Author Affiliations: Hepatogastroenterology Unit, 2nd Department of Internal Medicine and Research Institute, “Attikon” University General Hospital, Medical School, University of Athens, Athens, Greece (Tziatzios G, Gkolfakis P, Papanikolaou IS, Dimitriadis G and Triantafyllou K)

Corresponding Author: Konstantinos Triantafyllou, MD, Hepatogastroenterology Unit, 2nd Department of Internal Medicine and Research Institute, “Attikon” University General Hospital, Medical School, University of Athens, 1 Rimini Street, 124 62 Athens, Greece (Tel: +30-210-5832089; Fax: +30-210-5326422; Email: ktriant@med.uoa.gr)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60402-7

Published online July 17, 2015.

 

 

Contributors: TK proposed the study. TG, GP and PIS collected the literature. TG and GP wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts. TK is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

ABSTRACT: Despite the effectiveness of endoscopic retrograde cholangiopancreatography (ERCP) for the treatment of choledocholithiasis, various complications have been described. We herein report the first case of prolonged post-ERCP jaundice due to toxicity of the contrast agent Iobitridol (®XENETIX, Guerbet, Roissy CdG Cedex, France) in a patient who underwent ERCP with sphincterectomy and common bile duct stone removal. While clinical improvement and normalization of aminotransferases and cholestatic enzymes after the procedure, an unexplained increase of direct bilirubin was noticed. A second ERCP was performed one week later, excluding possible remaining choledocholithiasis. Nevertheless, serum direct bilirubin increased further up to 15 mg/dL. Other potential causes of direct hyperbilirubinemia were ruled out and patient’s liver biopsy was compatible with drug-induced liver toxicity. Additionally, the cause-result time connection between the use of Iobitridol and bilirubin increase indicated the possibility of a toxic effect related to the repeated use of the particular contrast agent. Iobitridol, a contrast agent, can induce prolonged direct hyperbilirubinemia.

 

(Hepatobiliary Pancreat Dis Int 2016;15:220-222)

KEY WORDS: endoscopic retrograde cholangiopancreatography; jaundice; adverse effect; Iobitridol

Endoscopic retrograde cholangiopancreatography (ERCP) with sphincterectomy and stone removal remains the gold standard intervention for choledocholithiasis.^[1] The major complications related to ERCP involve acute pancreatitis, bleeding, sepsis and perforation. Multiple studies have defined an incidence rate of about 7%.^{[2, 3]} Prolonged post-ERCP jaundice has been described as a rare post-ERCP complication.^[4] We report one case of post-ERCP prolonged direct hyperbilirubinemia due to toxicity of a new generation contrast agent used for the procedure.

 

 

A 56-year-old Caucasian man presented with jaundice and right upper quadrant abdominal pain lasting for 3 days. The patient underwent laparoscopic cholecystectomy for acute cholecystitis two months before his admission. He was not taking any medication; he had no history of jaundice or anemia, hepatitis exposure, alcohol abuse, blood transfusion or travelling abroad. No signs of chronic hepatopathy were noticed. On admission, laboratory examinations revealed normal blood count, while liver function tests showed serum total bilirubin 9.6 mg/dL (normal <1.2 mg/dL), direct bilirubin 6.3 IU/L (normal <1.0 IU/L), alanine aminotransferase 440 IU/L (normal <41 IU/L), aspartate aminotransferase 213 IU/L (normal <38 IU/L), alkaline phosphatase 166 IU/L (normal <120 IU/L), and gamma-glutamyl transpeptidase (γ-GT) 490 IU/L (normal <70 IU/L). Laboratory results indicating acute inflammation were absent.

 

Abdominal ultrasound showed a dilated (9 mm) common bile duct and indicated the presence of a stone in the region of the ampulla of Vater. Two days later the patient underwent ERCP with sphincterectomy and stone extraction, under conscious sedation with 2 mg of midazolam. We used 10 mL of the contrast agent Iobitridol (®XENETIX, Guerbet, Roissy CdG Cedex, France) to opacify the bile duct. The drainage of the contrast from the common bile duct was complete after stone extraction. We observed clinical improvement as well as a progressive decrease of aminotransferases and cholestatic enzymes during the next days, while a marked increase was noted in both total (up to 15 mg/dL) and direct bilirubin (up to 12 mg/dL) (Fig.). One week later, a second abdominal ultrasonography was performed. Amorphous echogenic material detected in the common bile duct suggested a high suspicion of remaining choledocholithiasis, which led to the decision to perform a second ERCP. Midazolam 2 mg once again was used during ERCP for conscious sedation. Normal cholangiography using 10 mL of the same contrast agent ruled out choledocholithiasis. The following days, despite the normalization of aminotransferases and cholestatic enzymes, the levels of both total (up to 18 mg/dL) and direct bilirubin (up to 15 mg/dL) were increased further (Fig.).

 

Infections including hepatitis A, B, C and other hepatotropic viruses (cytamegalovirus, herpes simplex virus, and Epstein-Barr virus) were ruled out. Immunological studies on ANA, SMA, AMA, anti-M2 and anti-LKM showed negative results with the exception of a 3-fold increase in IgG-4 values (377 mg/dL). Ceruloplasmin and ferritin levels were normal. The patient underwent MRCP that was negative for intra- or extrahepatic bile duct pathology. The review of patient’s history provided no new information. Liver biopsy revealed mild inflammatory and lymphohistocytic infiltrations without bile duct loss or damage. Moderate intrahepatic cholestasis with occasional focal necrotic areas was also noticed, and findings were compatible with drug-induced liver toxicity. Without any treatment, the bilirubin level decreased slowly, and the patient was discharged 35 days after admission. Two months later, tests of liver function showed nothing abnormal (Fig.).

 

 

Intrahepatic cholestasis clinically characterized by jaundice may be attributed to many different causes. In our patient, infection with hepatotropic viruses was excluded by serological testing. Our patient did not use any medication and the only agent used during pro-, peri- or post-ERCPs was midazolam (2 mg), needed for conscious sedation. A study^[5] showed that midazolam is not related to cases of clinically apparent liver injury, although other benzodiazepines occasionally contribute to prolonged cholestasis (2-6 months). The quick normalization of cholestatic liver enzymes and the previous exposure to midazolam during cholecystectomy without increase of bilirubin level unlikely make midazolam and elevated bilirubin level related. However, this possibility cannot be excluded. In our patient, there was no evidence of an underlying autoimmune or metabolic disease since ceruloplasmin and ferritin levels were normal. An isolated elevation of IgG4 titers was insufficient to develop a possible autoimmune pancreatitis according to the Mayo Clinic HISORt criteria.^[6] During hospitalization, there was no evidence of co-existing sepsis as the underlying factor that triggered laboratory manifestations in our patient. The patient remained afebrile, and his white cell count and other inflammation markers (e.g. CRP) were constantly normal.

 

Pathological report suggested a possible liver toxic effect caused by the contrast agent used in ERCP.^[7] A “withdrawal test” was also relevant to a transient drug-induced liver injury since the liver test was normal after the removal of the potential toxicity (Fig.). A “re-challenge test” could confirm the diagnosis but it was thought to expose the patient to unnecessary danger and therefore was considered unethical. However, the repeated ERCP in differential diagnosis functioned as an unintentional re-challenge test. This allowed us to establish a clear time correlation between the administration of the contrast agent and the subsequent elevation of bilirubin level, thus strengthening our hypothesis of an underlying association.

 

Iobitridol is an iodinated contrast agent used for whole-body computed tomography, venography, intra-arterial angiography and ERCP.^[8] It is well tolerated^{[9, 10]} and its gastrointestinal side effects include nausea, vomiting and abdominal pain.^[8] The agent is not metabolized, not taken up by hepatocytes and does not interfere with liver metabolism. Nevertheless, local effects, immune toxicological effects, and cellular effects can never be excluded. To our knowledge, this is the first case of prolonged jaundice induced by Iobitridol.

 

There were 2 cases of prolonged cholestasis characterized by jaundice due to a similar iodinated contrast agent Meglumine Amidotrizoate (ANGIOGRAFIN®, Schering AG, Germany).^[4] The authors proposed the disruption of the plasma canalicular membranes caused by the high-pressure contrast agent infusion during ERCP as the possible mechanism of liver injury. This mechanism is difficult to explain hyperbilirubinemia in our patient since neither an alkaline phosphatase elevation nor an acinarization of the hepatic parenchyma during ERCP was observed. There is evidence that systemic distribution of the contrast agent from the bile duct might be responsible for direct toxic liver injury^[11-13] since the contrast agent fills in the bile duct and might spread extracellularly into the nearby tissues. The exact mechanism however remains unknown. In contrast to these reported cases, in whom corticosteroids were used,^[4] our patient presented complete normalization of biochemical results without any special treatment. This allows us to speculate a potential idiosyncratic reaction as the cause of the syndrome.

 

In conclusion, prolonged jaundice due to iodinated contrast agents could be considered as a rare post-ERCP complication, and physicians should be aware of it.

 

 

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2 Andriulli A, Loperfido S, Napolitano G, Niro G, Valvano MR, Spirito F, et al. Incidence rates of post-ERCP complications: a systematic survey of prospective studies. Am J Gastroenterol 2007;102:1781-1788. PMID: 17509029

3 Wang P, Li ZS, Liu F, Ren X, Lu NH, Fan ZN, et al. Risk factors for ERCP-related complications: a prospective multicenter study. Am J Gastroenterol 2009;104:31-40. PMID: 19098846

4 Dourakis SP, Mayroyannis C, Alexopoulou A, Hadziyannis SJ. Prolonged cholestatic jaundice after endoscopic retrograde cholangiography. Hepatogastroenterology 1997;44:677-680. PMID: 9222670

5 http://livertox.nih.gov/Midazolam.htm; Accessed on November 06, 2014.

6 Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 2006;4:1010-1016. PMID: 16843735

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8 MHRA. Summary of Product Characteristics. http://www.mhra.gov. uk/home/groups/spcpil/documents/spcpil/con1362976132452.pdf. Accessed on July 20, 2014.

9 Maurer M, Heine O, Wolf M, Freyhardt P, Schnapauff D, Hamm B. Safety and tolerability of iobitridol in general and in patients with risk factors: results in more than 160,000 patients. Eur J Radiol 2011;80:357-362. PMID: 20395094

10 McCormack PL. Iobitridol: a review of its use as a contrast medium in diagnostic imaging. Clin Drug Investig 2013;33:155-166. PMID: 23341290

11 Chavalitdhamrong D, Donepudi S, Pu L, Draganov PV. Uncommon and rarely reported adverse events of endoscopic retrograde cholangiopancreatography. Dig Endosc 2014;26:15-22. PMID: 24118211

12 Draganov P, Cotton PB. Iodinated contrast sensitivity in ERCP. Am J Gastroenterol 2000;95:1398-1401. PMID: 10894570

13 Draganov PV, Forsmark CE. Prospective evaluation of adverse reactions to iodine-containing contrast media after ERCP. Gastrointest Endosc 2008;68:1098-1101. PMID: 19028218