Antifungal induced jaundice unmasking Dubin–Johnson Syndrome in an adult patient: a case report

Antifungal induced jaundice unmasking Dubin–Johnson Syndrome in an adult patient: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Antifungal induced jaundice unmasking Dubin–Johnson Syndrome in an adult patient: a case report Soumaya Mrabet, Amel Medhioub, Raida Harbi, Imen Akkari, Elhem Ben Jazia This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8906934/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Dubin-Johnson syndrome (DJS) is an autosomal recessive genetic liver disease, characterized by chronic predominantly conjugated hyperbilirubinemia. Most people with DJS are asymptomatic, so their cases are often misdiagnosed and not properly taken care of. Our case illustrates a rare cause of jaundice in adults triggered by antifungal treatment, which is DJS, and the importance of screening for this disease in order to warn the patient before taking any hepatotoxic medication. Case presentation: We report here a case of a 40-year-old North African woman, who complained of chronic jaundice and abdominal pain. The history revealed that the patient had been taking an antifungal treatment for 1 month prior to the onset of jaundice, prescribed for onychomycosis.Biological and radiological examinations were performed, concluding in intrahepatic cholestasis. A liver biopsy was then performed and confirmes DJS. A conservative approach was adopted, with follow-up indicating a favorable outcome. Conclusions : DJS is a rare cause of jaundice in adults. The prognosis is favorable without progression to fibrosis. This entity does not require treatment in adolescents and adults. However, management requires a multimodal care strategy, including avoiding of potential triggers especially hepatotoxic drugs. Gastroenterology & Hepatology Dubin-Johnson syndrome jaundice hyperbilirubinemia antifungal therapy case report Figures Figure 1 Figure 2 Article highlights Dubin–Johnson syndrome should be considered in cases of isolated conjugated hyperbilirubinemia with preserved liver function. Antifungal therapy can trigger or exacerbate cholestasis, leading to diagnostic confusion with drug-induced liver injury. Drug-induced jaundice may unmask previously undiagnosed Dubin–Johnson syndrome in adults. Differentiation from drug-induced liver injury is essential to prevent misdiagnosis. The condition has a benign course and does not require specific treatment. Introduction Dubin-Johnson syndrome (DJS) is an autosomal recessive genetic liver disease, characterized by chronic predominantly conjugated hyperbilirubinemia [ 1 ].This condition is linked to mutations in the ABCC2 (adenosine triphosphate (ATP) binding cassette subfamily C member 2) gene, which codes for the MRP2 (multidrug resistance-associated protein 2) transporter, mainly present in the canalicular membrane of hepatocytes [ 1 , 2 ]. Although it is considered a rare disease worldwide, this desease is more common in Sephardic Jews. It affects both men and women, and usually appears during adolescence. Most people with DJS are asymptomatic. The main presenting symptom is mild-to-moderate jaundice without associated pruritus, often triggered by intercurrent illness, pregnancy or oral contraceptives. Minor symptoms such as abdominal pain and fatigue may be observed during outbreaks [ 3 ].Liver biopsy is the gold standard test for the diagnosis of DJS. Histological examination reveals an accumulation of dark lysosomal pigments similar to melanin in centro-lobular hepatocytes, with no change in liver architecture [ 2 ]. However, liver biopsy is not recommended to establish the diagnosis in the presence of an elevated coproporphyrin I fraction in the urine associated with conjugated hyperbilirubinemia without other liver test abnormalities [ 2 ]. DJS is a benign condition that does not progress to fibrosis and generally does not require medical treatment [ 3 ]. However, it is important to diagnose DJS to rule out other hepatobiliary disorders that may cause liver damage, and to diagnose those that can be treated. We report here a case of DJS revealed by mucocutaneous jaundice in a young adult follwing antifungal therapy. In the light of this observation and after a review of the literature, we review the pathogenesis, epidemiology, clinical presentation and diagnostic challenges of this disease. Presentation of case Physical examination showed no signs of hepatocellular insufficiency or portal hypertension. The history revealed that the patient had been taking an antifungal treatment for 1 month prior to the onset of jaundice, prescribed for onychomycosis. No herbal medicines were taken, and no viral contagion was reported. Initial diagnosis/assessment Laboratory investigations showed an elevated total bilirubin level of 510 umol/l and direct conjugated bilirubin of 325 umol/l. Gamma-glutamyl transferase was 470 IU/L (11.7 ULN), alkaline phosphatase was 350 IU/L (2.5 ULN), Aspartate aminotransferase was 108 IU/L (2.7 ULN) and alanine aminotransferase was 96 IU/L (2.4 ULN). Prothrombin and albumin levels were normal. Abdominal ultrasound showed thin intrahepatic and extrahepatic bile ducts without any signs of biliary obstructions or chronic liver disease. Further tests were conducted to investigate a viral or autoimmune origin. Alphabetical viral serologies (A, B, C and E) were all negative. First- and second-line immunological tests were negative. Thyroid function tests were normal. The pharmacovigilance investigation concluded that there was a low probability of hepatotoxicity due to antifungal treatment, given the absence of clinico-biological improvement after discontinuation of this treatment. Magnetic Resonance Cholangiography ( MRC) revealed a 3 mm biliary cyst in segment III of the liver, with no abnormalities of the bile ducts. Treatment/management Antifungal treatment was stopped. Clinical and biological monitoring was carried out Outcome and implications The course was spontaneously favorable, with regression of jaundice and normalization of the liver function tests. Discussion DJS is a rare genetic disorder inherited in an autosomal recessive pattern. The prevalence of DJS is estimated at less than one case per 100,000 people worldwide, but it is more common in Sephardic Jews [ 2 ]. To our knowledge, 10 cases have been reported in Tunisia [ 4 ]. DJS was first described in 1954 by Dubin et al, who reported several cases of young adults with chronic jaundice, conjugated hyperbilirubinemia and black liver, with no other features of hepatobiliary disease [ 5 ]. The underlying cause of DJS is a mutation in MRP2 also called canalicular multispecific organic anion transporter 1 (cMOAT), responsible for the excretion of conjugated bilirubin into the bile canaliculi. Indeed, Paulusma et al. Have demonstrated that a mutation in the MRP2 gene underlies the biliary transport defect observed in DJS [ 6 ]. These results were confirmed by the study of Ito et al, who reported that MRP2 expression is defective in patients with chronic hyperbilirubinemia [ 7 ].Recent studies have confirmed that mutations in the ABCC2 gene are responsible for the loss of MRP2 function and the onset of DJS [ 2 ]. DJS most commonly affects asymptomatic young adults with elevated bilirubin levels often detected incidentally. Occasionally, mild symptoms such as jaundice, asthenia and/or abdominal pain may be present. Pruritus is typically absent, as serum total bile acid levels remain normal. In some cases, affected women show no symptoms, but hyperbilirubinemia or jaundice may appear when taking oral contraceptives or during pregnancy [ 8 ]. In rare cases, DJS can occur during the neonatal period. It may manifest as severe cholestasis and hepatomegaly. Bilirubin levels may reach > 20 mg/dl. The increased severity in neonates has been attributed to immature biliary physiology combined with defective MRP2. As the liver matures, infants become asymptomatic until advanced age, when they may present with intermittent hyperbilirubinemia. DJS can be diagnosed by identifying an increased urinary coproporphyrin I to III ratio. In fact, the abnormal distribution of coproporphyrin isomers I and III in the urine is a distinctive feature of this desease. In normal subjects, coproporphyrin III predominates over coproporphyrin I in urine. In patients with DJS, the total urinary coproporphyrin content remains normal, however, the I isomer may account for up to 80% of the total, compared to the usual 25% [ 9 ]. Genetic analysis of the ABCC2 gene is a reliable method for diagnosing Dubin–Johnson syndrome (DJS). Togawa et al. described ten cases of neonatal DJS and concluded that both immunohistochemical staining of the liver for MRP2 and molecular genetic analysis of ABCC2 are essential for an accurate diagnosis in neonatal cases. Nevertheless, ABCC2 genotyping is not typically included in the routine clinical work-up [ 3 ]. Although not required for diagnosis, liver histology reveals an accumulation of melanin-like granular lysosomal pigments in the centrilobular hepatocytes of an otherwise normal liver, giving the organ its characteristic black appearance [ 3 ]. In the case for our patient, the diagnosis was confirmed after eliminating other etiologies of conjugated hyperbilirubinemia in association with the anatopathological appearance. Genetic study was not available DJS has a favorable prognosis, does not progress to fibrosis, and typically does not require treatment in adolescents and adults. Liu et al. even reported the use of a liver graft from a living donor with DJS for transplantation. The recipient was followed for one year with satisfactory results. However, long-term pigment accumulation in hepatocytes may lead to bile duct rupture, resulting in hepatocellular degeneration and necrosis. Therefore, in children with DJS who present with recurrent severe jaundice, treatment should be considered to reduce pigment accumulation in hepatocytes and prevent further hepatic injury. Phenobarbital or ursodeoxycholic acid may be considered to reduce jaundice and protect liver function, thereby decreasing clinical symptoms and the risk of hepatocyte injury [ 10 ]. The Table 1 illustrates selected cases of DJS that have been reported in the literature. Table 1 Clinical cases of Dubin-Johnson syndrome reported in the literature. Article Year Country Age of onset Symptoms Diagnosis Treatment Abdul Hannan Siddiqui et al [ 3 ] 2023 USA 17 years Jaundice Abdominal pain Liver biopsy ursodeoxycholic acid Rifampicin Huan et al [ 1 ] 2021 China 24 years Jaundice Liver biopsy Glutathione Zhao et al [ 2 ] 2022 China 29 years 18 years Jaundice Genetic analysis (ABCC2 mutation) Glutathione ursodeoxycholic acid Gubta et al [ 8 ] 2019 India 30 years (pregnancy) Jaundice Liver biopsy No treatment Guirat et al [ 4 ] 2019 Tunisia 9 years Jaundice Coproporphyrin measurement. Genetic analysis No treatment Declarations Authors’ contributions Soumaya Mrabet and Amel Medhoiub: Collecting patient data and litterature review Raida Harbi, Imen Akkari and Elhem Ben Jazia: Revinsing the manuscript The final version was approved by all co-authors Acknowledgements : None Disclosures: Ethics approval and consent to participate: We have obtained the consent of the patient before the redaction of the case. Consent for publication : Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal Competing interests : The authors declare no competing interest. Funding statement : This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References Wu H, Zhao XK, Zhu JJ (2021) Clinical characteristics and ABCC2 genotype in Dubin-Johnson syndrome: a case report and review of the literature. World J Clin Cases 9(4):878–885 Zhao C, Shi X, Zhang Y, Huang H Case report: three novel pathogenic ABCC2 mutations identified in two patients with Dubin–Johnson syndrome. Front Genet 2022 Aug :13:895247 Siddiqui AH, Alsabe MR, Tehseen Z, Hatamleh MI, Taslim S, Abdelrahman A et al (2023) Dubin-Johnson syndrome: a case report. Cureus 15(3):e36115 Guirat N, Abdelhedi F, Tfifha M, Charfi A, Sticova E, Jirsa M (2019) Dubin-Johnson syndrome in Tunisia: Spectrum of a rare disease. Presse Med 48(1):81–82 Dubin IN, Johnson FB (1954) Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine 33(3):155–197 Paulusma CC, Kool M, Bosma PJ, Scheffer GL, Ter Borg F, Scheper RJ et al (1997) A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 25(6):1539–1542 Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T, Sugiyama Y (1997) Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol 272(1):16–22 Gupta A, Tiwari P, Sachdeva P (2019) A case of Dubin-Johnson syndrome in pregnancy. Cureus 11(2):e4048 Frank M, Doss M, De Carvalho DG (1990) Diagnostic and pathogenetic implications of urinary coproporphyrin excretion in the Dubin-Johnson syndrome. Hepatogastroenterology 37(1):147–151 Meng LL, Qiu JW, Lin WX, Song YZ (2019) Clinical features and ABCC2 genotypic analysis of an infant with Dubin-Johnson syndrome. Zhongguo Dang Dai Er Ke Za Zhi 21(1):64–70 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8906934","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":593248476,"identity":"9f154b39-0d6b-4e6b-9116-f192eab37384","order_by":0,"name":"Soumaya 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pigments.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8906934/v1/dae0f7dfbb4506cd7eaa825f.jpg"},{"id":102998296,"identity":"04ef1844-fe76-4eae-8500-7c2e60362a91","added_by":"auto","created_at":"2026-02-19 12:39:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3472932,"visible":true,"origin":"","legend":"\u003cp\u003eHistological section of liver biopsy showing preserved architecture\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8906934/v1/d304e1bad5f4abe7f98f5d6b.jpg"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAntifungal induced jaundice unmasking Dubin–Johnson Syndrome in an adult patient: a case report\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Article highlights","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eDubin\u0026ndash;Johnson syndrome should be considered in cases of isolated conjugated hyperbilirubinemia with preserved liver function.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAntifungal therapy can trigger or exacerbate cholestasis, leading to diagnostic confusion with drug-induced liver injury.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDrug-induced jaundice may unmask previously undiagnosed Dubin\u0026ndash;Johnson syndrome in adults.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eDifferentiation from drug-induced liver injury is essential to prevent misdiagnosis.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe condition has a benign course and does not require specific treatment.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eDubin-Johnson syndrome (DJS) is an autosomal recessive genetic liver disease, characterized by chronic predominantly conjugated hyperbilirubinemia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].This condition is linked to mutations in the ABCC2 (adenosine triphosphate (ATP) binding cassette subfamily C member 2) gene, which codes for the MRP2 (multidrug resistance-associated protein 2) transporter, mainly present in the canalicular membrane of hepatocytes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although it is considered a rare disease worldwide, this desease is more common in Sephardic Jews. It affects both men and women, and usually appears during adolescence. Most people with DJS are asymptomatic. The main presenting symptom is mild-to-moderate jaundice without associated pruritus, often triggered by intercurrent illness, pregnancy or oral contraceptives. Minor symptoms such as abdominal pain and fatigue may be observed during outbreaks [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].Liver biopsy is the gold standard test for the diagnosis of DJS. Histological examination reveals an accumulation of dark lysosomal pigments similar to melanin in centro-lobular hepatocytes, with no change in liver architecture [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, liver biopsy is not recommended to establish the diagnosis in the presence of an elevated coproporphyrin I fraction in the urine associated with conjugated hyperbilirubinemia without other liver test abnormalities [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDJS is a benign condition that does not progress to fibrosis and generally does not require medical treatment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, it is important to diagnose DJS to rule out other hepatobiliary disorders that may cause liver damage, and to diagnose those that can be treated.\u003c/p\u003e \u003cp\u003eWe report here a case of DJS revealed by mucocutaneous jaundice in a young adult follwing antifungal therapy. In the light of this observation and after a review of the literature, we review the pathogenesis, epidemiology, clinical presentation and diagnostic challenges of this disease.\u003c/p\u003e"},{"header":"Presentation of case","content":"\u003cp\u003ePhysical examination showed no signs of hepatocellular insufficiency or portal hypertension.\u003c/p\u003e \u003cp\u003eThe history revealed that the patient had been taking an antifungal treatment for 1 month prior to the onset of jaundice, prescribed for onychomycosis. No herbal medicines were taken, and no viral contagion was reported.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eInitial diagnosis/assessment\u003c/strong\u003e \u003cp\u003eLaboratory investigations showed an elevated total bilirubin level of 510 umol/l and direct conjugated bilirubin of 325 umol/l. Gamma-glutamyl transferase was 470 IU/L (11.7 ULN), alkaline phosphatase was 350 IU/L (2.5 ULN), Aspartate aminotransferase was 108 IU/L (2.7 ULN) and alanine aminotransferase was 96 IU/L (2.4 ULN). Prothrombin and albumin levels were normal. Abdominal ultrasound showed thin intrahepatic and extrahepatic bile ducts without any signs of biliary obstructions or chronic liver disease. Further tests were conducted to investigate a viral or autoimmune origin. Alphabetical viral serologies (A, B, C and E) were all negative. First- and second-line immunological tests were negative. Thyroid function tests were normal. The pharmacovigilance investigation concluded that there was a low probability of hepatotoxicity due to antifungal treatment, given the absence of clinico-biological improvement after discontinuation of this treatment. Magnetic Resonance Cholangiography ( MRC) revealed a 3 mm biliary cyst in segment III of the liver, with no abnormalities of the bile ducts.\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eTreatment/management\u003c/strong\u003e \u003cp\u003eAntifungal treatment was stopped. Clinical and biological monitoring was carried out\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eOutcome and implications\u003c/strong\u003e \u003cp\u003eThe course was spontaneously favorable, with regression of jaundice and normalization of the liver function tests.\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eDJS is a rare genetic disorder inherited in an autosomal recessive pattern. The prevalence of DJS is estimated at less than one case per 100,000 people worldwide, but it is more common in Sephardic Jews [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. To our knowledge, 10 cases have been reported in Tunisia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. DJS was first described in 1954 by Dubin et al, who reported several cases of young adults with chronic jaundice, conjugated hyperbilirubinemia and black liver, with no other features of hepatobiliary disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The underlying cause of DJS is a mutation in MRP2 also called canalicular multispecific organic anion transporter 1 (cMOAT), responsible for the excretion of conjugated bilirubin into the bile canaliculi. Indeed, Paulusma et al. Have demonstrated that a mutation in the MRP2 gene underlies the biliary transport defect observed in DJS [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These results were confirmed by the study of Ito et al, who reported that MRP2 expression is defective in patients with chronic hyperbilirubinemia [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].Recent studies have confirmed that mutations in the ABCC2 gene are responsible for the loss of MRP2 function and the onset of DJS [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDJS most commonly affects asymptomatic young adults with elevated bilirubin levels often detected incidentally. Occasionally, mild symptoms such as jaundice, asthenia and/or abdominal pain may be present. Pruritus is typically absent, as serum total bile acid levels remain normal. In some cases, affected women show no symptoms, but hyperbilirubinemia or jaundice may appear when taking oral contraceptives or during pregnancy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In rare cases, DJS can occur during the neonatal period. It may manifest as severe cholestasis and hepatomegaly. Bilirubin levels may reach\u0026thinsp;\u0026gt;\u0026thinsp;20 mg/dl. The increased severity in neonates has been attributed to immature biliary physiology combined with defective MRP2. As the liver matures, infants become asymptomatic until advanced age, when they may present with intermittent hyperbilirubinemia.\u003c/p\u003e \u003cp\u003eDJS can be diagnosed by identifying an increased urinary coproporphyrin I to III ratio. In fact, the abnormal distribution of coproporphyrin isomers I and III in the urine is a distinctive feature of this desease. In normal subjects, coproporphyrin III predominates over coproporphyrin I in urine. In patients with DJS, the total urinary coproporphyrin content remains normal, however, the I isomer may account for up to 80% of the total, compared to the usual 25% [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Genetic analysis of the ABCC2 gene is a reliable method for diagnosing Dubin\u0026ndash;Johnson syndrome (DJS). Togawa et al. described ten cases of neonatal DJS and concluded that both immunohistochemical staining of the liver for MRP2 and molecular genetic analysis of ABCC2 are essential for an accurate diagnosis in neonatal cases. Nevertheless, ABCC2 genotyping is not typically included in the routine clinical work-up [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although not required for diagnosis, liver histology reveals an accumulation of melanin-like granular lysosomal pigments in the centrilobular hepatocytes of an otherwise normal liver, giving the organ its characteristic black appearance [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In the case for our patient, the diagnosis was confirmed after eliminating other etiologies of conjugated hyperbilirubinemia in association with the anatopathological appearance. Genetic study was not available\u003c/p\u003e \u003cp\u003eDJS has a favorable prognosis, does not progress to fibrosis, and typically does not require treatment in adolescents and adults. Liu et al. even reported the use of a liver graft from a living donor with DJS for transplantation. The recipient was followed for one year with satisfactory results. However, long-term pigment accumulation in hepatocytes may lead to bile duct rupture, resulting in hepatocellular degeneration and necrosis. Therefore, in children with DJS who present with recurrent severe jaundice, treatment should be considered to reduce pigment accumulation in hepatocytes and prevent further hepatic injury. Phenobarbital or ursodeoxycholic acid may be considered to reduce jaundice and protect liver function, thereby decreasing clinical symptoms and the risk of hepatocyte injury [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates selected cases of DJS that have been reported in the literature.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical cases of Dubin-Johnson syndrome reported in the literature.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArticle\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge of onset\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSymptoms\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDiagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdul Hannan Siddiqui et al [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eJaundice\u003c/p\u003e \u003cp\u003eAbdominal pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLiver biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eursodeoxycholic acid\u003c/p\u003e \u003cp\u003eRifampicin\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHuan et al [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eJaundice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLiver biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGlutathione\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhao et al [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 years\u003c/p\u003e \u003cp\u003e18 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eJaundice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGenetic analysis\u003c/p\u003e \u003cp\u003e(ABCC2 mutation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGlutathione\u003c/p\u003e \u003cp\u003eursodeoxycholic acid\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGubta et al [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 years\u003c/p\u003e \u003cp\u003e(pregnancy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eJaundice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLiver biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo treatment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuirat et al [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTunisia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eJaundice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCoproporphyrin measurement.\u003c/p\u003e \u003cp\u003eGenetic analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo treatment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSoumaya Mrabet and Amel Medhoiub: Collecting patient data and litterature review\u003c/p\u003e\n\u003cp\u003eRaida Harbi, Imen Akkari and Elhem Ben Jazia: Revinsing the manuscript\u003c/p\u003e\n\u003cp\u003eThe final version was approved by all co-authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate: We have obtained the consent of the patient before the redaction of the case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare no competing interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e: This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWu H, Zhao XK, Zhu JJ (2021) Clinical characteristics and ABCC2 genotype in Dubin-Johnson syndrome: a case report and review of the literature. World J Clin Cases 9(4):878\u0026ndash;885\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao C, Shi X, Zhang Y, Huang H Case report: three novel pathogenic ABCC2 mutations identified in two patients with Dubin\u0026ndash;Johnson syndrome. Front Genet 2022 Aug :13:895247\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiddiqui AH, Alsabe MR, Tehseen Z, Hatamleh MI, Taslim S, Abdelrahman A et al (2023) Dubin-Johnson syndrome: a case report. Cureus 15(3):e36115\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuirat N, Abdelhedi F, Tfifha M, Charfi A, Sticova E, Jirsa M (2019) Dubin-Johnson syndrome in Tunisia: Spectrum of a rare disease. Presse Med 48(1):81\u0026ndash;82\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDubin IN, Johnson FB (1954) Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine 33(3):155\u0026ndash;197\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaulusma CC, Kool M, Bosma PJ, Scheffer GL, Ter Borg F, Scheper RJ et al (1997) A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 25(6):1539\u0026ndash;1542\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto K, Suzuki H, Hirohashi T, Kume K, Shimizu T, Sugiyama Y (1997) Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol 272(1):16\u0026ndash;22\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGupta A, Tiwari P, Sachdeva P (2019) A case of Dubin-Johnson syndrome in pregnancy. Cureus 11(2):e4048\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrank M, Doss M, De Carvalho DG (1990) Diagnostic and pathogenetic implications of urinary coproporphyrin excretion in the Dubin-Johnson syndrome. Hepatogastroenterology 37(1):147\u0026ndash;151\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeng LL, Qiu JW, Lin WX, Song YZ (2019) Clinical features and ABCC2 genotypic analysis of an infant with Dubin-Johnson syndrome. Zhongguo Dang Dai Er Ke Za Zhi 21(1):64\u0026ndash;70\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dubin-Johnson syndrome, jaundice, hyperbilirubinemia, antifungal therapy, case report","lastPublishedDoi":"10.21203/rs.3.rs-8906934/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8906934/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDubin-Johnson syndrome (DJS) is an autosomal recessive genetic liver disease, characterized by chronic predominantly conjugated hyperbilirubinemia. Most people with DJS are asymptomatic, so their cases are often misdiagnosed and not properly taken care of. Our case illustrates a rare cause of jaundice in adults triggered by antifungal treatment, which is DJS, and the importance of screening for this disease in order to warn the patient before taking any hepatotoxic medication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe report here a case of a 40-year-old North African woman, who complained of chronic jaundice and abdominal pain. The history revealed that the patient had been taking an antifungal treatment for 1 month prior to the onset of jaundice, prescribed for onychomycosis.Biological and radiological examinations were performed, concluding in intrahepatic cholestasis. A liver biopsy was then performed and confirmes DJS. A conservative approach was adopted, with follow-up indicating a favorable outcome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDJS is a rare cause of jaundice in adults. The prognosis is favorable without progression to fibrosis. This entity does not require treatment in adolescents and adults. However, management requires a multimodal care strategy, including avoiding of potential triggers especially hepatotoxic drugs.\u003c/p\u003e","manuscriptTitle":"Antifungal induced jaundice unmasking Dubin–Johnson Syndrome in an adult patient: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-19 12:39:25","doi":"10.21203/rs.3.rs-8906934/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c5434670-3621-4a51-94a4-72f9be8ae419","owner":[],"postedDate":"February 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63128325,"name":"Gastroenterology \u0026 Hepatology"}],"tags":[],"updatedAt":"2026-02-19T12:39:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-19 12:39:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8906934","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8906934","identity":"rs-8906934","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}