Key words : Ethanol, Liver transplantation, Pancreati-cobiliary disorders, Tumor marker

Introduction

Carbohydrate antigen 19-9 (CA19-9) is a tumor marker commonly used in the diagnosis of pancrea-ticobiliary and gastric malignancies, demonstrating high sensitivity (96%) and specificity (91%) for pancreatic cancer. However, elevated levels of CA19-9 have also been observed in patients with non-neoplastic hepatic, biliary, and pancreatic dysfunction, and such elevated levels of CA19-9 often decrease with clinical improvement.^1-5 These findings have prompted questions regarding the true sensitivity and specificity of CA19-9 as a tumor marker, leading many researchers to advocate for its cautious interpretation, particularly in patients with pancreaticobiliary disorders.^2-5 Notably, ele-vated levels of CA19-9 have also been reported in individuals with alcohol (EtOH)-related liver disease and biliary obstruction in the absence of underlying gastrointestinal malignancy, which further chal-lenges the prognostic significance of elevated CA19-9.^6,7 We also observed high levels of CA19-9 in some of our EtOH-related liver disease patients who were undergoing liver transplant (LT) evaluation.

We evaluated CA19-9 levels in patients with EtOH-related liver disease and investigated whether EtOH exposure and time since last exposure influences CA19-9 expression. We aimed to refine the utility of CA19-9 as a diagnostic oncologic marker in the context of EtOH-associated hepatic dysfunction.

Materials and Methods

In this study, we performed a comparative analysis of patients who presented to a large, tertiary care LT center for LT evaluation in the setting of EtOH-related liver disease. We classified EtOH use as either recent or remote. Recent EtOH use was defined as a last alcoholic drink less than 6 months previous to CA19-9 measurement; remote EtOH use was defined as a last alcoholic drink more than 6 months previous to CA19-9 measurement. Twenty-seven patients were categorized in the recent-use group, and 16 patients were categorized into the remote-use group. All patients ultimately underwent deceased donor LT and had explant pathologyresults available for review. Patients with known malignancy that was confirmed during transplant evaluation on radiog-raphic studies and patients with hepatocellular carcinoma noted on explant pathology results were excluded from analysis. In addition, patients with obstructive biliary disease from gallstones were excluded from our study.

For all patients, we evaluated all pancreatico-biliary imaging in the form of ultrasonography, computed tomography, and/or magnetic resonance imaging to determine whether any imaging findings of pancreaticobiliary abnormalities were present. We also noted any procedural intervention, such as endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasonography. Finally, we evaluated liver explant pathology from all patients to determine the presence of hepatic malignancy.As previously noted, patients with known malig-nancy that was confirmed during transplant evaluation or on explant pathology, as well as patients with obstructive biliary pathologies, were excluded from our study. Conversely, patients with incidentally noted gallstones without obstructive disease or pancreatic abnormalities (such as inci-dentally noted cysts or calcifications) were included in our study.

Patients were identified via an electronic patient database, and this study was approved by the Johns Hopkins University School of Medicine Institutional Review Board (No. IRB00475074). Waiver of infor-med consent was obtained from the Institutional Review Board, and all research was conducted in accordance with both the Declarations of Helsinki and Istanbul.

Results

We compared the CA19-9 levels in patients of the recent-use group (last EtOH drink less than 6 months from CA19-9 measurement) versus the remote-use group (last EtOH drink more than 6 months from CA19-9 measurement). Patients with benign or malignant etiologies known to cause CA19-9 elevation were excluded. The reference level of serum CA19-9 is less than 37 U/mL. The average serum CA19-9 level in patients with recent EtOH use was 644.57 U/mL (95% CI, 109.01-1180.13). The average CA19-9 level in patients with remote EtOH use was 89.35 U/mL (95% CI, 49.9-128.8). These values were significantly different (P = .0431).

We also evaluated the pretransplant imaging of all LT patients. All patients had an available (1) abdominal ultrasonography and (2) either a computed tomography scan or a magnetic resonance imaging scan. All pancreaticobiliary imaging was reviewed for any abnormalities that could contribute to abnormal CA19-9 levels. In the recent-use group, 1 of 27 patients had pancreatic cyst lesions, which were likely intraductal papillary mucinous neoplasms, and 2 patients had incidentally noted cholelithiasis without noted biliary obstruction. In the remote-use group, 6 of 16 patients had cholelithiasis without noted biliary obstruction. One patient in the remote-use group had incidentally noted pancreatic calcifications without any underlying history of pancreatic disease or dysfunction.

We also evaluated whether any of our patients underwent ERCP. In our recent-use group, 2 patients underwent ERCP. In our remote-use group, 3 patients underwent ERCP. The pre-LT imaging of these patients did not reveal any pancreaticobiliary abnormalities that would indicate need for therapeutic intervention with ERCP.

Discussion

In this study, we evaluated the serum CA19-9 levels of patients with recent EtOH use and remote EtOH use in a pre-LT setting for patients with a diagnosis of EtOH-related liver disease. We attempted to control for factors known to cause elevated levels of CA19-9, such as malignancy and pancreaticobiliary abnormalities. After exclusion of such patients, we found that patients with EtOH-related liver disease, overall, had elevated serum CA19-9 levels. Furthermore, when stratified by recency of EtOH use, we found that patients with more recent EtOH use showed significantly higher CA19-9 levels.

Recent studies have evaluated environmental factors that may influence serum CA19-9 levels and the most recent literature has suggested an effect of tobacco use and diabetes.^8,9 Less research has been published on the effects of EtOH on serum CA19-9 levels. The results of our present study suggest that EtOH use, particularly with regard to recent use, may influence serum CA19-9 levels independent of malignancy or underlying pancreaticobiliary pathology. These findings have potential economic and health-related adverse consequences for patients. In our patient population, 5 of 43 patients (approximately 12%) underwent ERCP without imaging evidence of pancreaticobiliary abnormalities to warrant ERCP. In addition to potentially wasted health care costs, unnecessary invasive evaluation with modalities such as ERCP could result in serious patient harm (eg, post-ERCP pancreatitis).

From a biochemical perspective, CA19-9 elevation is postulated to occur in malignancies that result from excess production by malignant cells. Nevertheless, CA19-9 elevation is also known to occur with benign biliary obstruction and, in some circumstances, may resolve with restoration of biliary patency.¹⁰ Specifically, in cholangitis, CA19-9 elevation is postulated to occur due to excess production by the biliary ductal cells, which could be related to increased pressure or inflammation.^11,12 We postulate that EtOH use causes increased biliary ductal inflammation that results in an increased release of CA19-9 by biliary ductal cells. This scenario may be supported by the statistically significant elevations of CA19-9 in patients with recent EtOH use, indicating that a more recent insult (ie, EtOH use) to the biliary system results in significantly higher secretion of CA19-9 versus the levels induced by remote EtOH use.

It is important to recognize nonpathological causes of serum marker elevation, to avoid unne-cessary concern and diagnostic workup. Further research in larger patient populations is needed to more definitively elucidate the association between EtOH use, recency of EtOH use, and serum CA19-9 levels.

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