A Significant Increase in the Serum Carbohydrate Antigen 19-9 Level Accompanied by Acute Cholecystitis and Choledocholithiasis: A Case Report and Review of the Literature.

An 80-year-old Japanese man (height, 158 cm, weight 60.7 kg, body mass index 24.3 kg/m 2 ) presented to our hospital in March 2022 with jaundice and fatigue. On admission, his blood pressure, pulse rate, and body temperature were 104/64 mmHg, 89/min, and 36.9°C, respectively. A physical examination revealed conjunctival icterus and yellowish skin. No spontaneous pain or tenderness was observed in the abdominal region. The patient was being treated for alcoholic hepatitis, chronic pancreatitis, hypertension, angina pectoris, atrial fibrillation, hyperuricemia, and dementia. He had no allergies and no family history of malignancy. He drank three glasses of shochu (alcohol 60 g) every day and had smoked 20 cigarettes per day for 20 years but had quit smoking 20 years ago. Laboratory data on admission were as follows: white blood cell count 8,740 /μL, neutrophils 80.4%, C-reactive protein (CRP) 17.73 mg/dL, aspartate aminotransferase 191 U/L, alanine aminotransferase (ALT) 111 U/L, lactate dehydrogenase 266 (U/L), alkaline phosphatase 642 U/L, gamma-glutamyl transpeptidase 371 U/L, total bilirubin (T.Bil) 22.4 mg/dL, and direct bilirubin 17.2 mg/dL. The carcinoembryonic antigen (CEA) level was within the normal range, whereas that of CA19-9 was significantly increased to 29,512 U/mL ( Table 1 ). Laboratory Data on Admission. WBC: white blood cell count, RBC: red blood cell count, PT: prothrombin time, INR: international normalized ratio, TP: total protein, ALB: albumin, T.Bil: total bilirubin, D.Bil: direct bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, Ch-E: cholinesterase, UN: urea nitrogen, Cre: creatinine, T-Cho: total cholesterol, Glu: glucose, CRP: c-reactive protein, CEA: carcinoembryonic antigen, CA19-9: carbohydrate antigen 19-9, HBsAg: hepatitis B surface antigen, HCVAb: hepatitis C virus antibody Contrast-enhanced computed tomography (CT) revealed dilation of the intrahepatic and extrahepatic bile ducts. There was a high-density area (diameter, 7 mm) in the common bile duct. The gallbladder was swollen, and the wall was thickened, although gallstones were not present. Enlarged lymph nodes (diameter, approximately 10 mm) were observed in the hepatic hilum and para-aortic regions ( Fig. 1 ). In the pancreas, calcification was observed in the pancreatic uncinate process and pancreatic tail, which is a finding of chronic pancreatitis. Magnetic resonance cholangiopancreatography (MRCP) showed that the biliary tree was diffusely dilated, and the gallbladder was swollen ( Fig. 2a ). An area of low signal intensity (diameter, 7 mm) was observed in the common bile duct ( Fig. 2b ). Based on these findings, the patient was diagnosed with acute cholecystitis and choledocholithiasis; however, the possibility of malignant biliary diseases could not be ruled out. Although cholecystectomy was considered, the patient and his family declined, instead requesting endoscopic treatment. Contrast-enhanced computed tomography findings. a: Dilation of the intrahepatic and extrahepatic bile ducts was confirmed. b: The gallbladder was swollen, and its wall was thickened. c: The lymph node in the hepatic hilum was swollen (white arrow). d: High-density area in the common bile duct suggestive of the presence of a common bile duct stone (white arrow). Magnetic resonance cholangiopancreatography findings. a: The biliary tree was diffusely dilated, and the gallbladder was swollen. b: An area of a low signal intensity in the common bile duct was suggestive of the presence of a common bile duct stone (white arrow). c: Imaging performed three months after endoscopic sphincterotomy (EST). The dilated biliary tree and swollen gallbladder also improved. Antibiotic administration was initiated with sulbactam/cefoperazone. Endoscopic retrograde cholangiopancreatography (ERCP) performed the following day revealed a filling defect in the common bile duct ( Fig. 3a ). The duodenal papilla was markedly enlarged ( Fig. 3b ). After endoscopic sphincterotomy (EST), drainage of a large amount of biliary sludge was observed. The common bile duct stone was removed using a stone retrieval basket catheter (Trapezoid™ RX; Boston-Scientific, Natick, USA) and a stone retrieval balloon catheter (Extractor™ Pro; Boston-Scientific) ( Fig. 3c-e ). Abdominal ultrasonography was performed two days after EST ( Fig. 4 ). The gallbladder was enlarged circumferentially, and its wall was thickened to 6.5 mm. Biliary sludge deposits were observed in the lumen. Endoscopic retrograde cholangiopancreatography findings. a: A filling defect in the common bile duct was observed (white arrow). b: The duodenal papilla was markedly swollen. c: Endoscopic sphincterotomy (EST) was performed. After EST, a large amount of biliary sludge continued to flow for over 10 minutes. d: A common bile duct stone was removed. e: Swelling of the duodenal papilla improved after removal of the stone. Abdominal ultrasonography findings. The gallbladder was enlarged circumferentially, and its wall was thickened to 6.5 mm. Biliary sludge deposits were observed in the lumen. Antibiotics were continued, and the serum CRP level improved. The serum CA19-9 level decreased to 2,877 U/mL the day after EST, continuing to decline rapidly, and reached 25.5 U/mL, which was within the normal range, 1 month after EST. The serum T.Bil and CRP levels also decreased and normalized, respectively. The changes in CA19-9 and T.Bil levels are shown in Fig. 5 . MRCP performed three months after EST showed improvement in the dilated biliary tree and swollen gallbladder ( Fig. 2c ). Upper endoscopy and colonoscopy revealed no responsible tumor lesion which increased CA19-9 level. Changes in CA19-9 and T.Bil levels. After endoscopic sphincterotomy (EST), the serum CA19-9 levels decreased rapidly. The serum T.Bil levels also decreased. One month after EST, the CA19-9 level was within the normal range. One year after EST, the CA19-9 level was 31 U/mL, and CT and MRCP did not reveal any signs of malignancy.

We encountered a case of acute cholecystitis and choledocholithiasis with a significant increase in the serum levels of CA19-9 at 29,512 U/mL. After treatment of choledocholithiasis with EST, the CA19-9 level rapidly decreased to the normal range. Although CA19-9 is expressed at a very low level in epithelial cells of normal tissues, such as the gallbladder, bile duct, pancreatic ducts, stomach, salivary glands, bronchi, prostate, colon, rectum, and endometrium, high serum CA19-9 levels are often observed in malignant neoplasms, especially gastrointestinal and pancreatobiliary neoplasms. However, serum CA19-9 levels are also elevated in some patients with certain benign diseases, including cholelithiasis, cholecystitis, acute/chronic pancreatitis, gastritis, chronic hepatitis, cirrhosis, bronchitis, endometriosis, and diabetes mellitus, although the levels are typically mild (＜100 U/mL) in patients with acute cholecystitis and choledocholithiasis ( 3 ). Gastrointestinal cancers are suspected when CA19-9 levels exceed 1,000 U/mL ( 2 ). In the present case of benign biliary disease, a remarkable elevation in serum CA19-9 levels (29,512 U/mL) was atypically observed. Although the mechanisms underlying the increase in the level of CA19-9 in benign biliary disease remain unclear, a previous study suggested that an increased level of CA19-9 in the bile and its excretion from bile into the bloodstream are involved ( 4 ). In detail, severe inflammation associated with cholecystitis and cholangitis may promote the production of CA19-9 in the epithelia of the gallbladder and bile duct and increase the level of CA19-9 in the bile. Furthermore, CA19-9 may leak from the bile into the bloodstream as a result of tissue damage caused by inflammation as well as an elevated biliary pressure due to gallstones ( 4 ). In the present case, an elevated biliary pressure and inflammation may have contributed to an extremely significant increase in serum CA19-9 levels. In addition, alcoholic hepatitis and chronic pancreatitis may have contributed to the elevated CA19-9 levels. We performed a literature review using the Igaku Chuo Zasshi (ICHUSHI) and PubMed databases (up to May 2023). The search keywords used were “CA19-9,” “cholangitis,” “choledocholithiasis,” “cholecystitis,” and “cholelithiasis.” We identified 16 cases of benign biliary disease with CA19-9 levels exceeding 10,000 U/mL ( Table 2 ) ( 4 - 19 ). Only six cases have been reported in English-language journals. In the 16 previously reported cases and our present case (17 cases in total), the mean age of the patients was 65 years old, with a man-to-woman ratio of 7:10. Gallstones (gallbladder stones or common bile duct stones) were detected in all 17 cases. The highest reported CA19-9 level was 868,094 U/mL, which was significantly higher than that in other cases and was detected in a case of cholecystitis with liver abscess due to gallbladder stones ( 5 ). The patient also showed an increase in the serum CRP level (5+). Thus, severe inflammation may have contributed to elevated levels of CA19-9. In terms of inflammatory responses, 13 of 17 cases had elevated WBC counts (＞10,000 /μL) and/or CRP (＞5 mg/dL) levels. Immunohistological staining for CA19-9 was performed in 10 patients after cholecystectomy ( 5 , 6 , 8 , 9 , 11 , 13 , 14 , 17 - 19 ). It was confirmed that CA19-9 levels were positive at the mucosal epithelium of the gallbladder wall in all 10 patients. Sixteen Reported Benign Biliary Cases with Significantly Elevated Levels of CA19-9 Exceed 10,000 U/mL. GB stone: gallbladder stone, n.d.: no data, PTCD: percutaneous transhepatic cholangiography drainage, CBD stone: common bile duct stone, EST: endoscopic sphincterotomy Our patient showed a rapid decrease in serum CA19-9 levels after EST treatment. In our literature review, marked decreases in CA19-9 levels were observed in all 17 patients after endoscopic or surgical treatment or drainage. In 13 of the 17 cases, the level of CA19-9 was reduced to the normal range within 2 months of the attenuation of inflammation. Sheen-Chen et al. also showed that normalization of serum CA19-9 levels may be expected within two months after the solution of inflammation ( 20 ). In addition, Akimoto et al. suggested that measuring the serum CEA levels at the onset of symptoms may be effective for this distinction ( 18 ). In our literature review, the serum CEA levels at the onset of symptoms were within the normal range in 11 cases, including the present case (not reported in 5 cases). Thus, a rapid decrease in the serum CA19-9 level after treatment and a normal CEA level at the onset may help rule out malignancy. In conclusion, we report a case of a significant increase in the serum CA19-9 level accompanying acute cholecystitis and choledocholithiasis. A literature review suggested that an elevated biliary pressure and inflammation may contribute to such a significant increase in serum CA19-9 levels. In addition, a rapid decrease in the serum CA19-9 level after treatment for biliary diseases and a normal CEA level at the onset may be findings that help rule out malignancy.

Carbohydrate antigen 19-9 (CA19-9), discovered by Koprowski et al. in 1979 ( 1 ), is a well-known gastrointestinal cancer-related antigen. Initially, it was considered a tumor marker for colon cancer. Subsequent studies demonstrated that it is also highly expressed in pancreatic cancer and biliary tract cancer; therefore, it has been widely used as a pancreatobiliary tumor marker. Generally, gastrointestinal cancers are suspected when the CA19-9 level exceeds 1,000 U/mL ( 2 ). High levels of CA19-9 are occasionally detected in benign biliary diseases, such as cholelithiasis, cholecystitis, and cholangitis. However, increased CA19-9 levels under these conditions are typically mild (＜100 U/mL in most cases) ( 3 ). We encountered a case of acute cholecystitis and choledocholithiasis with a significant increase in CA19-9 levels (29,512 U/mL) that decreased to within the normal range after endoscopic treatment for choledocholithiasis. We herein report the present findings, along with a literature review.

The authors state that they have no Conflict of Interest (COI).