Vanishing Bile Duct Syndrome as an Uncommon Hepatic Paraneoplastic Syndrome in Hodgkin’s Lymphoma

Intrahepatic cholestasis related to vanishing bile duct syndrome in Hodgkin's disease.

Jaundice and morbilliform eruption in a 20-year-old female

Vanishing bile duct syndrome (VBDS) has been described in different pathologic conditions including infection, ischemia, adverse drug reactions, autoimmune diseases, allograft rejection, and humoral factors associated with malignancy. It is an acquired condition characterized by progressive destruction and loss of the intra-hepatic bile ducts leading to cholestasis. Prognosis is variable and partially dependent upon the etiology of bile duct injury. Irreversible bile duct loss leads to significant ductopenia, biliary cirrhosis, liver failure, and death. If biliary epithelial regeneration occurs, clinical recovery may occur over a period of months to years. VBDS has been described in a number of cases of patients with Hodgkin’s lymphoma (HL) where it is thought to be a paraneoplastic phenomenon. This case describes a 25-year-old man found on liver biopsy to have VBDS. Given poor response to medical treatment, the patient underwent transplant evaluation at that time and was found to have classical stage IIB HL. Early recognition of this underlying cause or association of VBDS, including laboratory screening, and physical exam for lymphadenopathy are paramount to identifying potential underlying VBDS-associated malignancy. Here we review the literature of HL-associated VBDS and report a case of diagnosed HL with biopsy proven VBDS.

Regulation and deregulation of cholangiocyte proliferation

Vanishing bile duct syndrome (VBDS) is a condition resulting from progressive destruction and loss of intrahepatic bile ducts leading to cholestasis, biliary cirrhosis, and liver failure. It occurs secondary to various pathologic conditions like autoimmune diseases, graft versus host disease, drug reactions, and as a paraneoplastic syndrome in malignancies. We here described a 9-year-old girl who presented with cervical lymphadenopathy and jaundice. This child was diagnosed as a case of Hodgkin lymphoma. All other causes of cholestasis were ruled out by appropriate investigations (particularly autoimmune, metabolic, infections, and drug-induced possibilities). On liver biopsy, her diagnosis was established as VBDS. In view of hepatic dysfunction, alternative chemotherapy with dexamethasone, high-dose cytarabine, and cisplatin (DHAP) was given, and she was started on hepatoprotective measures with ursodeoxycholic acid. Hepatic function gradually improved after the initiation of chemotherapy. VBDS is considered a dismal paraneoplastic syndrome with a high-case fatality. This case report highlights the importance of early recognition and initiation of appropriate full-dose chemotherapy as the only way to achieve complete resolution of VBDS.

BackgroundVanishing bile duct syndrome has been associated with different pathologic conditions (adverse drug reactions, autoimmune diseases, graft versus host disease, and cancer). Though its causes are unknown, an immune-related pathogenesis is the most likely one. Vanishing bile duct syndrome can evolve to hepatic failure and, eventually, to death. The treatment is uncertain, but it needs the resolution of the underlying pathologic condition.Case presentationWe describe the association of Hodgkin’s lymphoma with a syndrome characterized by cholestasis, aminotransferase elevation and an histological picture of bile duct loss. All other causes of hepatic function impairment were excluded (in particular, drugs, viral and autoimmune related diseases) eventually leading to the diagnosis of vanishing bile duct syndrome. Despite the fact that the dysfunction is not caused by hepatic Hodgkin’s lymphoma involvement, liver impairment can limit the optimal therapy of Hodgkin’s lymphoma. A treatment consisting of ursodeoxycholic acid, prednisone, and full dose chemotherapy restored hepatic function and achieved complete and long-lasting remission of Hodgkin’s lymphoma.ConclusionWe reviewed all case reports showing that vanishing bile duct syndrome is a dismal paraneoplastic syndrome being fatal in a high proportion of patients if not adequately treated. Indeed, this syndrome requires both an early recognition and an appropriate aggressive treatment consisting of full dose upfront chemotherapy which is the only way to achieve a resolution of the vanishing bile duct syndrome. Delayed or reduced intensity treatments unfavorably correlate with survival.

Introduction: Vanishing bile duct syndrome (VBDS) is characterized by cholestatic liver disease in the setting of disappearing intra-hepatic bile ducts. It can resemble other forms of cholestatic liver disease; however, imaging and biochemical tests will be unrevealing. We describe a case of a woman with Hodgkin lymphoma (HL) who developed cholestatic hepatitis with loss of intra-hepatic bile ducts. Case Description/Methods: A 23-year-old woman with a history of HL who presented for evaluation and treatment of HL. Two months prior she had been treated for CMV-associated gastroenteritis and sepsis. Initial examination revealed jaundice and bilateral conjunctival icterus. Lab results showed total bilirubin of 18.1 mg/dL, ALT 363 U/L, AST 149 U/L, alkaline phosphatase (ALP) of 2392 U/L, direct bilirubin of 15.5 mg/dL, INR of 2.07, and cytomegalovirus (CMV) PCR at 670 IU/mL. Other acute viral hepatitis studies, tests for intrinsic liver disease, and autoimmune markers were negative. Computerized tomography (CT) of the abdomen and pelvis showed extensive lymphadenopathy, sclerotic changes throughout the skeleton, splenomegaly, and hepatomegaly without focal liver lesions. Magnetic resonance cholangiopancreatography (MRCP) of the abdomen showed no evidence of biliary ductal dilatation. Treatment for her HL was initiated, as well as foscarnet for her CMV viremia. Liver biopsy showed benign liver parenchyma with marked cholestasis and paucity of bile ducts, no cirrhosis, and no viral inclusions. The patient was initiated on ursodeoxycholic acid (UDCA) at 15 mg/kg/d without resolution of symptoms or cholestasis. Given no improvement in her cholestasis, the prospects of liver transplantation (LT) were discussed, but the patient was not a candidate (Figure 1). Discussion: Liver involvement in HL typically manifests as parenchymal invasion, external compression, or paraneoplastic destruction of bile ducts (VBDS). VBDS tends to signify a poor prognosis with patients frequently progressing to liver failure. The pathogenesis of VBDS in HL is not yet defined with current evidence suggesting an immune-mediated response. Typically, viral causes should be excluded. In this case, the patient did have CMV viremia. Given her prior treatment, low viral load, and absence of viral inclusions on liver biopsy, CMV was excluded as a cause. Treatment for VBDS revolves around treating the underlying cause. UDCA can be used as a temporizing measure, but, if no improvement is observed over time, patients are referred for liver transplant.Figure 1.: Parenchymal liver biopsy: (A) and (B) Lobular cholestasis. The hepatic lobules show cholestasis within the hepatocytes and bile canaliculi. (C) Paucity of intrahepatic bile duct. No bile duct is seen in the portal tract. (D) CK-7 positive hepatocytes in chronic cholestasis. The hepatocytes in this case stain positive for CK-7.

Vanishing bile duct syndrome (VBDS) is an acquired condition characterized by the destruction and loss of intrahepatic bile ducts resulting in cholestasis. VBDS has been described in various conditions including neoplastic and immunologic disorders, infections, hepatic ischemia, and drug toxicity. The diagnosis is confirmed by liver biopsy revealing the loss of interlobular bile ducts in greater than 50% of portal tracts. Prognosis is variable and often unpredictable but appears to be influenced by the etiology of bile duct destruction and overall patient health. VBDS has been described as a rare paraneoplastic process in patients with Hodgkin lymphoma. This case describes a 26-year-old female who presented with a neck mass, jaundice, and pruritus. Initial workup revealed direct hyperbilirubinemia, transaminitis, elevated alkaline phosphatase, and elevated international normalized ratio. She went on to receive a diagnosis of stage II classical Hodgkin lymphoma, nodular sclerosing subtype, and biopsy-proven VBDS. Over the course of chemotherapy, complete metabolic resolution of Hodgkin lymphoma and complete normalization of bilirubin were achieved. She was given gemcitabine and cyclophosphamide as a liver sparing regimen initially with some improvement in liver function tests and a reduction in lymph node volumes. She received six cycles of adriamycin/bleomycin/vinblastine/dacarbazine (ABVD) with complete remission attained after four cycles by positron emission tomography/computed tomography criteria. This report illustrates asafe chemotherapy regimen in the presence of marked liver dysfunction. Workup for VBDS including liver biopsy should be pursued in Hodgkin lymphoma patients with evidence of cholestasis in the absence of extrahepatic bile duct damage or other known etiology of liver injury.

Disclosure: J. Martone: None. S. Douglas: None. M. Kristan: None.Introduction: Vanishing bile duct syndrome (VBDS) is a rare progressive condition defined by loss of intrahepatic bile ducts with complications of cholestasis and liver dysfunction. VBDS can be idiopathic, autoimmune, viral, due to malignancy, or secondary as a drug-induced side effect. Hyperlipidemia, though rare, is a severe side effect of VBDS in adults and is thought to be due to disrupted bile acid metabolism and lipid homeostasis. Management of drug-induced VBDS with hyperlipidemia has been underreported in the literature with one previous report. Ursodiol was initiated with subsequent improvement in the patient’s condition. Further documentation of ursodiol’s effect on drug-induced VBDS with hyperlipidemia is critical to patient outcomes. Case Report: A 61-year-old female with a history of metastatic sarcomatoid carcinoma of the breast presented with immune-mediated liver injury thought to be secondary to pembrolizumab, an immune checkpoint inhibitor. The patient had been on a stable dose of pembrolizumab for four months when routine labs revealed alarming liver function tests (LFTs), including elevated aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin. A diagnosis of immunotherapy-induced autoimmune hepatitis was reached, prompting the discontinuation of pembrolizumab and initiation of prednisone (80 mg), CellCept (2000 mg), and adriamycin cytoxan. Three months later, LFTs showed a continued elevation in total bilirubin, leading to a diagnosis of choledocholithiasis. Cholecystectomy and liver biopsy resulted in immune-mediated cholangiopathy with VBDS, likely due to pembrolizumab. The case was further complicated by hospital admission for sepsis days before the cholecystectomy, and steroid-induced hyperglycemia, hyponatremia, and Cushing syndrome. Prednisone was tapered to 40 mg daily. Additionally, repeat labs resulted in high total cholesterol (1168 mg/dL) and triglycerides (593 mg/dL). Ursodiol (500 mg BID) was initiated for VBDS with hyperlipidemia. One month post ursodiol, AST has declined from 350 to 127, ALT declined from 350 to 149, ALP declined from 1020 to 502, while total bilirubin has decreased from 10.1 to 7.5. Discussion: This case highlights VBDS with hyperlipidemia as a significant complication of pembrolizumab therapy. Physicians should consider VBDS secondary to pembrolizumab in the setting of prolonged elevated LFTs beginning 1-6 months after drug initiation. VBDS with hyperlipidemia is poorly researched in adults, with only one other case that resulted in LFT and lipid abnormalities being improved by ursodiol treatment. Further research regarding ursodiol treatment in VBDS is critical for adult VBDS cases complicated by hyperlipidemia.Presentation: Saturday, July 12, 2025

Vanishing bile duct syndrome (VBDS) is characterized by cholestasis and progressive destruction of the intrahepatic bile ducts (ductopenia). The current definition of ductopenia is the loss of interlobular bile ducts in more than 50% of portal tracts. Ductopenia is believed, at a molecular level, to result from the misbalance in cell regeneration and apoptosis. In the literature various etiologies have been reported to cause ductopenia, with Hodgkin's lymphoma (HL) being listed as a rare example. How HL causes ductopenia remains ambiguous, and seems to be related to a paraneoplastic phenomenon causing cytokine release from lymphoma cells, not tumor infiltration or obstructive lymphadenopathy. VBDS is generally considered irreversible, unlike its histopathological counterpart, idiopathic cholestasis, where ductopenia is not present and liver function improves with therapy. Therefore, a distinction between the two is warranted. There have been only 19 case reports in the English literature associating VBDS with HL. Here we report a 64-year-old female patient who presented with distributive shock and jaundice. Initial laboratory values revealed leukocytosis, mild transaminase elevation with significantly elevated alkaline phosphatase, along with direct hyperbilirubinemia. During hospital stay, the patient's liver function progressively worsened. Further workup did not reveal ductal dilation or obstruction and there were unremarkable results for infectious and autoimmune etiologies. Imaging studies with biopsy revealed extensive lymphadenopathy consistent with HL; liver biopsy showed cholestasis and ductopenia. Despite chemotherapy the patient succumbed to progressive liver failure and sepsis.

Vanishing bile duct syndrome related to DILI and Hodgkin lymphoma overlap: A rare and severe case

Vanishing bile duct syndrome (VBDS) is an acquired syndrome characterized by clinical and laboratory signs of cholestasis with pathologic findings of interlobular bile duct paucity in liver biopsy specimens. VBDS can result from a variety of conditions including infections, autoimmune diseases, adverse drug reactions, and neoplastic processes. Hodgkin lymphoma (HL) is a rare cause of VBDS. The mechanism by which HL leads to VBDS remains unknown. Development of VBDS in patients with HL portends an extremely poor prognosis due to the risk of progression to fulminant hepatic failure. Treatment of the underlying lymphoma has been demonstrated to offer increased probability of recovery from VBDS. The decision to treat and choice of treatment of the underlying lymphoma is often complicated by the hepatic dysfunction characteristic of VBDS. We present the case of a patient who presented with dyspnea and jaundice in the context of recurrent HL and VBDS. We additionally review the literature on HL complicated by VBDS with specific focus on treatment paradigms for management of these patients.

Vanishing bile duct syndrome (VBDS) is a condition resulting from severe bile duct injury, progressive destruction, and disappearance of intrahepatic bile ducts (ductopenia) leading to cholestasis, biliary cirrhosis, and liver failure. VBDS can be associated with a variety of disorders, including Hodgkin's lymphoma (HL). We describe a 33-year-old male patient who presented with lymphadenopathy and jaundice, and was diagnosed to have HL. Serum bilirubin worsened progressively despite chemotherapy, with a cholestatic pattern of liver enzymes. Diagnosis of VBDS was established on liver biopsy. Although remission from HL was achieved, the patient died of liver failure. Presence of jaundice in HL patients should raise the possibility of VBDS. This report discusses the difficulties of delivering chemotherapy in patients with liver dysfunction. HL-associated VBDS carries a high mortality but lymphoma remission can be achieved in some patients. Therefore, liver transplantation should be considered early in these patients.

We present a case of a 60-year-old man with a remote history of non-Hodgkin Lymphoma (NHL) who developed cirrhosis during the course of his lymphoma. Investigation into the underlying cause of cirrhosis was negative including viral and autoimmune serologic markers and imaging studies of biliary tree. He had no history of alcohol abuse. While his NHL was eventually successfully treated with chemotherapy, he developed multiple sequelae of end stage liver disease including variceal bandings, spontaneous bacterial peritonitis, and acute coagulopathic episodes before successful liver transplantation nearly two decades after his diagnosis of NHL. Histologic exam of the explanted liver showed a biliary pattern of cirrhosis with near total loss of interlobular bile ducts. Chronic biliary injury and cholestasis was confirmed by the presence of excess copper deposition and copper binding protein by copper and Victoria blue stains, respectively. There were no features of primary sclerosing cholangitis or primary biliary cirrhosis. There was no steatosis, no evidence of alpha-1-antitrypsin disease, hemochromatosis, or veno-occlusive disease. There was no evidence of lymphomatous involvement. It was determined that the patient had likely developed VBDS and biliary cirrhosis in association with his NHL. Vanishing bile duct syndrome (VBDS) refers to a clinicopathologic group of conditions resulting from progressive destruction and disappearance of intrahepatic bile ducts. It can be seen in a variety of conditions including primary liver disorders or manifestations of systemic illnesses. VBDS has also been reported in association with many drugs. VBDS is an uncommon but potentially fatal complication of Hodgkin lymphoma, and in exceptionally rare cases, NHL. The exact mechanism is unknown but is thought to be a paraneoplastic phenomenon, or possible sequelae of drug induced/chemotherapy injury. There are only 3 prior published cases of VBDS in association with NHL. In 2 of the cases the patients died, one of acute liver failure and the other of multiple organ failure secondary to his underlying lymphoma. The third case demonstrated reversibility of the VBDS with near normalization of total bilirubin levels 6 weeks after onset of chemotherapy. To our knowledge, our case is the first to demonstrate a prolonged course of VBDS in association with NHL, eventually leading to chronic end stage liver disease and biliary cirrhosis, despite complete remission of NHL.

Vanishing Bile Duct Syndrome (VBDS) is a rare, acquired disorder, characterized by progressive destruction and loss of intrahepatic bile ducts. The main clinical manifestations are jaundice and pruritus, caused by intralobular cholestasis. Although the pathogenic mechanism is poorly understood, VBDS has been associated with numerous etiologies such as medications, malignancies, infections and autoimmune diseases. This syndrome can appear as a paraneoplastic phenomenon in patients with Hodgkin’s Lymphoma (HL). Diagnosis is based on clinical evaluation and confirmed via liver biopsy, while treating the underlying cause is the main therapeutic target. If bile duct regeneration does not occur, possible outcomes include cirrhosis, hepatic failure and death, with liver transplantation being the only curative option. In this paper, we describe a case of HL-related VBDS in a 31-year-old female patient, who presented with jaundice, pruritus and cervical lymphadenopathy. The stage of HL was determined as IIA and a liver biopsy was performed, which confirmed the degeneration of bile ducts. The patient was treated with the ABVD regimen and dexamethasone. Follow-up tests were normal and supported the full remission hypothesis. We conducted an analytical literature review and collected the available data from 38 confirmed cases, regarding the epidemiology, viral infections, clinical findings, therapeutic options and outcome.