Assessing endotoxemia in alcoholic hepatitis.

Abstract

Potential conflict of interest: Nothing to report. To the Editor: In the September 2015 issue of hepatology, Dr. Michelena and colleagues published a commendable study, in which a serum endotoxin level of more than 1.3 endotoxin units (EUs)/mL at admission predicted the development of in‐hospital infections, nonresponsiveness to corticosteroid therapy, and a high mortality in a subgroup of 50 patients with alcoholic hepatitis.1 As mentioned in the article, the results should be confirmed in independent studies in order to acquire external validity. Before starting prospective studies, it seems necessary to standardize the measurement of circulating endotoxin levels. Michelena and colleagues measure serum endotoxin levels with the limulus amebocyte lysate (LAL) QCL‐1000 test. According to the manufacturer's guidelines (http://bio.lonza.com/uploads/tx _m waxmarketingmaterial/Lonza_ManualsProduct Instructions_QCL‐1000_Product_Insert.pdf), the QCL‐1000 assay is not intended to detect endotoxemia in humans and may be substituted for the rabbit pyrogenic test for end‐product testing of human and animal parenteral drugs, biological products, and medical devices. The term “EU” indicates the national standard biological activity in the LAL assay, which was determined by the US Food and Drug Administration and other organizations based on the relationship between the LAL and the rabbit pyrogenic test. Although the Food and Drug Administration initially defined 1 EU as the endotoxin activity of 200 pg of a reference standard endotoxin, the conversion ratio is dependent on the source of the endotoxin used for each LAL assay, resulting in being between 1 EU to 20 pg and 1 EU to 500 pg.2 Given these findings, blood endotoxin levels should be shown as picograms per milliliter in future multicenter studies. As mentioned earlier, we should remember that the LAL is not prepared for detection of endotoxemia, but it is intended only for in vitro diagnostic purpose. Endotoxin antagonists,3 antibiotics, plasma proteins, and unknown substances4 in the blood can activate or interfere with the LAL test. The LAL assay is not absolutely specific for endotoxin but can react with some fungal glucans. There are ample opportunities for contamination because endotoxins are ubiquitous in the indoor environment. Given these situations, using multiple measurements of circulating endotoxin seems more feasible than one measurement at admission to assess the severity of endotoxemia due to increased gut permeability and dysbiosis associated with alcoholic hepatitis.