Vanishing Bile Duct Syndrome Following Cytomegalovirus Infection in a Child With Hodgkin Lymphoma
Hepatic involvement is uncommon (5%) at diagnosis in Hodgkin lymphoma (HL).1,2 Causes include hepatic infiltration, biliary obstruction, or viral infections.2–5 Vanishing bile duct syndrome (VBDS) is a rare paraneoplastic phenomenon associated with HL.1,5–7 We report a child with HL who developed VBDS following cytomegalovirus (CMV) infection.
A 7-year-old boy presented with intermittent fever and cervical nodes for 2 years. Diagnosis was classic HL, stage IVB (Figs. 1A–C). During evaluation, he developed fever, vomiting, jaundice, and clay-colored stools. Bilirubin was 6mg/dL (direct, 3.4mg/dL; alanine transaminase, 212U/L; aspartate transaminase, 219U/L; alkaline phosphatase, 576U/L; γ-glutamyl transferase, 243U/L). This increased to 12mg/dL over the next week. He was started on ursodeoxycholic acid and received vitamin K and lactulose. Hepatitis A, B, D, and E; human immunodeficiency virus; Epstein––Barr virus Viral capsid antigen IgM and immunoglobulin titers were normal. CMV-DNA copy number was 24,513/mL. He received IV ganciclovir until CMV was undetectable (2wk), and, thereafter, oral valgancyclovir (4wk). Simultaneously he received attenuated chemotherapy with prednisolone, bleomycin, and darcarbazine over 2 weeks. Bilirubin continued to increase to 18mg/dL. A liver biopsy was performed, which confirmed VBDS (Figs. 1D–G). He received 3 cycles of minimally hepatotoxic chemotherapy with dexamethasone, cisplatin, and cytarabine (DHAP). Bilirubin reduced to 12mg/dL, and the nodes reduced in size after the first cycle. However, subsequent increase in nodes, progressive hepatic failure, and lack of an option for liver transplantation because of financial limitations prompted the family to opt for palliative care.
Etiology of VBDS includes drugs, infections, and autoimmune, paraneoplastic, and ischemic insults.8 Mechanisms implicated in pathologic biliary apoptosis include Fas/FasL, perforin and granzyme B, tumor necrosis factor-α, oxidative stress, and downregulation of BCL-2. Management consists of use of ursodeoxycholic acid and immunosuppressants, and liver transplantation. In HL, lymphomatous infiltration followed by cytokine and T-lymphocyte–mediated destruction is the plausible pathogenesis. Despite adequate treatment, the majority die of liver failure or disease progression, the latter conceivably because of difficulty in administering potentially hepatotoxic chemotherapy with cholestasis.6,7,9 Sporadic reports of resolution exist.1,5,6,9 In a review of 37 adults with HL-associated VBDS, 1-year overall survival and liver failure–free survival were 43% and 41%, respectively; stage I/II disease, complete response of HL, and use of radiotherapy were predictive of survival. Overall, 65% (24/37) of such patients died, the majority (87%) from liver failure.7 Another review reported progression to hepatic failure in 49% of cases, with cure in 37%; the remaining had an unknown outcome of failure because of other causes (n=49). Interestingly, response rates of 51% and 12%, respectively, were reported, with upfront full-intensity versus attenuated chemotherapy.6 Liver transplantation has been recommended for cases progressing to hepatic failure on the basis of selected reports of survival (43%; n=7) in adults with idiopathic ductopenia, although the majority of these survivors (67%) persisted to have abnormal liver function.8
A unique phenomenon in the index patient was the onset of VBDS following CMV infection. CMV antigenemia/disease has been reported in HL (7%), and CMV-specific immune responses are altered early.10 CMV-associated VBDS has been previously reported in neonates and patients with human immunodeficiency virus–acquired immunodeficiency syndrome.11 It is plausible that CMV infection triggered an autoimmune destruction of bile ducts in the altered immunologic milieu of an underlying, long-standing HL.12
In conclusion, VBDS is a rare paraneoplastic phenomenon with poor outcome in a highly curable malignancy-like HL. Early histopathologic diagnosis and aggressive management of malignancy with preparedness for a liver transplantation in case of progressive hepatic failure might cure a subset of patients.