmaceut Biomed Anal 2001; 26: 811818.
  • 3
    Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. HEPATOLOGY 2009; 50: 638644.

Radhakrishna K. Rao*, * Department of Physiology, University of Tennessee, Memphis, TN.