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.     

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.     

Intrahepatic cholangiocarcinoma in a worker at an offset color proof‐printing company: An autopsy case report

A 40‐year‐old Japanese man visited our hospital after test results indicated elevated hepatobiliary enzymes. He had worked at a printing plant for 8 years and been exposed to organic solvents, including 1,2‐dichloropropane (1,2‐DCP) and dichloromethane (DCM). Abdominal computed tomography (CT) showed an intrahepatic tumor with dilation of the intrahepatic bile duct. He was diagnosed with intrahepatic cholangiocarcinoma. He had no known risk factors for cholangiocarcinoma. Extended left hepatectomy with lymph node dissection was performed and the tumor was histologically diagnosed as well‐differentiated adenocarcinoma. A histological examination also showed biliary intraepithelial preneoplastic lesions in non‐cancerous liver areas. Two years after surgery, the patient developed jaundice, esophageal varices and ascites. A CT examination showed liver cirrhosis without recurrence of the cholangiocarcinoma. Although a liver transplantation was planned as a therapeutic option for his liver cirrhosis, his liver failure progressed rapidly and he died before transplantation could be performed. At autopsy, fibrosis was found in the whole liver, especially in the wall of the bile duct and periductal area suggesting chronic bile duct injury due to exposure to organic solvents. Taken together, the current case may suggest that exposure to organic solvents, including 1,2‐DCP and DCM, is a risk factor for cholangiocarcinoma. Identifying risk factors for cholangiocarcinoma will help identify the mechanism and help prevent development of the disease.     

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)     

Case Report: Severe cholestatic jaundice induced by Epstein-Barr virus infection in the elderly

Infectious mononucleosis due to Epstein-Barr virus (EBV) is almost always a self-limited disease, most commonly seen in young adults. Hepatitis is a well-recognized complication of EBV infection that usually resolves spontaneously. Jaundice occasionally results from the unusual complication of autoimmune haemolytic anaemia rather than hepatitis. We report a 60-year-old man with severe cholestatic jaundice whose history, liver histology and laboratory findings suggested EBV infection. He also developed significant jaundice related to his hepatitis, but not to autoimmune haemolysis, a situation that led to diagnostic delay. Costly diagnostic laboratory tests and invasive procedures were performed to rule out a malignant extrahepatic biliary obstruction. Physicians need to be aware of this complication and EBV infection should be included in the differential diagnosis of cholestatic jaundice in the elderly.     

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 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.     

Idiopathic adulthood ductopenia

In 1981, a 26 year old man occasionally demonstrated elevated serum transaminase concentrations. He had no history of medication, or a personal or family history of jaundice, except for prolonged physiological jaundice as a neonate. Serum hepatitis B surface antigen, hepatitis C virus antibody and anti-mitochondrial antibody were absent. A wedge biopsy specimen revealed ductular proliferation, mild inflammation of the portal area and disappearance of bile ducts from 80% of the portal tracts. Serial sections demonstrated a vanishing bile duct. Endoscopic retrograde choledo-chopancreatography, portography and arteriography demonstrated no abnormalities. In 1994, the patient died of hepatic failure following a 12 year observation period. He was subsequently diagnosed with idiopathic adulthood ductopenia on the basis of the criteria proposed by Ludwig.     

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.     

Cytomegalovirus infection persists in the liver graft in the vanishing bile duct syndrome.

Cytomegalovirus infection is one factor implicated in the cause of the vanishing bile duct syndrome complicating liver transplantation. To further investigate the role of cytomegalovirus in this syndrome, we studied serial liver biopsy material by in situ hybridization for cytomegalovirus DNA using a highly sensitive technique that allows the localization of viral replication. Cytomegalovirus DNA was identified in hepatocytes in 10 of 12 patients with the vanishing bile duct syndrome, 1 of whom had no serological evidence of cytomegalovirus infection. It was also present in all 18 patients with uncomplicated cytomegalovirus infection but was not identified in any of 10 subjects with transplants who had neither complication. Nine of the patients in this series underwent a diagnostic liver biopsy at 1 wk and subsequently had cytomegalovirus infection develop; cytomegalovirus DNA was identified in liver tissue of all nine patients, indicating that cytomegalovirus replication commences at an early stage. In those with uncomplicated cytomegalovirus, infection occurred earlier (p less than 0.05) but was eliminated more quickly (p less than 0.0005), and the number of infected hepatocytes was greater (p less than 0.05) when compared with those with the vanishing bile duct syndrome; in these, cytomegalovirus DNA was detectable until death or retransplantation. Cytomegalovirus DNA was never identified in either biliary or endothelial tissue. These data indicate that the vanishing bile duct syndrome is associated with persistent cytomegalovirus replication within hepatocytes.     

Cholestatic syndrome with bile duct damage and loss in renal transplant recipients with HCV infection

BACKGROUND/AIMS: Bile duct cells are known to be susceptible to hepatitis B and C virus, while it has been recently suggested that hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may have a direct role in the pathogenesis of vanishing bile duct syndrome (VBDS) after liver transplantation. We report the development of a cholestatic syndrome associated with bile duct damage and loss in four HCV-infected renal transplant recipients. METHODS: All four patients were followed up biochemically, serologically and with consecutive liver biopsies. Serum HCV RNA was quantitatively assessed and genotyping was performed. RESULTS: Three patients were anti-HCV negative and one was anti-HCV/HBsAg positive at the time of transplantation and received the combination of methylprednisolone, azathioprine and cyclosporine A. Two patients became anti-HCV positive 1 year and one patient 3 years post-transplantation. Elevation of the cholestatic enzymes appeared simultaneously with seroconversion, or 2-4 years later, and was related to lesions of the small-sized interlobular bile ducts. Early bile duct lesions were characterized by degenerative changes of the epithelium. Late and more severe bile duct damage was associated with bile duct loss. The progression of the cholestatic syndrome coincided with high HCV RNA serum levels, while HCV genotype was 1a and 1b. Two patients (one with HBV co-infection) developed progressive VBDS and died of liver failure 2 and 3 years after biochemical onset. One patient, despite developing VBDS within a 10-month period, showed marked improvement of liver function after cessation of immunosuppression because of graft loss. The fourth patient, who had mild biochemical and histological bile duct changes, almost normalized liver function tests after withdrawal of azathioprine. CONCLUSION: A progressive cholestatic syndrome due to bile duct damage and loss may develop in renal transplant patients with HCV infection. The occurrence of the lesions after the appearance of anti-HCV antibodies and the high HCV RNA levels are indicative of viral involvement in the pathogenesis. Withdrawal of immunosuppressive therapy may have a beneficial effect on the outcome of the disease.     

A maxed-out liver: a case of acute-on-chronic liver failure

A 51-year-old man from Puerto Rico with Child-Turcotte-Pugh Class C decompensated cirrhosis due to genotype 1a chronic hepatitis C was referred for worsening jaundice and diuretic-resistant ascites. He began experiencing symptoms of hepatic decompensation 5 months prior to referral with new-onset ascites and spontaneous bacterial peritonitis, evolving into diuretic-resistant ascites, increasing jaundice, and a MELD increase from 12 to 29. During his hospitalization, his MELD score increased to >40 from a rapidly increasing international normalized ratio (INR) and evolving type 1 hepatorenal syndrome. Clinically, the patient appeared quite well despite such a high MELD score. After an extensive pretransplant evaluation and exclusion of infection, he underwent successful orthotopic liver transplantation. After histologic examination of the explanted liver, he subsequently admitted to 5 months of daily use of a detoxifying supplement known as MaxOne (?), containing D-ribose- L-cysteine, consistent with a drug-induced acute-on-chronic liver failure. The use of complementary and alternative medicines and its potential for causing drug-induced liver injury and acute-on chronic liver failure requires a high index of suspicion and increased awareness among health care providers.     

Newly developed autoimmune cholangitis without relapse of autoimmune pancreatitis after discontinuing prednisolone

A 57-year-old man presented with a 2-wk history of painless jaundice and weight loss. He had a large ill-defined enhancing mass-like lesion in the uncinate process of the pancreas with stricture of the distal common bile duct. Aspiration cytology of the pancreatic mass demonstrated inflammatory cells without evidence of malignancy. Total serum immunoglobulin G level was slightly elevated, but IgG4 level was normal. After the 2-wk 40 mg prednisolone trial, the patient’s symptoms and bilirubin level improved significantly. A follow-up computed tomography (CT) scan showed a dramatic resolution of the pancreatic lesion. A low dose steroid was continued. After six months he self-discontinued prednisolone for 3 wk, and was presented with jaundice again. A CT scan showed newly developed intrahepatic biliary dilatation and marked concentric wall thickening of the common hepatic duct and the proximal common bile duct without pancreatic aggravation. The patient’s IgG4 level was elevated to 2.51 g/L. Prednisolone was started again, after which his serum bilirubin level became normal and the thickening of the bile duct was resolved. This case suggests that autoimmune pancreatitis can progress to other organs that are not involved at the initial diagnosis, even with sustained pancreatic remission.     

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.     

NASOGALLBLADDER DRAINAGE FOR MIRIZZI’S SYNDROME

The authors experienced a case of Mirizzi’s syndrome successfully treated with endoscopic nasogallbladder drainage (ENGBD). The patient was a 63‐year‐old man. He was admitted with abdominal pain and jaundice. Laboratory data indicated leukocytosis and elevation of serum bilirubin level. Abdominal ultrasound showed marked swelling of gallbladder and debris in the gallbladder, therefore, the authors strongly suspected Mirizzi’s syndrome. He had past history of acute myocardial infarction and treated with anticoagulation therapy. Then, the authors couldn’t perform surgical removal or percutaneous transhepatic drainage, and tried endoscopic transpapillary drainage. Endoscopic retrograde cholangiopancreatography revealed smooth stricture in the superior portion of common bile duct and occlusion of the cystic duct, and ENGBD was then performed. After ENGBD, his complaints, laboratory data, swelling of gallbladder and stricture of common bile duct were all remarkably improved.     

Life-threatening hemorrhage from the papilla following stent removal (with video)

A 73-year-old man was admitted with acute cholangitis due to stent occlusion. He had had type B chronic hepatitis for 14 years but no liver cirrhosis or coagulopathy. The stent was placed 2 months previously for the treatment of obstructive jaundice due to a very large hepatoma. Emergency endoscopic retrograde cholangiopancreatography was performed. Immediately after removing the stent, using snare forceps through the working channel of the endoscope, spurting and continuous bleeding was seen from the papilla. Biliary deep cannulation was successfully performed using a conventional catheter and guidewire. The tip of the catheter was advanced into the left intrahepatic bile duct for pressure hemostasis. Ten minutes later, the bleeding completely stopped and a 10-Fr stent was inserted into the bile duct.     

A case of extrahepatic portal vein aneurysm with the remarkably bent bile duct by its displacement]

A 50-year-old man with type B liver cirrohosis was admitted with jaundice and ascites. He had undergone an operation for esophageal variceal rupture at another hospital. Abdominal CT scan and ultrasonography showed cystic dilatation of the extrahepatic portal vein, and Doppler ultrasonography showed it to be a portal vein aneurysm. After admission, jaundice progressed, and not only liver failure but also biliary tract obstruction was suspected as its etiology. Therefore, endoscopic retrograde cholangiography was performed, and it showed a remarkably bent extrahepatic bile duct thought to be caused by extrinsic compression. By combining the finding of endoscopic ultrasonography, we considered that the portal vein aneurysm had displaced the bile duct. We suspected that it also caused cholestasis and cholangitis.     

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.     

A quantitative analysis of T lymphocyte populations in human liver allografts undergoing rejection: the use of monoclonal antibodies and double immunolabeling

The aim of this study was to quantitate T-cell populations infiltrating portal tracts, bile ducts and hepatic lobules in 82 biopsy specimens from 25 patients after orthotopic liver transplantation. Biopsy specimens taken immediately after revascularization of the graft were used as controls. Patients studied include 18 with initial rejection episodes, 11 with unresolved rejection, five with vanishing bile duct syndrome and eight patients with other forms of liver injury. Quantitation was done in a blinded fashion for the first 20 biopsy specimens. A double immunolabeling technique was used to simultaneously immunolabel bile duct structures (with anti-major histocompatibility complex class II or antikeratins) and lymphoid populations (with anti-CD2, anti-CD4 or anti-CD8). This facilitated the accurate quantitation of intraepithelial lymphocytes within bile ducts. This technique also enabled simultaneous detection of CD4 and CD8 antigens on lymphocytes in portal tracts. The predominant lymphocyte subtype within biliary epithelium during acute and chronic rejection was of the CD2+/CD8+ phenotype. CD8+/CD4+ ratio in bile ducts was approximately 5:1 in acute, unresolved and chronic rejection. In vanishing bile duct syndrome, double immunolabeling enabled the detection of destroyed interlobular bile duct remnants that were not apparent on routine hematoxylin and eosin staining. Attached to some of these structures were CD8+ lymphocytes. Lobular CD8+ cells were not prominent in acute rejection but increased significantly in biopsy specimens from patients with unresolved and chronic rejection. In chronic rejection, a selective increase was seen in these CD8+ cells in centrizonal regions.(ABSTRACT TRUNCATED AT 250 WORDS)