Beyond the Hue: A Peculiar Case of Hyperbilirubinemia

Drug-induced liver injury (DILI) presentations range from a hepatocellular damage with increased transaminases, to a cholestatic hepatitis with mainly elevated alkaline phosphatase (ALP) and/or bilirubin, or it can present as a mixed type where these features overlap. DILI can be due to an idiosyncratic reaction that occurs after the exposure to a drug linked to an unpredictable reaction [1,2]. In our case the patient presented elevated bilirubin levels with slightly elevated transaminases (ALT 81) and mildly elevated ALP (275). Upon calculation of the R-value of 0.69 was obtained falling into the category of cholestatic injury [9]. Informations about hyperbilirubinemia in this scenario can be confusing. In fact, a liver damage secondary to cetirizine and cephalosporins [10] have been described even though, according to Livertox, the latter are more likely to induce liver damage compared to cetirizine [11]. In addition, data on patients who showed a worsening of hyperbilirubinemia after contrast exposure are available [3,4,12,13].

Several options can be taken into account, in particular ceftriaxone, in this case administered as cholangitis prophylaxis, can be associated with reversible biliary sludge and pseudolithiasis. Ceftriaxone can also lead to an immunoallergic form of cholestatic hepatitis [14]. Moreover, few cases in the literature have been linked to post ERCP prolonged hyperbilirubinemia and only one case has been linked to enhanced MRCP [15]. Exact mechanism is unknown, but it is speculated that it may happen due to contrast agent or cephuroxime administered as prophylaxis [4].

Our patient had a marked increase in bilirubinaemia five days after enhanced-CT scan and prior to ERCP to treat the obstruction previously described.The patient had no previous history of hyperbilirubinemia and no history of liver disease in the relatives. The increase in hyperbilirubinemia was not associated to infections even though the patient developed later on during the stay in the hospital bacteremia due to acinetobacter baumanii [16]. Serology for hepatitis viruses were negative, other etiologies (autoimmune, alcoholic, Wilson and haemocromatosis) were excluded. No signs of haemolysis were present. A liver biopsy revealed marked intrahepatic cholestasis.

Given that, we hypothesized that a genetic bilirubinaemia disorder could be involved in promoting this clinical presentation. Qian et al. described a case of a patient with Gilbert Syndrome who developed post-ERCP hyperbilirubinemia after exposure to the same contrast agent (iopromide) used in the CT scan performed at the Emergency room with worsening levels of bilirubin after enhanced MRCP [15]. Gilbert syndrome is an inherited metabolic disorder characterized by an abnormality in the function of the hepatic enzyme glucuronyl-transferase, which is responsible for bilirubin metabolism. This condition is associated with recurrent episodes of hyperbilirubinemia despite the absence of structural liver diseases or other evident causes of jaundice. It is one of the most common forms of hereditary jaundice, with a prevalence estimated at 2-10% in the general population [17].

Among these conditions, benign recurrent intrahepatic cholestasis (BRIC) is a rare genetic disease characterized by episodes of cholestasis that last from weeks to years, the course is usually benign even though cases of progression from BRIC to progressive familial intrahepatic cholestasis (PFIC) have been described in the literature [18]. Trigger factors include infection, hormonal changes (pregnancy and oral contraceptive pills) and drugs [19,20]. Given the history of the patient (age of the patient and the two previous pregnancies) and the prevalence of the disease we deemed unlikely for the patient to have BRIC and decided to test for UGT1A1 polymorphisms, confirming the homozygous presence of the polymorphism [8].

At present data on contrast agent metabolism and Gilbert syndrome are scarcely available, but it is possible that this disorder may exacerbate the reaction to a cholestatic liver damage [15].

Patients with Gilbert syndrome may experience intermittent jaundice, typically occurring after prolonged fasting, drugs, physical stress, or intercurrent illnesses. However, the condition is generally benign and does not lead to permanent liver damage [6]. Some drugs may selectively affect hepatic bilirubin metabolism as they undergo glucuronidation by UGT1A1. However, the list of drugs and other compounds that affect UGT1A1 activity is much longer, and this UGT1A1 inhibitory activity should be considered in the clinical setting [7].

In this respect, the European Medicines Agency and US Food and Drug Administration now recommend studying the inhibition of UGT1A1 when testing new drugs [21].

To our knowledge, this is the first case of jaundice post intravenous iodinated contrast agent administration by enhanced CT scan but not post exposure during ERCP.

Based on the available data we opted to therapy with UDCA as it is the most common therapeutic option for cholestatic DILI [22]. Alternatively, corticosteroids can be used even though they are more commonly prescribed in hepatocellular injury [23]. In our case bilirubin levels quickly dropped after the introduction of UDCA so no additional treatment was needed.

The case suggested that also contrast agents have to be taken into account among other several drugs in case of prolonged jaundice despite resolution of biliary obstruction. Radiological and sierological findings as well as hystological features ruled out several causes of jaundice.

DILI remains a diagnosis of exclusion and has to be always considered and, among possible trigger of liver damage, also contrast agent.