Dehydrogenase Interference with Enzymatic Ethanol Assays: Forgotten but Not Gone

We have observed a positive interference affecting the Siemens (previously Bayer) Advia 1650® ethanol assay in samples collected from 3 patients with marked hepatocellular necrosis. During a recent 2-month period, we encountered 3 cases of acetaminophen-induced hepatocellular necrosis at our institution that demonstrated this effect (Table 1 ). The spurious ethanol results were in the 30–40 mmol/L range. Gas chromatography subsequently demonstrated that all 3 samples contained no detectable ethanol (<2 mmol/L). Additionally, ethanol was undetectable (<2 mmol/L) on the Dade Behring RXL MAX® platform using the Dade Behring Dimension® Flex® reagent cartridge. As it happened, we were alerted to a potential problem by the unusually large negative osmolal gaps in all 3 patients. Calculated osmolality was determined with this equation: Osmolality ≈ 2[Na] + [urea] + [glucose] + 1.25[ethanol] (all concentrations in mmol/L). The 1.25 multiplication factor for the concentration of ethanol is empirically derived and accounts for ethanol’s larger-than-expected contribution to measured osmolality (1). Initial laboratory investigations for the 3 patients with hepatocellular necrosis secondary to acetaminophen ingestion.1 Acetaminophen concentrations were measured at approximately 24, 96, and 48 h after ingestion for patients 1, 2, and 3, respectively. AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; EtOH, ethyl alcohol. Initial laboratory investigations for the 3 patients with hepatocellular necrosis secondary to acetaminophen ingestion.1 Acetaminophen concentrations were measured at approximately 24, 96, and 48 h after ingestion for patients 1, 2, and 3, respectively. AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; EtOH, ethyl alcohol. Based on their own experiments spiking LDH and lactate into ethanol-free serum specimens, Siemens informed us that that to generate a spurious ethanol result >80 mg/dL (17.4 mmol/L), LDH would have to be >100 000 U/L (by a lactate-to-pyruvate methodology) in the presence of a lactate concentration above the normal reference interval (correspondence from Siemens). Based on this information, none of our patients had LDH/lactate combinations high enough to generate the observed spurious ethanol results. Therefore, we suspect that endogenous dehydrogenases and substrates other than LDH and lactate may be implicated in NADH production, leading to the false ethanol increases. This issue has ramifications for patient safety. For example, our third patient presented to the emergency department with epigastric abdominal pain. After the spurious ethanol was reported, a presumptive diagnosis of alcoholic gastritis was made, and the diagnosis of acetaminophen toxicity and therapy with N-acetylcysteine was substantially delayed. Until the manufacturer can address this issue, we have implemented a policy requiring alanine aminotransferase (ALT) to be measured in all patients with ethanol concentrations >5 mmol/L. Out of concern that hepatocellular necrosis may have cause spurious ethanol elevation, when the ALT is >500 U/L, we refer the specimen to another local hospital for ethanol analysis using their Dade Behring RXL MAX to get a rapid preliminary confirmation and by gas chromatography (GC) for a final confirmation. Our experience serves as a reminder that laboratories should inquire how the manufacturers of their ethanol assays have addressed the issue of dehydrogenase interference. Grant/Funding Support: None declared. Financial Disclosures: None declared. Acknowledgments: We thank Morris Pudek of Vancouver General Hospital (Vancouver, British Columbia, Canada) for confirmatory ethanol analysis by Dade-Behring RXL MAX and GC.

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