Dubin-Johnson Syndrome as Differential Diagnosis for Neonatal Cholestasis

Abstract

Objectives: Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder in which multidrug-resistance-associated protein 2 (MRP2) deficiency causes an excretion disorder of conjugated bilirubin from hepatocytes into bile canaliculi. Its clinical presentation as neonatal cholestasis (NC) is rare but represents an important differential diagnosis. We aimed to define DJS-specific characteristics in NC, in particular in contrast to biliary atresia (BA) patients, and to highlight diagnostic tools that can help to avoid invasive diagnostic tests. Methods: We performed a review of case records from 2006 to 2020 and compared 4 DJS patients to 26 patients with proven BA consecutively diagnosed from 2014 to 2017. DJS was diagnosed by urine coproporphyrin analysis (UCA) and by genetic analysis (GA) for disease-associated ABCC2 variants. Results: Four male patients with NC were diagnosed with DJS by UCA and GA. DJS patients presenting as NC showed significantly lower values for aspartate aminotransferase (AST) (P < 0.001), for alanine aminotransferase (ALT) (P ¼ 0.002) and for gamma-glutamyl transferase (GGT) (P < 0.001) compared with BA patients. Other examinations, however, could not clearly discriminate them (e.g.: stool colour, serum bile acids, total serum bilirubin). Conclusions: DJS is not only a rare differential diagnosis in NC with a suspicious phenotype (almost normal AST, ALT) but also shows overlapping features with BA. It should, therefore, be considered in every infant with NC and an atypical liver enzyme pattern to protect patients from unnecessary, invasive examinations. For this, UCA is a fast and reliable diagnostic tool. Confirmation based on GA is recommended. DJS patients have a good long-term prognosis.

Clinical, Biochemical, and Molecular Characterization of Neonatal-Onset Dubin–Johnson Syndrome in a Large Case Series From the Arabs

“…For example, UCPA, available in very few centers, is the most helpful non-invasive test with a very high diagnostic performance. Our data and others (14,19) suggest that a percentage of UCP isomer I > 80% of the total UCPs would be consistent with a diagnosis of DJS. HIDA scan is another useful non-invasive tool to evaluate and orient the diagnosis toward DJS that it is more readily available than UCPA, however is less sensitive and specific than UCPA.…”

“…The mutational spectrum of the ABCC2 gene in DJS patients includes more than 60 different variants, described from different populations (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), that are predicted to cause defects in the protein structure, maturation, localization to the canalicular membrane, or the function of correctly localized protein (23). These variants vary across different ethnic groups.…”

“…Our laboratory used different ALT and AST tests during the study period with different normal cut off reference ranges (Table 1), therefore in addition to reporting the absolute values of the transaminases, we calculated the proportion of ALT and AST to the upper limit of normal (ULN). Several previous studies on DJS patients showed that serum ALT levels were typically normal (9)(10)(11)(12)(13)(14). To evaluate the utility of serum ALT level as a biochemical discriminative indicator of DJS, we compared the ALT values in DJS patients with ALT values in other major etiologies contributing to infantile cholestasis in Saudi Arabia.…”

“…The MRP2, which is located on the canalicular membrane of hepatocytes, is important in excretion of conjugated bilirubin from hepatocytes into the bile (2). Since molecular characterization of the first ABCC2 gene variant responsible for DJS in 1997 (1), several variants of ABCC2 gene were identified in DJS patients from different populations and ethnicities, particularly from Far-East Asia (Japan, Taiwan, Korea, and China), Israel (Iranian and Moroccan Jews), and Europe (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Most of these studies included children and adults (3)(4)(5)(6)(7)(8), however neonatal-onset DJS was rarely reported, and the reports constituted only few case reports and small case series (9)(10)(11)(12)(13)(14).…”

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

“…Reduced cholic acid (CA) clearance was also detected in sheep exhibiting inherited defects in hepatic bilirubin transport similar to human Dubin-Johnson syndrome ( Engelking and Gronwall, 1979 ). More recent work reports that net plasma concentrations of BAs are often increased in individuals with Mrp2 mutations ( Togawa et al, 2018 ; Junge et al, 2021 ), although exceptions also exist ( Fu et al, 2021 ). To date, individual BAs in individuals with Mrp2 mutations have not been analyzed.…”