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

Vanishing bile duct syndrome is a rare acquired condition, characterized by progressive loss of intrahepatic bile ducts leading to ductopenia and cholestasis. It can be associated with infections, ischemia, drug adverse reactions, neoplasms, autoimmune disease, and allograft rejection. Prognosis is variable and depends on the etiology of bile duct injury. We report the case of a 25-year-old female with cholestatic hepatitis and concomitant intakes of hepatotoxic substances, such as garcinia, field horsetail, and ketoprofen. On suspicion of a drug-induced liver injury, the drugs were promptly withdrawn and ursodeoxycholic acid was started with initial clinical and laboratory improvement, and the patient was discharged from the hospital. One month later, she had a new increase in bilirubin levels and canalicular enzymes, requiring a liver biopsy that showed significant loss of intrahepatic bile ducts, which was compatible with vanishing bile duct syndrome. This was confirmed by using cytokeratin 19 on immunohistochemistry. There was subsequent lymph node enlargement in several chains, and relevant weight loss. Histological analysis of a cervical lymph node revealed nodular sclerosis-subtype classic Hodgkin lymphoma. In this setting, vanishing bile duct syndrome was related to Hodgkin lymphoma and a drug-induced liver injury overlap, leading to progressive cholestasis with a worse prognosis. The patient's response to chemotherapy was poor, requiring biological therapy with brentuximab vedotin. It is crucial for physicians to create a broad differential diagnosis in suspected vanishing bile duct syndrome patients, especially to rule out malignancies.     

Hodgkin's disease presenting as cholestatic hepatitis with prominent ductal injury

In advanced stages of Hodgkin's disease, liver involvement is common. However, Hodgkin's disease mimicking cholestatic hepatitis at presentation is rare. We describe a patient with Hodgkin's disease who was initially considered to have acute cholestatic hepatitis. Liver biopsy demonstrated prominent bile duct injury associated with a florid inflammatory reaction. These changes may represent an early stage of ductal injury, subsequently leading to vanishing bile duct syndrome, a recently documented mechanism of cholestasis in Hodgkin's disease.     

Drug-induced cholestasis

The spectrum of drug-induced cholestasis ranges from 'bland' reversible cholestasis to chronic forms due to the vanishing bile duct syndrome. Agents known for many years to cause cholestasis include estrogens and anabolic steroids, chlorpromazine, erythromycin, and the oxypenicillins; structurally similar congeners of these drugs (tamoxifen, newer macrolides) may also cause cholestasis. Contemporary drugs linked to cholestastic liver injury include ticlopidine, terfenadine, terbinafine, nimesulide, irbesartan, fluoroquinolones, cholesterol-lowering 'statins,' and some herbal remedies (greater celandine, glycyrrhizin, chaparral). Amoxillin-clavulanate, ibuprofen, and pediatric cases of the vanishing bile duct syndrome are recent additions to a long list of drugs associated with the vanishing bile duct syndrome. Particular human leukocyte antigen profiles have recently been identified among those who have developed cholestasis with specific drugs (tiopronin and amoxicillin-clavulanate), and the mechanistic relevance of these genetic associations is being explored. The treatment of drug-induced cholestasis is largely supportive. The offending drug should be withdrawn immediately. Cholestyramine or ursodeoxycholic acid are used to alleviate pruritus, with rifampicin and opioid antagonists being reserved for those who fail first line therapy. Nutritional support is essential for those with prolonged cholestasis, a subgroup who are at risk of developing biliary cirrhosis and liver failure. Timely referral for liver transplant assessment is crucial in these patients.     

Drug and toxin-induced bile duct disorders

Various drugs of toxins have been implicated in the development of a particular form of liver damage predominantly involving the bile ducts. Such liver toxicity is often associated with a clinical picture of prolonged cholestasis and may even evolve in rare instances, into the full picture of the vanishing bile duct syndrome, eventually complicated with biliary cirrhosis. Drug and toxins potentially responsible for bile duct injury are reviewed as well as the characteristics of its clinical presentation. The pathophysiologic aspects of the syndrome are also reviewed including recent data, which are strongly in favor of the role of a genetic predisposition.     

Severe jaundice, due to vanishing bile duct syndrome, as presenting symptom of Hodgkin's lymphoma, fully reversible after chemotherapy

Liver involvement in Hodgkin's lymphoma is common and is caused by hepatic infiltration, biliary obstruction by lymphoma, hepatitis, sepsis or complications of chemotherapeutic treatment. Jaundice caused by the vanishing bile duct syndrome related to Hodgkin's lymphoma is very rare. The mechanism is poorly understood but a paraneoplastic effect seems most likely as liver biopsy samples show cholestasis in the absence of lymphoma cells. Despite adequate treatment almost all reported patients died of liver failure or disease progression. Disease progression is explained partly by the difficulties encountered in the administration of potential hepatotoxic chemotherapy in severely cholestatic patients. We describe a 17-year-old man with vanishing bile duct syndrome and Hodgkin's lymphoma who was treated successfully with chemotherapy. The markedly elevated serum bilirubin levels completely normalized. Our case demonstrates that although dosing of chemotherapy in this situation can be very difficult, a good clinical outcome is possible, which makes the attempt at curative treatment worthwhile.     

Vanishing bile duct syndrome

Perhaps no condition associated with chronic cholestasis is less understood than vanishing bile duct syndrome, a term that refers loosely to the group of acquired disorders associated with progressive destruction and disappearance of the intrahepatic bile ducts and, ultimately, cholestasis. Although the array of insults resulting in poor bile flow is vast, most adult patients who have chronic cholestasis have either primary biliary cirrhosis (or primary sclerosing cholangitis; in some cases, however, a cause cannot be identified. This article reviews the multiple causes, postulated pathophysiology, clinical features, and treatment options for this syndrome.     

Acute hepatitis with prolonged cholestasis and disappearance of interlobular bile ducts following tibolone and Hypericum perforatum (St. John's wort). Case of drug interaction?

The case of a patient under tibolone therapy for two years who developed a mixed-type liver injury with prolonged cholestasis and features of the vanishing bile duct syndrome following a ten weeks treatment with St. John wort (Hypericum Perforatum) infusions is reported. In the absence of evidence of a potential role for concomitant medication i.e. hydroxychloroquine sulfate to play a role in the clinical, biochemical and morphological picture, an interaction between the herbal preparation and tibolone was suspected as the likely cause of liver damage.     

The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation

The acute vanishing bile duct syndrome can be defined as an irreversible, rejection-related condition that affects hepatic allografts within 100 days after orthotopic liver transplantation and whose presence requires retransplantation. We have observed the acute vanishing bile duct syndrome in 5 of 48 consecutive patients (approximately 10%) who underwent orthotopic liver transplantation. In 4 cases, the condition progressed relentlessly within approximately 7 to 11 weeks after orthotopic liver transplantation from mild rejection to severe rejection to acute vanishing bile duct syndrome. A fifth patient had severe rejection in the first week and required retransplantation after 17 days because of thrombotic venoocclusive disease complicating the acute vanishing bile duct syndrome. Clinically, signs of impending acute vanishing bile duct syndrome included abrupt onset of fever and jaundice and marked elevation of serum bilirubin and alkaline phosphatase levels which persisted despite antirejection treatment. Biopsy specimens revealed destructive cholangitis (rejection cholangitis), ductopenia, and, if retransplantation was delayed, presence of noninflammatory, "burnt-out" portal tracts without bile ducts. We recommend to base the diagnosis of acute vanishing bile duct syndrome on documentation of severe ductopenia in at least 20 portal tracts which may require several consecutive needle biopsies. Rejection arteriopathy which was found in 3 of our 5 cases might have been another important diagnostic clue but could not be recognized prior to retransplantation. The pathogenesis of acute vanishing bile duct syndrome is not clear; until the condition had manifested itself, we found no qualitative differences between acute reversible and irreversible rejection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Drug-induced cholestasis

Drug-induced cholestasis is a common entity, seen with numerous classes of pharmacological agents. A high index of suspicion is required for the correct diagnosis. Different clinical syndromes may be recognized, with variable degrees of hepatitis in association with cholestasis. The most important aspect of treatment is prompt discontinuation of the offending drug. Several agents have been used for symptomatic relieve of the pruritus associated with cholestasis, including cholestyramine, ursodeoxycholic acid, and opiate antagonists, with limited results. Prognosis is usually good, with few cases of prolonged cholestasis leading to vanishing bile duct syndrome. Liver failure may rarely occur if diagnosis goes unrecognized and the inciting drug is not withdrawn.     

Macrophage activating syndrome is associated with lobular hepatitis and severe bile duct injury with cholestasis

Macrophage activating syndrome (MAS) is a rare hematological disorder associated with uncontrolled systemic T-cell activation. Persistent fever, fatigue and hepatosplenomegaly are frequent clinical manifestations, whereas hyperferritinemia, elevated serum lactate dehydrogenase levels and cytopenia are key criteria for the diagnosis of MAS. The nature of liver pathology in MAS has been partially elucidated but destructive biliary lesions have been rarely described. This report illustrates four cases of MAS developing marked cholestasis, leading to one case of biliary cirrhosis necessitating liver transplantation. Histologically, liver involvement was characterized in all cases by acute lobular hepatitis, marked hepatocyte apoptosis and small bile duct injury similar to the vanishing bile duct syndrome. Immuno-histological studies showed that the inflammatory changes and bile duct lesions were dominated by the presence of activated macrophages and T-cells, in particular CD8+ lymphocytes, and in part NK-cells. These findings suggest that in MAS, various T-cell triggers such as infection, autoimmune disease and malignancy might result in the release of cytokines, which in turn activate macrophages to trigger a systemic acute phase response and local tissue damage. This communication suggests that a macrophage, T- and NK-cell network is operational in the pathogenesis of the cholangiocyte, hepatocyte and sinus endothelial cell damage in MAS.     

Drug-induced cholestasis

Acute, drug-induced hepatocellular cholestasis (either pure or cholestatic hepatitis) is a common manifestation of drug-induced hepatic injury. The drugs most frequently responsible are hormonal steroids and psychopharmacological agents (in particular phenothiazines and some antidepressants). Cholestasis usually subsides without sequelae in less than six months. Acute, drug-induced ductular cholestasis is uncommon and can resemble biliary tract obstruction. Complete recovery occurs promptly after the withdrawal of the causative drug in most cases. The pathogenetic mechanism may be immunoallergic. Prolonged ductular or ductal cholestasis can follow drug-induced acute hepatitis despite prompt withdrawal of the offending drug. This syndrome, observed mainly with chlorpromazine and uncommonly with twenty other drugs, is characterized by the progressive disappearance of small bile ducts and by manifestations mimicking primary biliary cirrhosis. However, its prognosis appears to be better than that of primary biliary cirrhosis, the condition being reversible in the majority of cases or even subsiding completely. The mechanism is still unknown, but several features suggest some form of autoimmunity. Extrahepatic cholestasis related to sclerosing cholangitis is a frequent and long-term complication of intra-arterial infusion of floxuridine in patients treated for hepatic metastases from colorectal carcinoma. Although it may be reversible, floxuridine-induced sclerosing cholangitis has a poor prognosis and can lead to death in a few patients. The mechanism is probably related to the vascular supply of the common hepatic duct and its relationship to the perfusion territory of floxuridine.     

Vanishing bile duct syndrome in a patient with advanced AIDS

A 39-year-old HIV-infected woman developed signs and symptoms of obstructive jaundice and cholestasis. Serological tests were positive for cytomegalovirus (CMV) infection. There was no evidence of AIDS cholangiopathy in ultrasonography or magnetic resonance cholangiopancreatography (MRCP). A liver biopsy revealed marked ductopenia and the patient was diagnosed with vanishing bile duct syndrome, thought to be secondary to CMV infection as a result of profound immunosuppression. To the best of our knowledge, this is the first reported case of vanishing bile duct syndrome diagnosed in a patient with HIV/AIDS.     

Hodgkin's lymphoma-related vanishing bile duct syndrome: A case report and literature review

We report the case of a 38-year-old man who developed vanishing bile duct syndrome in association with Hodgkin's lymphoma. He was noted to have cervical lymphadenopathy and marked elevation of total serum bilirubin at diagnosis. He achieved complete remission with normalization of serum bilirubin after eight courses of Adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed with autologous hematopoietic cell transplantation. Consecutive liver biopsies performed at diagnosis and at the stage of complete remission revealed the disappearance and regeneration of interlobular bile ducts, respectively. Our case provides pathological evidence that Hodgkin's lymphoma-related vanishing bile duct syndrome is a reversible bile duct injury disease. Bilirubin is a reliable serum marker to monitor the treatment response of these cases. The mechanism to develop hyperbilirubinemia with vanishing bile duct in such a case of Hodgkin's lymphoma remains to be studied. A literature review was carried out.     

Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant

The clinical and pathological findings of four females with primary biliary cirrhosis (PBC) with an unusual and hitherto not well recognised course are reported. Patients suffered severe pruritus and weight loss with progressive icteric cholestasis which did not respond to such treatments as ursodeoxycholic acid and immunosuppressives. In all cases liver histology revealed marked bile duct loss without however significant fibrosis or cirrhosis. Further diagnostic studies and repeat biopsies confirmed the absence of liver cirrhosis as well as other potential causes of hyperbilirubinaemia. Comparison of the fibrosis-ductopenia relationship for our cases with that for a group of 101 non-cirrhotic PBC patients indicated that in the former the severity of bile duct loss relative to the amount of fibrosis was significantly higher. The proportion of portal triads containing an interlobular bile duct was 3%, 4%, 6%, and 10% compared with 45% (median; range 8.3--100%) for controls (p<0.001). Three patients received a liver transplant 6--7 years after the first manifestation of PBC because of progressive cholestasis, refractory pruritus, and weight loss, while the fourth patient is considering this option. In one case cirrhosis had developed at the time of transplantation while the others still had non-cirrhotic disease. These cases suggest that cholestatic jaundice in non-cirrhotic PBC may be secondary to extensive "premature" or accelerated intrahepatic bile duct loss. Although the extent of fibrosis may be limited initially, progression to cirrhosis appears to be inevitable in the long run. Despite intact protein synthesis and absence of cirrhotic complications, liver transplantation in the pre-cirrhotic stage for preventing malnutrition and to improve quality of life should be considered for these patients.     

腹腔镜胆囊切除术胆管损伤的诊断及处理

目的总结腹腔镜胆囊切除术（LC）胆管损伤的特点及诊断和处理的经验教训。方法回顾性分析23例LC胆管损伤的诊治情况。结果主胆管损伤12例，其中胆总管横断6例，肝总管横断2例，右肝管横断1例，胆总管横行夹闭1例，胆总管和肝总管裂孔各1例。副肝管损伤11例，其中迷走胆管损伤1例，细小副肝管损伤7例，较粗大的副肝管损伤3例。本组病例全部治愈。结论LC较开腹胆囊切除术更易发生胆管损伤，且损伤更为隐蔽、复杂，处理难，预后差。应根据不同的情况选择适当的手术方式．     

Clinical and pathological features of a prolonged type of acute intrahepatic cholestasis

Aim: We examined the clinical and pathological features of drug-induced acute intrahepatic cholestasis (AIC) to elucidate the pathogenesis of prolonged cases. Methods: Twenty-six cases of drug-induced AIC were divided into prolonged and non-prolonged groups. Serum bilirubin levels and other biochemical data were compared between the two groups. Biopsy liver specimens were examined by light and electron microscopy. The localization of multidrug resistance protein 2 (MRP2) was immunohistochemically assessed by the Envision technique. Results: The causative drugs of four prolonged cases were found to be tiopronin, chlorpromazine and diclofenac. Two of the patients either died or underwent liver transplantation. The maximal total bilirubin levels (35.2 +/-> 13.8 mg/dL) were significantly higher and a half-life of total bilirubin (78.8 +/-> 69.6 days) was markedly longer in the prolonged cases, in comparison to the non-prolonged cases (16.8 +/-> 8.1 mg/dL, 22.1 +/-> 12.7 days, respectively). The liverbiopsy specimens revealed canalicular cholestasis and a slight degree of lobular inflammation. In the prolonged cases, liver cell injury and cholestasis was marked, and the interlobular bile ducts disappeared in the portal triads. The reaction products of MRP2, recognized on the bile canaliculi in a control liver, were weakened and found in the pericanalicular vesicles in AIC. Conclusion: These results indicated disturbances in the canalicular bilirubin transport through MRP2 in the prolonged cases, resulting from severe cholestasis, liver cell injury and vanishing bile ducts. The histological findings of the liver at the acute icteric phase may be important to understand the pathogenesis and to predict the prognosis in AIC.     

IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver

Inflammatory destruction of intrahepatic bile ducts is a common cause of vanishing bile duct syndrome and cholestasis, often progressing to biliary cirrhosis and liver failure. However, the molecular mechanisms underlying the pathogenesis of inflammatory biliary disease are poorly understood. Here, we show that the two IkappaB kinases, IKK1/IKKalpha and IKK2/IKKbeta, display distinct collaborative and specific functions that are essential to protect the liver from cytokine toxicity and bile duct disease. Combined conditional ablation of IKK1 and IKK2, but not of each kinase alone, sensitized the liver to in vivo LPS challenge, uncovering a redundant function of the two IkappaB kinases in mediating canonical NF-kappaB signaling in hepatocytes and protecting the liver from TNF-induced failure. Unexpectedly, mice with combined ablation of IKK1 and IKK2 or IKK1 and NEMO spontaneously developed severe jaundice and fatal cholangitis characterized by inflammatory destruction of small portal bile ducts. This bile duct disease was caused by the combined impairment of canonical NF-kappaB signaling together with inhibition of IKK1-specific functions affecting the bile-blood barrier. These results reveal a novel function of the two IkappaB kinases in cooperatively regulating liver immune homeostasis and bile duct integrity and suggest that IKK signaling may be implicated in human biliary diseases.     

Vanishing bile duct syndrome associated with elevated pancreatic enzymes after short-term administration of amoxicillin

Amoxicillin is a widely used antibiotic, rarely being considered a cause of hepatic injury. We report the case of a 45-year-old woman who developed a vanishing bile duct syndrome 8 weeks after initiation of amoxicillin therapy. Liver biopsy showed destruction and loss of preformed bile ducts together with an inflammatory infiltrate involving eosinophilic leucocytes. Cholestasis was progressive despite prednisolone treatment and was accompanied by elevation of pancreatic enzymes. The patient died after 18 months from progressive liver failure. This case illustrates that amoxicillin alone can be a cause of progressive and ultimately fatal vanishing bile duct syndrome.     

Ductal regeneration in vanishing bile duct syndrome in Hodgkin's lymphoma

We present the case of a 17-year-old male patient with Hodgkin's lymphoma (nodular sclerosis) in the mediastinum. During the postoperative period treatment with erythromycin was started and the patient developed progressive jaundice and cholestasis. Treatment modified for the lymphoma was initiated, which achieved complete remission and subsequent improvement and resolution of the cholestasis. Histological study of the liver revealed massive loss of bile ducts. After resolution of the cholestasis, consecutive biopsies revealed ductal proliferation. The present report therefore illustrates a case of ductopenia or vanishing bile duct syndrome (VBDS) with ad integrum regeneration of the bile ducts simultaneous with lymphoma remission. Because the 2 possible causes, erythromycin toxicity and Hodgkin's lymphoma, occurred simultaneously, the etiology of the VBDS cannot be definitively established.     

Lack of association between cytomegalovirus infection, HLA matching and the vanishing bile duct syndrome after liver transplantation.

In this study we evaluated the association between cytomegalovirus infection alone or in relation to human leukocyte antigen matching and the development of vanishing bile duct syndrome, a form of chronic hepatic allograft rejection. A total of 81 consecutive liver transplant recipients were studied. Cytomegalovirus infection developed in 46 recipients (57%), and vanishing bile duct syndrome occurred in 9 recipients (11%). Cytomegalovirus infection developed in only five of the nine patients with vanishing bile duct syndrome. Univariate analysis of pretransplant recipient/donor cytomegalovirus serological tests and human leukocyte antigen typing showed they were not significant risk factors for the development of vanishing bile duct syndrome. Time-dependent analysis of cytomegalovirus infection after transplantation as a risk factor for vanishing bile duct syndrome, in a multivariate analysis with human leukocyte antigen match, showed no statistical significance. In our study, no association was found between cytomegalovirus infection alone or in relation to class I or II human leukocyte antigen match and the subsequent development of vanishing bile duct syndrome.