Reactive Bile Duct Research Articles

S3119 Patient With Autoimmune Hepatitis Requiring Liver Transplant: Case Report and Literature Review

Introduction: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease caused by autoimmune-induced damage to the hepatocytes. AIH is known for elevated anti-smooth muscle antibodies (ASMA) and serum globulin levels. A liver biopsy is needed for the diagnosis. Despite its favorable prognosis, few cases can progress to fulminant liver failure. Case Description/Methods: 71-year-old male maintained on Descovy as preexposure prophylaxis for HIV for 1 year, was admitted 3 consecutive times over 1 month due to fatigue and jaundice. He was noted to have elevated transaminase and bilirubin levels. His presentation was suspected to be secondary to Descovy. Abdominal ultrasound was notable for hepatomegaly otherwise normal. He reported social alcohol consumption. He denied acetaminophen or new medication use. PE showed stable vital signs with jaundiced skin and hepatomegaly. The laboratory workup is shown below. Descovy was stopped and he was discharged. He was readmitted 1 week later for worsening symptoms. Workup showed positive ASMA for which he underwent a liver biopsy which was consistent with AIH. Infectious workup was unremarkable. He was started on a prednisone taper. Liver enzymes stabilized and he was discharged with plans to start azathioprine as an outpatient. However, he was admitted 2 weeks later for abdominal pain and encephalopathy. His labs showed worsening bilirubin, INR, and creatinine levels. CT head and abdomen were unremarkable. Doppler ultrasound demonstrated patent hepatic vasculature. He was placed on IV hydration, lactulose, and rifaximin. Due to concerns for hepato-renal syndrome, midodrine, octreotide, and albumin were added. He had a liver transplant evaluation which he underwent successfully. After prolonged hospitalization, he was discharged to post-acute rehab with a regimen consisting of tacrolimus, azathioprine, and prednisone (Figure 1). Discussion: The initial treatment for AIH is glucocorticoid therapy. Azathioprine can be added in moderate to severe cases or when there is a contraindication from using high-dose steroids. Few studies showed that tacrolimus can be effective in some cases that do not respond to steroids. Response to treatment is assessed by improvement of symptoms, laboratory tests, and liver histology. A liver transplant remains a rare indication in AIH and is reserved for patients who do not respond to immunosuppressants or progress to fulminant liver failure. The recurrence rate is reported to be 20-40% with a possibility of developing de novo AIH in a few cases.Figure 1.: Image A is showing portal tract with reactive bile ducts, abundant plasma cells, and interface hepatitis (H&E stain, 10×). Image B is showing Lobular aggregate of plasma cells adjacent to a central vein and involving hepatocytes which show reactive changes including ballooning (H&E stain, 20×). Table 1. - Test Admission #1 Admission #2 Admission #3 Post-transplant Reference range AST 481 952 264 32 5-45 U/L ALT 1048 1284 501 61 12-78 U/L ALP 236 184 166 66 46-116 U/L Total bilirubin 15.29 36.00 42.02 0.68 46-116 U/L Direct bilirubin 11.47 26.99 30.82 0.24 0.00 - 0.20 mg/dL Total protein 7.5 7.2 6 7 6.4-8.2 g/dL Albumin 3.3 2.7 2.1 3.7 3.5-5.0 g/dL PT 14.5 17.9 44 13.5 11.5-14.5 seconds INR 1.13 1.49 5.04 1.07 0.84-1.19 BUN 20 19 107 39 5-25 mg/dL Creatinine 1.28 1.39 4.03 4.37 0.6-1.3 mg/dL eGFR 56 51 13 12 ml/min/1.73sq.m Hemoglobin 17 16.5 16.7 11.3 12.0-17.0 g/dL WBC 7.89 8.74 16.2 6.13 4.31-10.16 thousands/uL Platelets 125 118 165 165 149-390 thousands/uL Sodium 134 132 131 139 136-145 mmol/L Potassium 3.7 3.7 5.3 4.4 3.5-5.3 mmol/L Chloride 100 100 103 103 100-108 mmol/L Calcium 8.9 9.2 9.2 10.1 8.3-10.1 mmol/L Ammonia 31 24 53 N/A 11 - 35 umol/L ASMA 40 0-19 U AMA < 20 0-20 U ANA Negative Negative IMMUNOGLOBULIN AIMMUNOGLOBULIN G IMMUNOGLOBULIN M 101112393 50-500 mg/dL650-2000 mg/dL40-270 mg/dL Acetaminophen < 2 10-20 ug/ml Urine drug screen Negative Negative Ceruloplasmin 22.2 16-31 mg/dL A1 antitrypsin 131 90-200 mg/dL Viral hepatitis panel Negative Negative HIV 1/2 AB-AG Negative Negative AST: Aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; INR: international normalized ratio; PT: prothrombin time; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; WBC: white blood count; ASMA: Anti-smooth muscle antibody; AMA: anti-mitochondrial antibody; ANA: antinuclear antibody.

Mechanisms of ductular reaction in non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum caused in part by insulin resistance and genetic predisposition. This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage. Histologically, NAFLD is divided into several periods: simple steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. With the increasing prevalence of obesity and hyperlipidemia, NAFLD has become the main cause of chronic liver disease worldwide. As a result, the pathogenesis of this disease is drawing increasing attention. Ductular reaction (DR) is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes, cholangiocytes, and hepatic progenitor cells. Recently, DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis, providing new research and treatment options. This study reviews several DR signaling pathways, including Notch, Hippo/YAP-TAZ, Wnt/β-catenin, Hedgehog, HGF/c-Met, and TWEAK/Fn14, and their role in the occurrence and development of NASH.

Genetically Engineered Mouse Models of Liver Tumorigenesis Reveal a Wide Histological Spectrum of Neoplastic and Non-Neoplastic Liver Lesions.

Genetically engineered mouse models (GEMM) are an elegant tool to study liver carcinogenesis in vivo. Newly designed mouse models need detailed (histopathological) phenotyping when described for the first time to avoid misinterpretation and misconclusions. Many chemically induced models for hepatocarcinogenesis comprise a huge variety of histologically benign and malignant neoplastic, as well as non-neoplastic, lesions. Such comprehensive categorization data for GEMM are still missing. In this study, 874 microscopically categorized liver lesions from 369 macroscopically detected liver “tumors” from five different GEMM for liver tumorigenesis were included. The histologic spectrum of diagnosis included a wide range of both benign and malignant neoplastic (approx. 82%) and non-neoplastic (approx. 18%) lesions including hyperplasia, reactive bile duct changes or oval cell proliferations with huge variations among the various models and genetic backgrounds. Our study therefore critically demonstrates that models of liver tumorigenesis can harbor a huge variety of histopathologically distinct diagnosis and, depending on the genotype, notable variations are expectable. These findings are extremely important to warrant the correct application of GEMM in liver cancer research and clearly emphasize the role of basic histopathology as still being a crucial tool in modern biomedical research.

Ductular Reaction in Liver Diseases: Pathological Mechanisms and Translational Significances.

Ductular reaction (DR) is characterized by the proliferation of reactive bile ducts induced by liver injuries. DR is pathologically recognized as bile duct hyperplasia and is commonly observed in biliary disorders. It can also be identified in various liver disorders including nonalcoholic fatty liver disease. DR is associated with liver fibrosis and damage, and the extent of DR parallels to patient mortality. DR raises scientific interests because it is associated with transdifferentiation of liver cells and may play an important role in hepatic regeneration. The origin of active cells during DR can be cholangiocytes, hepatocytes, or hepatic progenitor cells, and associated signaling pathways could differ depending on the specific liver injury or animal models used in the study. Although further studies are needed to elucidate detailed mechanisms and the functional roles in liver diseases, DR can be a therapeutic target to inhibit liver fibrosis and to promote liver regeneration. This review summarizes previous studies of DR identified in patients and animal models as well as currently understood mechanisms of DR.

Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice

Cholangiocyte proliferation and ductular reaction contribute to the onset and progression of liver diseases. Little is known about the role of the transcription factor nuclear factor-κB (NF-κB) in this process. We investigated the activities of the RELB proto-oncogene NF-κB subunit in human cholangiocytes and in mouse models of liver disease characterized by a ductular reaction. We obtained liver tissue samples from patients with primary sclerosing cholangitis, primary biliary cholangitis, hepatitis B or C virus infection, autoimmune hepatitis, alcoholic liver disease, or without these diseases (controls) from a tissue bank in Germany. Tissues were analyzed by immunohistochemistry for levels of RELB and lymphotoxin β (LTB). We studied mice with liver parenchymal cell (LPC)-specific disruption of the cylindromatosis (CYLD) lysine 63 deubiquitinase gene (Cyld), with or without disruption of Relb (CyldΔLPC mice and Cyld/RelbΔLPC mice) and compared them with C57BL/6 mice (controls). Mice were fed 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or standard chow diets to induce biliary injury or were given injections of CCl4 to induce non-cholestatic liver fibrosis. Liver tissues were analyzed by histology, immunohistochemistry, immunoblots, in situ hybridization, and quantitative real-time polymerase chain reaction. Cholangiocytes were isolated from normal human liver, incubated with LTB receptor agonist, and transfected with small interfering RNAs to knock down RELB. In liver tissues from patients with primary sclerosing cholangitis, primary biliary cholangitis, chronic infection with hepatitis B or C virus, autoimmune hepatitis, or alcoholic liver disease, we detected increased nuclear translocation of RELB and increased levels of LTB in cholangiocytes that formed reactive bile ducts compared with control liver tissues. Human cholangiocytes, but not those with RELB knockdown, proliferated with exposure to LTB. The phenotype of CyldΔLPC mice, which included ductular reaction, oval cell activation, and biliary fibrosis, was completely lost from Cyld/RelbΔLPC mice. Compared with livers from control mice, livers from CyldΔLPC mice (but not Cyld/RelbΔLPC mice) had increased levels of mRNAs encoding cytokines (LTB; CD40; and tumor necrosis factor superfamily [TNFSF] members TNFSF11 [RANKL], TNFSF13B [BAFF], and TNFSF14 [LIGHT]) produced by reactive cholangiocytes. However, these strains of mice developed similar levels of liver fibrosis in response to CCl4 exposure. CyldΔLPC mice and Cyld/RelbΔLPC mice had improved liver function on the DDC diet compared with control mice fed the DDC diet. Reactive bile ducts in patients with chronic liver diseases have increased levels of LTB and nuclear translocation of RELB. RELB is required for the ductular reaction and development of biliary fibrosis in CyldΔLPC mice. Deletion of RELB and CYLD from LPCs protects mice from DDC-induced cholestatic liver fibrosis.

Novel immunohistochemical markers differentiate intrahepatic cholangiocarcinoma from benign bile duct lesions

AimsThe distinction between intrahepatic cholangiocarcinoma (ICC) and benign bile duct lesions can be challenging. Using our previously identified potential biomarkers for ICC, we examined whether these are useful for the...

Elevated CA19-9 Is Associated With Increased Mortality In A Prospective Cohort Of Hepatocellular Carcinoma Patients.

Objectives:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. CA19-9 is a glycoprotein that predicts poor prognosis in pancreatic and biliary malignancies. We evaluated it as a prognostic biomarker for patients with HCC.Methods:We prospectively enrolled 145 patients with HCC, diagnosed using American Association for Study of Liver Diseases criteria, between October 2008 and November 2012. We examined whether baseline serum CA19-9 levels predicted overall survival. We also examined immunostains of hepatic resections and explants of patients with elevated and normal serum CA19-9.Results:In a cohort of predominantly hepatitis C and B patients, CA19-9 ≥100 U/ml was associated with a 2.7-fold increased mortality (hazard ratio (HR): 2.72; 95% confidence interval (CI): 1.52–4.88, P<0.001). It remained a significant predictor (HR: 2.58; 95% CI: 1.41–4.72, P=0.002) in a multivariable model adjusted for Child–Pugh score, alpha-fetoprotein, Barcelona Clinic Liver Cancer stage, and Model for End-Stage Liver Disease. CA19-9 immunohistochemistry performed on a subset of liver resection and explant specimens showed increased CA19-9 immunostaining of non-tumor liver parenchyma in patients with elevated serum CA19-9. It also showed staining of native and reactive bile ducts, and of progenitor-like cells at the periphery of cirrhotic nodules.Conclusions:Elevated serum CA19-9 ≥100 U/ml is an independent predictor of poor overall survival in this hypothesis-generating study. The unfavorable prognosis seen with elevated serum levels may be related to progenitor-like cells in the non-tumor liver.

Intrahepatic Clear Cell Cholangiocarcinoma

Clear cell cholangiocarcinoma is a very unusual variant of peripheral bile duct carcinoma. We present 3 cases on which we performed a broad spectrum of immunohistochemical analysis. The tumors showed a glandular and trabecular growth pattern with abundant desmoplastic stroma and clear cell change of about 80% of the tumor cells. Positive expression of CK7 indicated a cholangiocellular origin. A primary hepatocellular carcinoma and metastatic clear cell tumors of the kidney, gastrointestinal tract, and the thyroid gland were excluded by absence of CK20, CD10, HepPar1, and TTF1. No mucin could be detected within the cytoplasm of the clear cells. Electronmicroscopy revealed only a few glycogen granula, but numerous cytoplasmic lipoid vacuoles as a possible explanation for the clear cell phenotype. All 3 tumors exhibited positive expression of CD56 (NCAM) in a significant amount of the clear cells. Beside the clear cell component, one tumor also showed an adenocarcinomalike and a well-differentiated tubular component. CD56 expression was detected in all 3 tumor areas. This report of 3 cases demonstrates that clear cell cholangiocarcinomas are not only of unusual histomorphology. They also show CD56 expression which is a very uncommon finding for intrahepatic cholangiocarcinomas. As CD56 expression is also found in reactive bile ducts and bile duct adenomas, one may speculate that these rare neoplasms may originate from reactive bile ducts or cholangiomatous lesions.

Pathology of renal and hepatic anomalies in Meckel syndrome

We describe 9 cases of Meckel syndrome (dysencephalia splanchnocystica), ranging in gestational age from 17 to 39 weeks. Five were liveborn, and the longest survival was 30 hours. Six of the 9 had all 3 elements of the classically defined triad, namely occipital encephalocele, renal cystic dysplasia, and postaxial polydactyly. The remaining 3 cases had only 2 elements of the triad. The renal abnormalities in the 9 cases resembled one another closely, varying only slightly in severity. They consisted of renal cystic dysplasia with different degrees of nephronic differentiation. The 8 available livers all contained intrahepatic bile duct anomalies. Seven of them had the classic "ductal plate malformation," as defined by Jorgensen [1977]; the remaining case had a less severe form of this malformation. The livers of the Meckel syndrome fetuses were compared to those of age-matched control fetuses, and it was concluded that the hepatic abnormality represents an arrested development of the intrahepatic biliary system at the stage of biliary cylinders with varying degrees of reactive bile duct proliferation, bile duct dilatation, portal fibrosis, and portal fibrous vascular obliteration superimposed on the arrested pattern. The case showing the least severe hepatic lesion also had the least severe renal lesion. The anomalies that were present are listed. The relationship of the different lesions to each other is briefly discussed. It was concluded that the hepatic lesion appears to be a consistent manifestation in Meckel syndrome and is of diagnostic value as the renal lesion has previously been shown to be.