Vanishing Bile Duct Syndrome Research Articles

Weathering the Cytokine Storm: Successful Liver Transplantation for Refractory Macrophage Activation Syndrome: 2017 Presidential Poster Award

Vanishing bile duct syndrome (VBDS) represents a group of acquired disorders leading to progressive destruction of the intrahepatic bile ducts. While multiple etiologies can result in this final common pathology; macrophage activation syndrome (MAS), a multisystemic inflammatory disorder, can rarely present as VBDS. Role of liver transplant (LT) for VBDS in MAS is not well-defined due to a paucity of experience, and is controversial due to a theoretical risk of post-transplant recurrence. A 36 year-old previously healthy male was admitted with a 2-week history of high fever, myalgia, sore throat and nausea. Physical exam was significant for bilateral iridouveitis and truncal maculopapular rash. Blood tests showed leukocytosis, direct hyperbilirubinemia, elevated transaminases, ferritin, erythrocyte sedimentation rate and C-reactive protein. Abdominal ultrasound and magnetic resonance scans were normal. Infectious causes were excluded by extensive pertinent testing. A working diagnosis of adult onset Still's disease (AOSD) was made. The subsequent labs showed elevated triglycerides and soluble interleukin-2 receptor (sIL2R). A bone marrow biopsy showed hemophagocytic lymphohistiocytosis. Liver biopsy showed near-complete loss of interlobular bile ducts without ductular reaction and minimal inflammation. PET scan was negative for malignancy. A diagnosis of VBDS and MAS in the setting of AOSD was made. He was treated sequentially with pulsed steroids, anakinra, adalimumab and rituximab but did not improve. A 2nd liver biopsy 6 months later showed persistent loss of interlobular bile ducts. He then underwent plasmapheresis with intravenous immunoglobulins; followed by cyclosporine and alemtuzumab. His sIL2R improved but he developed lymphopenia with bacteremia; all immunosuppression except steroids was stopped. Two months later he was admitted with acute kidney injury function and active MAS with ferritin of 16,700 ng/ml, and underwent successful liver transplant with an extended criteria donor liver. The explanted liver showed near-complete loss of interlobular bile ducts without ductular reaction, and focal necrosis. LT may be considered for treatment-refractory hepatic involvement from MAS. It has been previously reported in 4 adult patients with MAS, and 3 are alive at the time of reporting. Our patient remains well 2 years post-LT without recurrence. Presence of active MAS should not be a contraindication and should not delay the LT when indicated.

“Bile Ducts: Now You See Them, Now You Donʼt!” - A Case of Vanishing Bile Duct Syndrome in HIV/AIDS

“Bile Ducts: Now You See Them, Now You Donʼt!” - A Case of Vanishing Bile Duct Syndrome in HIV/AIDS

Pseudohyponatremia Secondary to Cholestasis in a Patient With Drug-Induced Liver Injury

Pseudohyponatremia secondary to cholestasis may occur in patients with biliary obstruction who have markedly elevated total serum cholesterol and lipoprotein-X. A 69-year-old male patient, recently diagnosed with biopsy-proven drug-induced liver injury secondary to sulfamethoxazole/trimethoprim, presented with asymptomatic hyponatremia. Physical exam was unremarkable with no signs of hypo- or hypervolemia. His past medical history was significant for IgG-4 related pachymeningitis, Crohn's Disease (in remission off medications), atrial fibrillation, type 2 diabetes mellitus and hypertension. His home medications were notable for prednisone, quinapril, warfarin, insulin glargine and lispro. The laboratory data was notable for sodium=119 mmol/L, glucose 142 mg/dL, AST=397 U/L, ALT=1366 U/L, Alkaline Phosphatase=554 U/L, bilirubin=34 mg/dL and INR= 2.6. Serum potassium, chloride, blood osmolality, urine osmolality, urine sodium, urine creatinine and antidiuretic hormone levels were within normal range. His lipid panel was remarkable for total cholesterol=1041 mg/dL, LDL cholesterol= 992 mg/dL, VLDV cholesterol=38 mg/dL, HDL cholesterol= 11 mg/dL and triglyceride=190 mg/dL. Lipoprotein-X was not able to be assessed due to lack of available laboratory testing. The patient experienced a protracted course related to drug-induced cholestatic liver injury, and he did not improve with supportive measures or with ursodeoxycholic acid. His severe cholestasis was thought to be the result of drug-induced vanishing bile duct syndrome. The total cholesterol level remained markedly elevated and the sodium level was persistently low, and he eventually required liver transplantation. Postoperatively, the patient's cholesterol and sodium levels both normalized. Although uncommon, marked hypercholesterolemia in patients with severe cholestasis can cause pseudohyponatremia. This effect should be considered in the differential diagnosis of hyponatremia prior to initiation of any therapies.

Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury

IntroductionHepatotoxicity from T-cell checkpoint blockade is an increasingly common immune-related adverse event, but remains poorly characterised and can be challenging to manage. Such toxicity is generally considered to resemble autoimmune hepatitis, although this assumption is extrapolated from limited clinicopathological reports of anti-cytotoxic T-lymphocyte-associated protein 4-induced hepatotoxicity.MethodsHere we report, with full clinicopathological correlation, three cases of T-cell checkpoint inhibitor-induced hepatotoxicity associated with anti-programmed cell death protein 1 agents.ResultsWe find that a major feature of these cases is biliary injury, including a unique case of vanishing bile duct syndrome, and that such toxicity was poorly responsive to long-term immunosuppression (corticosteroids and mycophenolate mofetil). Any potential benefits of long-term immunosuppression in these cases were outweighed by therapy-related complications.DiscussionWe discuss potential aetiologies and risk factors for immune-mediated biliary toxicity in the context of the limited literature in this field, and provide guidance for the investigation and supportive management of affected patients.

Drug-induced cholestasis.

Cholestatic drug‐induced liver injury (DILI) can be a diagnostic challenge due to a large differential diagnosis, variability in clinical presentation, and lack of serologic biomarkers associated with this condition. The clinical presentation of drug‐induced cholestasis includes bland cholestasis, cholestatic hepatitis, secondary sclerosing cholangitis, and vanishing bile duct syndrome. The associate mortality of cholestatic DILI can be as high as 10%, and thus prompt recognition and removal of the offending agent is of critical importance. Several risk factors have been identified for drug‐induced cholestasis, including older age, genetic determinants, and properties of certain medications. Antibiotics, particularly amoxicillin/clavulanate, remain the predominant cause of cholestatic DILI, although a variety of other medications associated with this condition have been identified. In this review, we summarize the presentation, clinical approach, risk factors, implicated medications, and management of drug‐induced cholestatic liver injury. (Hepatology Communications 2017;1:726–735)

Liver Involvement in Hodgkin's Lymphoma: Types of Injuries and Therapeutic Implications

The hepatocytolysis raises questions on following therapeutic conduct when it occurs during chemotherapy for Hodgkin's lymphoma, expression of its liver toxicity. But the onset of primary liver Hodgkin's lymphoma, including the form manifested by acute liver failure, poses even greater problems, as in the case of occurrence of vanishing bile duct syndrome - expression of a paraneoplastic syndrome, hemophagocytic lymphohistiocytosis, peliosis hepatis or association of lymphoma with infection with hepatitis viruses or human immunodeficiency virus or different autoimmune diseases. This review summarizes the clinical experience acquired on the relationship between Hodgkin's lymphoma and liver, from the point of view of clinical manifestations, used treatments and clinical evolution. Suggestions on the course of treatment in patients with Hodgkin's lymphoma and liver damage have been formulated starting from the metabolism and elimination of chemotherapy drugs and taking into account the clinical experience of published clinical trials and cases. This review is a synthesis of knowledge obtained in this field, during the time, of therapeutic possibilities and limits, and formulates potential future milestones for research.

Clinicopathologic features of drug-induced vanishing bile duct syndrome

Vanishing bile duct syndrome (VBDS) manifests as progressive destruction and disappearance of the intrahepatic bile duct caused by various factors and cholestasis. VBDS associated with drug-induced liver injury (D-VBDS) is an important etiology of VBDS, and immune disorder or immune imbalance may be the main pathogenesis. According to its clinical symptoms, serological markers, and course of the disease, D-VBDS is classified into major form and minor form, and its clinical features are based on various pathomorphological findings. Its prognosis is associated various factors including regeneration of bile duct cells, number of bile duct injuries, level and range of bile duct injury, bile duct proliferation, and compensatory shunt of bile duct branches. This disease has various clinical outcomes; most patients have good prognosis after drug withdrawal, and some patients may experience cholestatic cirrhosis, liver failure, and even death. Due to the clinical manifestation and biochemical changes are similar to the primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), it need to identify by clinical physician.

Lipoprotein-X in cholestatic patients causes xanthomas and promotes foam cell formation in human macrophages

Lipoprotein-X (Lp-X) is an abnormal phospholipid-rich lipoprotein found in patients with cholestatic liver disease. Some patients exhibit skin xanthomas and severe hyperlipidemia. We investigated whether Lp-X induces foam cell formation in human-derived macrophages. To compare the atherogenic properties of Lp-X and modified LDL, we isolated Lp-X from 2 patients who had drug-induced cholestasis and xanthoma striata in the interphalangeal folds. We prepared oxidized LDL and acetylated LDL from healthy volunteers for the positive control experiments. When human monocyte-derived macrophages were incubated with these lipoproteins, the isolated Lp-X induced more prominent lipid accumulation than oxidized LDL or acetylated LDL. One case underwent liver biopsy, with the bile ducts showing marked damage, fulfilling the criteria for vanishing bile duct syndrome. The other case was clinically diagnosed as drug-induced hypersensitivity syndrome. In both cases, Lp-X levels decreased markedly and the xanthomas disappeared completely after the improvement of cholestasis. This study indicates that Lp-X induces foam cell formation in human-derived macrophages. Our findings strongly suggest that persistently elevated Lp-X may cause xanthomas.

Vanishing Bile Duct Syndrome

Vanishing Bile Duct Syndrome

A Rare Case of Minoxidil Associated Vanishing Bile Duct Syndrome

Minoxidil, an antihypertensive agent used in severe refractory hypertension is metabolized by the liver and excreted by the kidneys. It is not known to be hepatotoxic but dose adjustments are required in renal failure. We report a case of a 73 year old female with elevated bilirubin and unresolving pruritus of 2 months duration. She complained of rash, pruritus, yellow discoloration of eyes and dark urine. She denied abdominal pain, anorexia, nausea, vomiting, fever or confusion. She also denied use of alcohol, illicit drugs, herbals or over-the-counter medications. Patient was on long term treatment with clonidine, losartan-hydrochlorothiazide, metoprolol, and insulin detemir. She started hemodialysis three months prior for end stage renal disease. Minoxidil was initiated two months prior for uncontrolled hypertension, which coincided with the onset of her symptoms. Vital signs were normal except an elevated blood pressure. Physical examination was unremarkable but for sclera icterus and maculopapular rash on her back and arms. Laboratory showed mild normocytic anemia, normal platelets, and white cell count 13,700/cmm, blood urea nitrogen 28 mg/dl, creatinine 4.7 mg/dl, total bilirubin 23.6 mg/dl, direct bilirubin > 15 mg/dl, aspartate aminotransferase 109 U/L, alanine aminotransferase 101 U/L, albumin 2.9 g/dl, and alkaline phosphatase 759 U/L. She was diagnosed with cholestatic hepatitis. Abdominal computed tomography showed cholelithiasis with normal bile ducts. Hepatitis panel, including AMA, ANA, IgG, ACE levels were normal. Antibiotics and supportive treatment were initiated. Magnetic resonance cholangiopancreatography showed no abnormalities. Bilirubin and transaminases remained elevated despite regular hemodialysis. Liver biopsy was attempted, during which she suffered peritoneal bleeding, hypotension and ultimately cardiac arrest. Subsequent mesenteric angiogram and embolization were unsuccessful. Patient expired the next day after multiple cardiac arrests. Liver biopsy at autopsy revealed vanishing biliary duct syndrome (VBDS). VBDS, also known as ductopenia, is associated with destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Patients can present with fatigue, anorexia, pruritus, abnormal liver chemistries with cholestatasis.Imaging and laboratory values aide in diagnosis, however liver biopsy is confirmatory. This case illustrates an importance to consider VBDS as a differential diagnosis of cholestasis.

Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis After Minimal Change Disease

Vanishing Bile Duct Syndrome with Hemophagocytic Lymphohistiocytosis After Minimal Change Disease

Vanishing Bile Duct Syndrome Leading to Biliary Cirrhosis in a Patient With Remote History of Non-Hodgkin Lymphoma

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.

Cholestasis: A Paraneoplastic Syndrome

Hodgkin's lymphoma(HL) must be included as a differential in cases of fever of unknown origin and idiopathic cholestasis with non specific hepatitis on liver biopsy. Early bone marrow examination in such cases may allow timely therapy and improve morbidity and mortality. A 60-year-old African American man presented with a two month history of recurrent high grade fever and progressive jaundice. He was treated multiple times with empiric antibiotics. Past history was significant for hypertension, alcohol and tobacco use. He denied any history of travel, new medication intake or prior malignancy. Examination revealed pale, emaciated and weak old man with no lymphade-nopathy and normal chest, cardiovascular and abdominal examination. Initial lab results revealed mild normochromic anemia and cholestatic pattern of hepatic injury with normal hepatitis serology. Elevated 5-Nucleotidase levels confirmed alkaline phosphatase to be of hepatic origin. MRCP showed normal hepatobiliary system. Enhanced CT chest and abdomen revealed small confluent lymphadenopathy with calcifications in subcarinal and peri-hilar regions. On liver biopsy we found nonspecific chronic hepatitis with mild portal fibrosis and no steatosis or granulomas with no features suggestive of autoimmune hepatitis, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis or viral hepatitis. On further evaluation, bone marrow biopsy revealed hypercellular marrow with fibrohistiocytic infiltrates and large atypical cells suggestive of lymphoma. Immuno-staining of marrow confirmed large atypical cells to be Reed-Sternberg cells (CD 30+, CD15+, CD 45-, CD20-) confirming classical HL. Patient was started on chemotherapy and following two cycles, LFTs started to improve and normalized. Patient initially tolerated chemotherapy well until he developed septic shock and multiorgan failure and eventually passed away. HL has bimodal incidence affecting ages 15-35 and >50 years. It is associated with a diverse array of paraneoplastic syndromes ranging from complex neurological syndromes to rare entities like vanishing bile duct syndrome and idiopathic cholestasis. However, other etiologies of intrahepatic cholestasis should be ruled out like alcohol, viral, drug induced, PBC and PSC. Mortality can be as high as 65% from liver involvement. Intrahepatic cholestasis is an uncommon presentation of HL (3-13% of cases), and even more so rare are cases with negative liver biopsy despite clinical picture consistent with a cholestatic pattern of liver injury. Thus, liver biopsy may not necessary reflect the underlying etiology as highlighted by our case. Although treatment of underlying HL results in normalization of liver enzymes, however, its prognostic value remains undetermined.

Drug Induced Vanishing Bile Duct Syndrome

Drug Induced Vanishing Bile Duct Syndrome

A Rare Case of Vanishing Bile Duct Syndrome in a Patient With Hodgkinʼs Lymphoma

A Rare Case of Vanishing Bile Duct Syndrome in a Patient With Hodgkinʼs Lymphoma

Inhibition of MDR3 Activity in Human Hepatocytes by Drugs Associated with Liver Injury.

MDR3 dysfunction is associated with liver diseases. We report here a novel MDR3 activity assay involving in situ biosynthesis in primary hepatocytes of deuterium (d9)-labeled PC and LC-MS/MS determination of transported extracellular PC-d9. Several drugs associated with DILI such as chlorpromazine, imipramine, itraconazole, haloperidol, ketoconazole, sequinavir, clotrimazole, ritonavir, and troglitazone inhibit MDR3 activity. MDR3 inhibition may play an important role in drug-induced cholestasis and vanishing bile duct syndrome. Several lines of evidence demonstrate that the reported assay is physiologically relevant and can be used to assess the potential of chemical entities and their metabolites to modulate MDR3 activity and/or PC biosynthesis in hepatocytes.

Secondary Sclerosing Cholangitis and Hodgkin's Lymphoma.

CONTEXTLiver damage is relatively common in patients affected by HL, but paraneoplastic cholestasis is an uncommon presenting symptom in HL.CASE REPORTWe report the case of a 38-year-old man who came to our hospital with jaundice, pruritis, nausea, vomiting, weight loss, and recurrent episodes of fever without any hepatosplenomegaly or lymphadenopathy. Laboratory findings showed abnormal liver functioning with mixed hepatocellular and cholestatic patterns. Sonographic evaluation of the biliary tract was normal. We ruled out viral infections, autoimmune process, and hemochromatosis. The patient was put on ursobile and NAC (N-acetyl-systeine) and prednisolone treatment. In magnetic resonance cholangiopancreatography examination, there were multiple strictures in the intrahepatic and extrahepatic bile ducts with mild dilatation. Histologic finding of liver biopsy was compatible with sclerosing cholangitis or drug-induced cholestasis. General condition and laboratory examination results of the patient became better, but we found lymph-adenopathy on monthly follow-up examination. Histological finding of the lymph node was compatible with HL.CONCLUSIONThis report emphasizes that HL can be presented with different paraneoplastic symptoms and that one of them is secondary sclerosing cholangitis. It has better prognosis than vanishing bile duct syndrome, and perhaps steroid treatment can be suggested.

Infliximab/Plasmapheresis in Vanishing Bile Duct Syndrome Secondary to Toxic Epidermal Necrolysis

Vanishing bile duct syndrome (VBDS) is a rare disorder characterized by loss of interlobular bile ducts and progressive worsening cholestasis. The acute presentation of this disease is typically associated with a drug hypersensitivity and Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN). The mainstay of treatment has been ursodeoxycholic acid with mixed results from immunosuppressive regimens. Anti-tumor necrosis factor-α and plasmapheresis have been speculated to be of potential benefit. It is hoped that early identification and intervention in VBDS secondary to Stevens-Johnson syndrome/TEN with continued reporting will lead to better regimens and outcomes. Our case report details the first reported use of infliximab and plasmapheresis, in addition to steroids, in a patient with VBDS secondary to TEN, as well as a literature review that supports a mechanism for why these modalities could be effective treatments. Unfortunately, our patient died, and the use of these therapies had an unclear benefit on his liver and skin disease. We hope that additional work can be published to confirm or refute their utility in the treatment of these diseases.

Levofloxacin as a Cause of Vanishing Bile Duct Syndrome

Levofloxacin as a Cause of Vanishing Bile Duct Syndrome

One case of vanishing bile duct syndrome

One case of vanishing bile duct syndrome