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Vanishing Bile Duct Syndrome Mashhood Ali et al. Case Report Vanishing Bile Duct Syndrome Abstract A 33 year old male presented with 5 weeks history severe pruritis , anorexia, weight loss and malaise .He underwent extensive workup including USG Abdomen ,MRCP, Viral serology and workup for autoimmune diseases which were all normal. He then underwent ERCP and findings on ERCP were consistent with Vanishing Bile Duct Syndrome which a rare entity in itself. He underwent Liver biopsy and findings were consistent with VBDS and he was subsequently followed up on outdoor basis and his symptoms improved with medications. Introduction Vanishing bile duct syndrome refers to a group of acquired disorders resulting in progressive destruction and disappearance of the intrahepatic bile ducts and ultimately cholestasis. Ductopenia (a pathologic description) refers to the associated reduction in the number of intrahepatic bile ducts, a process that ultimately leads to cholestasis.1-3 It’s a rare entity and many causes have been implicated and causes maybe developmental (syndromatic or non syndromatic paucity of interlobular bile ducts),immunological(primary biliary cirrhosis ,graft versus host disease, primary sclerosing chloangitus)infective(Vascular or chemical in origin).Several drugs including chlorpromazine, carbamazepine, ibuprofen, clindamycin, fluoroquinolones, antifungal drugs, tricyclic antidepressants and trimethopirim- sulfamethoxazole have been showed to be associated with VBDS.VBDS has also been reported in children with histiocytosis x and adult non hodgkin lymphoma patient.4-9,10 We report a patient who presented with severe progressive intrahepatic cholestasis due to VBDS for which a cause was not found Case Report Mashhood Ali** Haseeb Noor* Yasir Rafique Rajwana* Asif Imran* *Resident, **Senior Registrar, Department of Gastroenterology, Pakistan Institute of Medical Sciences (PIMS), Islamabad Address for Correspondence Dr. Haseeb Noor Department of Gastroenterology, Pakistan Institute of Medical Sciences (PIMS), Islamabad Email: [email protected] were added to his complaints for the last 4 weeks. He had no history of previous jaundice, blood transfusion, alcohol abuse or recent drug ingestion and no family history of liver disease. On admission his physical examination was remarkable for jaundice, itch marks all over the body and shiny nails attributed to persistent itching. There was no fever, hepatosplenomegaly or lymphadenopathy. Laboratory findings on admission revealed: White cell count:9900/microlit, platelets 373000/microliter, ESR 90mm/h, INR 1.4,(decreased normal value after treatment with vitamin k). Biochemical features consistent with cholestasis: total bilirubin:36.39 mg/dl(NV 0.3-1.2), alkaline phosphatase:232 U/L(NV 40-1300),alanine aminotransferase:112 U/L(NV 4-42), aspartate aminotransferase 110 U/L(10-42), g-glutamyltranspeptidase 400 U/L (nv 7-60). Serum immunoglobulins and combs test were normal. Serological tests for hepatitis A, B,C,E were negative. Blood, urine and stool cultures for bacteria and fungi were negative. Antimitochondrial antibody and antinuclear tests were negative. Autoimmunehepatitis, hemochromatosis and wilsons disease were ruled out . Additionally C-ANCA and P-ANCAS were also negative. Abdominal ultrasound revealed minimal hepatomegaly. Magnetic resonance cholangiopancreatography did not reveal any abnormality. (Figure 1) A 33 year old male presented with 5 weeks history severe pruritis, anorexia, weight loss and malaise. Painless jaundice, dark coloured urine and pale stools Ann. Pak. Inst. Med. Sci. 2014; 10(2):110-112 110 Vanishing Bile Duct Syndrome Mashhood Ali et al. started on cap ursodeoxycholic acid(750 mg daily),rifampicin(150 mg daily),sertraline (50 mg daily) for both pruritis and cholestasis. Within two weeks patients symptoms improved though not settling completely and owing to untreatable pattern of disease he was discharged with follow up in outdoor clinic. Figure 1: MRCP of the patient Endoscopic retrograde cholangiopancreatography demonstrated normal common bile duct with very small intrahepatic ducts suggestive of vanishing bile duct syndrome. (Figure 2) Figure 3: Percutaneous liver biopsy findings in the patient. Discussion Figure 2: ERCP of the patient. Percutanous liver biopsy revealed seven portal tracts with paucity of bile duts, marked cholestasis ,minimal acute on chronic inflammation, no significant fibrosis and mild to moderate steatosis. (Figure 3) Patient was Ann. Pak. Inst. Med. Sci. 2014; 10(2): 110-112 The term “idiopathic adulthood ductopenia ” was first mentioned by Ludwig, in 1988, to describe those patients those patients with biliary ductopenia (the absence of interlobular bile ducts in at least 50% of small portal tracts)not associated with any specific underlying cause.1-3 In VBDS HLA class 2 antigens are displayed on the bile ducts and recognition of biliary antigens by cytotoxic Tcells leads to destruction of interlobular ducts. The clinical course and clinical manisfestations are highly variable reflecting the varied underlying causes.Disease 111 Vanishing Bile Duct Syndrome onset can be rapid as in acute cellular rejection; as in our patient; or gradual ,as in primary biliary cirrhosis. The diagnosis is established by liver biopsy in the appropriate clinical setting.Evaluation should include imaging tests to exclude extrahepatic biliary obstruction and appropriate serological evaluation when there is suspicion for a particular clinical diagnosis (e.g antimitochondrial antibodyin patients suspected of having primary biliary cirrhosis).A careful history including all recent prescription and non prescription drug use is efabnorssential since drug induced cholestasis is common and drug withdrawal is essential.However in our patient all such causes were ruled out. There are generally two potential outcomes in patients with ductopenia:progressive,irreversible bile duct loss leading to extensive ductopenia and biliary cirrhosis(although the time course varies considerably)or biliary epithelial regeneration and clinical recovery over months to years as in our patient. Few cases of VBDS have been published it being a rare entity. All of the cases reported had an underlying cause but we here have reported a case for which no cause was found. Nationally only one case has been reported and that too was associated Hodgkins Lymphoma. A recent international study reported a patient of VBDS secondary to Toxic epidermal Necrolysis (TEN). 1,3,7,8,11 The mechanism of VBDS is poorly understood. There is no recognized treatment for VBDS. A few reports have described the use of ursodeoxycholic acid in drug induced VBDS. The above mentioned case report of VBDS secondary to TEN first reported use of Infliximab and plasmapharesis in addition to steroids and made efforts to support a mechanism for why these modalities could be effective treatments in the future. Since VBDS is a relatively recent defined entity, clinicians may not always be aware of its existence or its associations. This report emphasizes that VBDS should be considered in a patient with cholestatic jaundice.1,3 1. 2. References Schumaker AL, Okulicz JF. Meropenem-induced vanishing bile duct syndrome. Pharmacotherapy 2010; 30: 953. PubMed Citation (60 year old woman developed jaundice and pruritus while on meropenem and 3 weeks after course of ceftriaxone, metronidazole and vancomycin [bilirubin 11.2 rising to 26 mg/dL, ALT 83 U/L, Alk P 1467 U/L], with persistent jaundice and liver biopsy showing absence of bile ducts, improving but not completely resolving over next 6 months on ursodiol). Kochar R, Nevah MI, Lukens FJ, Fallon MB, Machicao VI. Vanishing bile duct syndrome in human immunodeficiency virus: nevirapine hepatotoxicity revisited. World J Gastroenterol 2010; 16: 3335- Ann. Pak. Inst. Med. Sci. 2014; 10(2): 110-112 Mashhood Ali et al. 8. PubMed Citation (28 year old pregnant woman with HIV infection developed jaundice 4 weeks after starting zidovudine, lamivudine and nevirapine to prevent perinatal transmission of HIV [bilirubin 10.5 mg/dL, ALT 179 U/L, Alk P 496 U/L], with persistent jaundice and liver biopsy showing ductopenia; follow up not provided). 3. Gökçe S, Durmaz O, Celtik C, Aydogan A, Güllüoglu M, Sökücü S. Valproic acid-associated vanishing bile duct syndrome. J Child Neurol 2010; 25: 909-11. PubMed Citation (8 year old girl developed persistent jaundice and itching 2 months after starting valproic acid [bilirubin rising to 20.2 mg/dL, ALT 118 U/L, Alk P 2787 U/L, normal INR], liver biopsy showing severe bile duct loss, bilirubin falling to normal after 8 months on ursodiol therapy but with persistence of Alk P elevations). 4. Juricic D, Hrstic I, Radic D, Skegro M, Coric M, Vucelic B, Francetic I. Vanishing bile duct syndrome associated with azithromycin in a 62year-old man. Basic Clin Pharmacol Toxicol 2010; 106: 62-5. PubMed Citation (62 year old man developed Stevens Johnson syndrome 3 days after a 3 day course of azithromycin and became jaundiced during recovery [bilirubin 15.2 mg/dL, ALT 1545 U/L, Alk P 545 U/L], with persistent jaundice and pruritus and liver biopsy showing absence of interlobular bile ducts at time of transplantation 10 months later). 5. Robinson W, Habr F, Manlolo J, Bhattacharya B. Moxifloxacin associated vanishing bile duct syndrome. J Clin Gastroenterol 2010; 44: 72-3. PubMed Citation (82 year old man received azithromycin, ceftriaxone and 7 days of moxifloxacin and developed jaundice [bilirubin 15.3 rising to 25.8 mg/dL, ALT 441 U/L, Alk P 821 U/L], with biopsy showing ductopenia with persistence of jaundice; outcome not provided). 6. Bhayana H, Appasani S, Thapa BR, Das A, Singh K. Lamotrigine induced vanishing bile duct syndrome in a child. J Pediatr Gastroenterol Nutr 2011. PubMed Citation (12 year old boy developed rash 2 weeks after starting lamotrigine followed by jaundice [bilirubin 14.8 mg/dL, ALT 321 U/L, Alk P 123 U/L], liver biopsy showing ductal paucity with incomplete recovery on ursodiol and referral for transplantation 2 years later). 7. Ichikawa T, Sato H, Kaira K, Oh-I S, Kakizaki S, Sato K, Takagi H, Mori M. Prolonged intrahepatic cholestasis after exposure to loxoprofen. Clin Ther 2008; 30: 2402-6.PubMed Citation (36 year old woman developed jaundice 5 days after starting loxoprofen [bilirubin 27.5 mg/dL, ALT 470 U/L, Alk P 1082 U/L], liver biopsy showing paucity of bile ducts, with protracted course and slow resolution 14 months after onset). 8. Orman ES, Conjeevaram HS, Vuppalanchi R, Freston JW, Rochon J, Kleiner DE, Hayashi PH; DILIN Research Group. Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol. 2011; 9: 517-23. PubMed Citation (12 cases of liver injury due to fluoroquinolones including one due to moxifloxacin that resulted in VBDS and liver transplantation 16 months after onset of acute cholestatic hepatitis). 9. Farouj NE, Cadranel JF, Mofredj A, et al. Ductopenia related liver sarcoidosis. World J Hepatol 2011; 3:170 10. Yusuf MA, Elias E, Hubscher SG. (2000) Jaundice caused by the vanishing bile duct syndrome in a child with Hodgkin lymphoma. J Pediatr Hematol Oncol. 22(2):154-157 11. Jason C. White and Stephanie Appleman. Infliximab/Plasmapheresis in Vanishing Bile Duct Syndrome Secondary to Toxic Epidermal Necrolysis. September 22, 2014;Pediatrics;Official journal of the American academy of Pedriatics. 112