Bile Duct Loss Research Articles

Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: Interobserver agreement

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3, and HA0-3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

Is there a role for tetrathiomolybdate in the treatment of primary biliary cirrhosis?

I n this issue of Translational Research, Askari et al 1 provide the results of a double-blinded, randomized, clinical trial for the treatment of primary biliary cirrhosis (PBC) with tetrathiomolybdate (TM). A total of 28 patients were randomized to either ursodeoxycholic acid (UDCA) and TM or to UDCA and placebo, and these patients were followed for a median of 14 months. PBC is a chronic cholestatic liver disease that predominantly involves middle-aged women; it is characterized by portal inflammation and loss of the epithelial cells in the small and middle-sized bile ducts, which occur at different rates and with varying degrees of severity in different patients. If untreated, PBC is a slowly progressive disease that causes substantial loss of intrahepatic bile ducts and ultimately results in advanced fibrosis, cirrhosis, and liver failure. As such,

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC.

Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study

This long-term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT). We reviewed "blindly" allograft biopsy specimens of women who underwent transplantation for PBC (n = 84), and women who received a transplant for chronic hepatitis C virus infection (CHCV ) (n = 108). All needle liver biopsy specimens obtained more than 6 months post-OLT were examined, including 83 specimens from 44 PBC patients and 152 specimens from 58 CHCV patients. Granulomatous destructive cholangitis was found in five biopsies from four PBC patients (P = 0.0048). Non-necrotizing epithelioid cell granulomas were present in four biopsies from four PBC patients, and in two biopsies from one CHCV patient. Piecemeal necrosis (P = 0.0002), lobular necroinflammatory activity (P < 0.0001), steatosis (P < 0.0001) and fibrosis (P < 0.0001) were more prevalent in CHCV patients than PBC patients. Four PBC patients developed histologic evidence of autoimmune hepatitis (AIH), at a mean time of 3.66 years post-OLT. One of these patients had histologic features of AIH/PBC overlap syndrome. All four patients developed bridging fibrosis (n = 2) or cirrhosis (n = 2). No other PBC patient had evidence of cirrhosis after OLT. Histologic findings indicative of recurrent PBC were present in 15.9% of the PBC patients undergoing biopsy in this series. However, this group of patients did not suffer significant bile duct loss or fibrosis, as compared to the control group, suggesting that recurrent PBC is a mild or slowly progressive disease. Histologic evidence of AIH was observed in allograft biopsies of some PBC patients.

Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by progressive loss of intrahepatic small bile ducts. Cellular immune mechanisms involving T cell reaction are thought to be involved significantly in the pathogenesis of PBC. Recent studies have independently revealed enhanced T helper type 17 (Th17) response and weakened T regulatory cell (T(reg)) response in some autoimmune diseases, indicating a role of Th17/T(reg) imbalance in the pathogenesis of autoimmunity. This prompted us to investigate whether the Th17/T(reg) balance was broken in the peripheral blood of patients with PBC and, if it was, what cytokine circumstances might contribute to this imbalance. The expression of 11 Th17/T(reg) differentiation-related genes and serum concentrations of the corresponding cytokines in 36 patients with PBC, 28 patients with chronic hepatitis B and 28 healthy controls were measured by real-time quantitative-polymerase chain reaction and enzyme-linked immunosorbent assay respectively. Peripheral Th17 and T(reg) cells were analysed by flow cytometry. Th17-related cytokines were increased significantly in patients with PBC. Consistent with the cytokine profile, the Th17 cell population and retinoid-related orphan receptor gammat expression were increased markedly. In contrast, the T(reg) cell population and forkhead box P3 expression were decreased dramatically in the peripheral blood of patients with PBC. Our study revealed that the Th17/T(reg) imbalance, both cytokine profile and cell numbers, exists in patients with PBC, suggesting its potential role in the breakdown of immune self-tolerance in PBC. Interleukin-23, which characterized the imbalanced cytokine profile, may play an essential role in Th17-related human autoimmunity.

The Clinicopathological Parameters for Making the Differential Diagnosis of Neonatal Cholestasis

Background : The diseases that cause neonatal cholestasis display several overlapping clinical feature. Making the differential diagnosis using liver biopsy specimens from infants with neonatal cholestasis is important for delivering the proper treatment. Methods : We assessed the clinical manifestations, laboratory data, and histopathologic features of the pretreatment liver biopsy specimens from patients suffering with biliary atresia (n=66), intrahepatic bile duct paucity (n=15), and neonatal hepatitis (n=21). Results : The gender distribution was nearly equal for the patients with biliary atresia and intrahepatic bile duct paucity, whereas males predominated for the cases of neonatal hepatitis. Only the gamma-glutamyl transferase level differed significantly amongst the groups. The diagnostic features for making the differential diagnosis of bile duct lesions included marked bile ductular proliferation, severe fibrosis, and bile duct loss. The difference of the average percentage of portal tracts with bile duct loss was statistically significant between the patients with intrahepatic bile duct paucity (73.9%) and those patients with neonatal hepatitis (39.1%) (p<0.001). Conclusions : Bile ductular proliferation, bile duct loss, and advanced fibrosis are useful for the differential diagnosis of neonatal cholestasis. Moreover, stricter diagnostic criteria for bile duct loss (more than 2/3 of bile ducts) should be applied for the definitive diagnosis of intrahepatic bile duct paucity, because bile duct loss also frequently occurs in infants suffering with neonatal hepatitis.

A Case of Idiopathic Adulthood Ductopenia

Idiopathic adulthood ductopenia (IAD) is a chronic cholestatic liver disease of unknown etiology characterized by adult onset, an absence of autoantibodies, inflammatory bowel disease, and a loss of interlobular bile ducts. In the present report, a case fulfilling the IAD criteria is described. A 19-year-old man was admitted to the hospital for persistent elevation of transaminases and alkaline phosphatase without clinical symptoms. Viral hepatitis markers and autoantibodies were absent. The patient had a normal extrahepatic biliary tree and had no evidence of inflammatory bowel disease. A liver biopsy specimen showed absence of interlobular bile ducts from 58% of the portal tracts. He was diagnosed with IAD and was treated with ursodeoxycholic acid.

Cyclosporine, but Not mTOR Inhibitors, Hampers the Reconstitution of Bone Marrow-Derived Tregs in Long-Term Complete Donor chimeras .

Chronic graft-versus-host disease (GVHD) is the most common complication in the late stage after allogenic hematopoietic-stem-cell-transplantation (SCT), but the pathophysiology and treatment strategy of chronic GVHD remain poorly defined. Prolonged administration of cyclosporine (CSA) did not decrease the risk of chronic GVHD. Recent studies using a mouse model have shown that regulatory T cells (Tregs) can influence immune responses, and Tregs in the grafts can prevent acute GVHD when injected together with donor T cells. However, it is not known whether Tregs remain in the grafts in the late stage of SCT and play a role in preventing chronic GVHD.First, we examined the origin of Tregs using a major histocompatibility complex (MHC) mismatched mouse SCT model. Lethally irradiated C3H/HeN(H-2k) recipient mice received 10x106 T-cell-depleted bone marrow (BM) cells from B6.Ly-5a(H-2b, CD45.1) mice and 1x106 spleen cells from C57BL/6(B6, H-2b, CD45.2) mice. Spleen cells were collected from SCT recipient mice at serial time points and subjected to fluorescence-activated cell sorting (FACS) analysis. Transplanted mice displayed complete donor hematopoietic chimerism and mild acute GVHD at day14. On day 21 (early stage) after SCT, host type Tregs (CD4+FoxP3+ H-2k) were no longer detectable, and most of the Tregs (83±3%) were derived from donor spleen Tregs (H-2b, CD45.2). However, the homeostatic expansion of spleen Tregs gradually contracted and newly arising donor BM-derived Tregs (H-2b CD45.1) became dominant (93.8±0.5%) in the late stage of SCT (day 120). As in the spleen, BM-derived Tregs reconstitution in the late stage was seen in the thymus and mesenteric lymph nodes. Moreover, in a minor MHC-mismatched SCT model (B6 into C3H.SW), Tregs in the late stage were derived from donor BM cells (97.0±0.2%). These BM-derived Tregs suppress alloreactivity in the same manner as naturally occurring Tregs isolated from naïve mice in the MLR.Next, we compared the effects of CSA and the mTOR inhibitor rapamycin (RAPA) on Tregs reconstitution. Mice receiving CSA or RAPA showed the same Tregs reconstitution pattern: in the early and late stages, Tregs were derived from donor spleen and BM cells, respectively. However, the number of Tregs in the spleen was reduced significantly in mice receiving CSA, as compared to control mice receiving phosphate-buffered saline (PBS; 1.3±0.2x106 vs. 2.4±0.6x106) at day 110. In particular, the number of Tregs in the thymus was reduced dramatically in mice receiving CSA (0.7±0.2 x105 vs. 2.6±0.5x105 , P<0.02). By contrast, the numbers of Tregs in both the thymus and spleen from RAPA-treated mice were the same as those from PBS-treated mice. Mice treated with everolimus, another mTOR inhibitor, also showed no reduction in the numbers of Tregs. Histologic examination revealed that CSA-treated mice showed pathogenic features of chronic GVHD, including sclerodermatous skin changes, bile duct loss, fibrosis in the portal area of the liver and fibrosis and atrophy of acinar tissue in the salivary glands, while RAPA-treated mice showed no sign of chronic GVHD.Our findings indicate that a) Tregs cannot remain in grafts in the late stage, and newly arising donor BM-derived Tregs became dominant; b) CSA hampers BM-derived Tregs reconstitution and may be associated with the development of chronic GVHD; and c) mTOR inhibitors do not hamper Tregs reconstitution and might prove beneficial for the treatment of both acute and chronic GVHD. [Display omitted]

Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis

Background and aims:Progression of chronic cholestatic disorders towards ductopenia results from the dysregulation of cholangiocyte survival, with cell death by apoptosis prevailing over compensatory proliferation. Currently, no therapy is available...

Hedgehog signaling in biliary fibrosis

Congenital and acquired diseases of the biliary tree, or cholangiopathies, represent a significant source of morbidity and mortality in both children and adults. In late stages of the disease, cholangiocytes can no longer proliferate, resulting in loss of bile ducts, increased fibrosis, and ultimately cirrhosis and liver failure. Epithelial-mesenchymal transition has been proposed as a potential mechanism underlying both cholangiocyte proliferation and fibrogenesis in biliary diseases. In this issue of the JCI, using a myofibroblast-cholangiocyte coculture system and genetically modified mice, Omenetti and colleagues present evidence supporting the importance of paracrine hedgehog signaling between the two cell types and increased expression of mesenchymal markers in cholangiocytes (see the related article beginning on page 3331). These findings set the stage for future studies to further investigate the contribution of hedgehog signaling in both cholangiocyte repair and fibrogenesis in biliary diseases.

Secondary sclerosing cholangitis after intensive care unit treatment: clues to the histopathological differential diagnosis

Secondary sclerosing cholangitis (SSC) is a chronic cholestatic disorder caused by mechanical, infectious, toxic, or ischemic factors. A new variant of SSC occurring after long-term treatment in intensive care units (ICU) has been recently described and characterized from the clinical point of view. The aim of this study was the histomorphological characterization of ICU-treatment-related SSC (ICU-SSC) and the definition of histological changes occurring over time based on the morphological findings. Liver biopsies of ten patients affected by ICU-SSC obtained at different time points (1.5 to 57 months) after the initial injury were analyzed. The main morphological alterations included degenerative changes of portal bile ducts, portal edema, inflammation, and fibrosis as well as biliary interface activity and bilirubinostasis. Perivenular necroses and bile infarcts were found in eight and six patients, respectively. Bile duct loss was not observed. No correlation between morphological features of biopsies and liver chemistry tests or outcome could be established. Based on the morphological observation, a possible disease-progression model starting with an initial damage of portal bile ducts (primary insult) with associated portal/periportal changes (inflammation, ductular reaction) and resulting in secondary parenchymal changes is proposed.

Dicloxacillin-Induced Mixed Cholestatic Liver Injury

Purpose: Background: Dicloxacillin (Diclox) is semi-synthetic penicillin (PCN) used for treatment of a variety staphylococcal infections. It is the predominant beta-lactam PCN prescribed in the U.S. Severe liver reactions associated with its use are very rare. Case: A previously healthy 74 year-old white male presented with a 2 week history of jaundice, severe pruritus, dark urine, nausea and anorexia. He received a 10 day course of diclox 250 mg po qid for cellulitis of his right arm one month prior to this presentation. Pretreatment LFT's had been normal. Atorvastatin, which he had taken for three years was discontinued at the onset of his jaundice. He was non-smoker and drank alcohol rarely. His physical exam was remarkable only for scleral icterus and jaundice. An ultrasound of the abdomen was normal. Serological evaluation was negative for viral, autoimmune, chronic cholestatic, and hereditary liver diseases. He was started on ursodiol 300 mg po tid and also received a short tapering course of prednisone. A marked clinical improvement paralleled a decrease in liver enzymes over the course of next several weeks. Discussion: The clinical picture of a mixed cholestatic-hepatocellular injury pattern, significant eosinophilia, and a negative evaluation for other potential causes of liver injury was felt to be most consistent with a diclox-induced drug reaction, likely due to hypersensitivity. The long prior use of atorvastatin with normal LFTs just prior to diclox excluded statin induced hepatopathy. Given the improvement in LFTs and clinical improvement on ursodiol therapy, no liver biopsy was performed. Diclox induced liver injury is rare with an estimated frequency of adverse hepatic events of 1.8 reactions per million daily doses. An immunoallergic reaction mediated through formation of drug modified hepatic protein adducts is the likely mechanism. Older age and a prolonged course of therapy are important risk factors. Mixed cholestatic injury can occur up to several weeks after taking diclox, similar to that seen with amoxicillin-clavulante. Jaundice and pruritus typically are severe and protracted. Conclusion: Bile duct loss has been reported and liver tests may remain abnormal for months after resolution of clinical symptoms, although ursodiol therapy may shorten the course.Table

An Itching Complication

Purpose:Purpose: Vanishing Bile Duct Syndrome (VBDS) is an acquired disorder of cholestasis characterized by the destruction and ultimate disappearance of the intrahepatic bile ducts. The presentation of VBDS is highly variable due to its numerous underlying causes. Outcomes range from favorable with gradual regeneration and recovery to devastating with progressive and irreversible bile duct loss. We describe a case of an elderly male with jaundice following moxifloxacin exposure found to have VBDS on liver biopsy. Despite drug discontinuation cholestatic hepatitis persists. Case: An 82 year-old male with no significant past medical history was admitted to the hospital with empyema that was treated with intravenous antibiotics and drainage. On hospital day 21, he was discharged on a continuing course of oral moxifloxacin 400 mg daily. Eight days later he presented with jaundice and mild pruritis. He denied fevers, nausea, vomiting, abdominal pain, or change in stools. The exam was notable for marked jaundice and a palpable liver edge 3 cm below the costal margin. Laboratories revealed an alkaline phosphatase of 821 IU/L, ALT of 441 IU/L, total bilirubin of 15.3 mg/dl, and direct bilirubin of 9.2 mg/dl. Viral hepatitis and autoimmune serologies, iron studies, abdominal CT scan, right upper quadrant ultrasound with dopplers, MRCP, and ERCP produced inconclusive results. A liver biopsy was performed revealing cholestatic hepatitis with bile stasis and marked ductopenia. He was started on ursodiol (15 mg/kg) and cholestyramine (4 mg). At 3 months follow-up, the patient reported improved pruritis however liver chemistries remained markedly elevated with an alkaline phosphatase of 226 IU/L, ALT of 128 IU/L, total bilirubin of 25.8 mg/dl, and direct bilirubin of 14.5 mg/dl. Discussion: Cholestasis due to drug toxicity accounts for 2–5% of admissions for jaundice and up to 20% of cases of jaundice in the geriatric population. Moxifloxacin is a known hepatotoxin producing symptoms 3–10 days after drug ingestion and has been reported to cause fulminant hepatic failure and death. VBDS in association with flouroquinolone use is exceedingly rare with only one case reported in the literature. Most cases of VBDS resolve within 6 months, however VBDS can persist and lead to secondary biliary cirrhosis, liver failure, and death. The proposed mechanism of bile duct loss is T-cell toxicity and a dysregulation of apoptosis. Treatment requires recognition and prompt discontinuation of the inciting agent, although this does not uniformly lead to improvement. Corticosteroids, rifampicin, and opiate antagonists have been used for symptom management, however evidence regarding their efficacy is limited.

AMA Negative Primary Biliary Cirrhosis (PBC) and Small Duct Primary Sclerosing Cholangitis (PSC) Overlap Syndrome

Purpose: Overlap syndromes of two autoimmune liver diseases are not uncommon and usually involve autoimmune hepatitis with either PBC or PSC. We describe a case of AMA negative PBC and small duct PSC overlap syndrome, an extremely rare cause of autoimmune liver disease. Case Report: A 58 year old male was referred for evaluation of elevated liver enzymes: total bilirubin 2.4 mg/dL, alkaline phosphatase 630 IU/L, AST 262 IU/L, and ALT 447 IU/L. These were associated with fever, night sweats, dark urine, and pruritis. Serologies revealed an elevated pANCA (1:1280) but negative ANA, AMA, and ASMA. Complete serologic evaluation, including viral and metabolic serologies, was otherwise negative. Abdominal ultrasound revealed a normal liver and gallbladder. MRCP revealed normal intrahepatic ducts, common hepatic duct, and common bile duct. No strictures or irregularities of the biliary tree were identified. Liver biopsy revealed features of both PBC and PSC: portal hepatitis, a florid duct lesion, granulomas, and loss of small bile ducts. There was also concentric periductal fibrosis (“onion skinning”), affecting multiple small bile ducts. Trichrome and reticulin stains noted periportal fibrosis. A repeat AMA was performed using the more specific mitochondrial M2 test; this was also negative. The patient was assigned the diagnosis of AMA negative PBC and small duct PSC overlap syndrome. He was started on ursodeoxycholic acid 1200 mg daily in divided doses. Liver enzymes returned to normal within 6 months of therapy and he has had no further symptoms. The patient had undergone a screening colonoscopy 1 year prior to the elevated liver enzymes. This had revealed a hyperplastic colon polyp with normal appearing colon mucosa. Discussion: Overlap syndromes are noted in approximately 18% of patients with autoimmune liver disease and usually involve autoimmune hepatitis and either PBC or PSC. The very rare variant of PBC and PSC overlap syndrome has been reported in 4 cases in the literature. Our patient with features of both AMA negative PBC and small duct PSC represents an additional case of this extremely rare overlap syndrome.

Interface hepatitis is associated with a high incidence of late graft fibrosis in a group of tightly monitored pediatric orthotopic liver transplantation patients

Chronic graft dysfunction, manifesting with elevated liver enzymes and histological features of interface hepatitis (IH), is being increasingly recognized as a long-term problem after liver transplantation. The aim of this study was to characterize our group of post-orthotopic liver transplantation (OLT) patients with respect to clinical, laboratory, and histological signs of IH. A retrospective study of charts and liver biopsy specimens from patients transplanted between 1986 and 1999 was used. Histological features of IH were found in 29/119 patients at a median interval of 23.9 months (95% confidence interval -28.2 to 52.6) after OLT. All patients with IH had risk factors for chronic rejection, such as steroid-resistant rejection, acute rejection later than 3 months post-OLT, female receiver of male graft, or pretransplant cytomegalovirus (CMV)-positive serology with a CMV-negative donor liver. None of the 29 had features favoring a diagnosis of de novo autoimmune hepatitis, but 4 had isolated hypergammaglobulinemia, and 4 had non-organ-specific autoantibodies without hyperimmunoglobulin G. Sixteen of 29 patients also had features of chronic rejection, such as foam cell arteriopathy, loss of bile ducts, or pericentral fibrosis. After abnormal biopsy, all but 1 patient were switched to tacrolimus. During a median follow-up of 12 years, death occurred in 5, retransplantation occurred in 7, and definite cirrhosis occurred in 4. In conclusion, IH was detected in 24.4% of our patients and was associated with a high degree of fibrosis development. Most likely, IH represents a form of chronic rejection directed against periportal hepatocytes.

Activation of ATM signaling pathway is involved in oxidative stress-induced expression of mito-inhibitory p21 WAF1/Cip1 in chronic non-suppurative destructive cholangitis in primary biliary cirrhosis: An immunohistochemical study

Biliary epithelial cells (BECs) of chronic non-suppurative destructive cholangitis (CNSDC) in primary biliary cirrhosis (PBC) reportedly express p21 WAF1/Cip1 and p16 INK4a, which may induce cell cycle arrest and are related to progressive loss of BECs of PBC. Given that the ATM pathway plays a role in the induction of p21 WAF1/Cip1, we examined its possible involvement in bile duct damage of PBC. The expression of phosphorylated-ATM (p-ATM) reflecting the activation of ATM, p21 WAF1/Cip1 and 8-hydroxy-deoxyguanosine (8-OHdG), an oxidative stress marker, was examined immunohistochemically in the liver tissues of 20 cases of stage 1/2 PBC, 9 extrahepatic biliary obstruction (EBO), 35 chronic viral hepatitis (CVH), 17 nonalcoholic steatohepatitis (NASH), and 18 histologically normal liver. p21 WAF1/Cip1, p-ATM and 8-OHdG were frequently and extensively co-expressed in the nuclei of CNSDC in PBC, and their expressions were correlated. In contrast, the expression of these three molecules was absent or faint in small bile ducts in normal livers, CVH, and EBO, and these molecules were clearly expressed in the nuclei of hepatocytes of NASH, in which oxidative stress is involved in hepatocellular damage. In conclusion, oxidative stress-induced p21 WAF1/Cip1 expression in BECs in PBC is closely associated with activation of the ATM pathway and the resultant reduced regeneration or cell cycle arrest of BECs may be related to the progressive loss of small bile ducts of PBC.

Central perivenulitis: A common and potentially important finding in late posttransplant liver biopsies

Central perivenulitis: A common and potentially important finding in late posttransplant liver biopsies

Cholangiocyte Injury and Ductopenic Syndromes

Cholangiopathies are characterized by a predominantly bile duct-directed inflammatory response that leads to bile duct injury and, if the injury is persistent, bile duct loss and the chance of developing bile duct cancer (cholangiocarcinoma). Although the cholangiopathies have broad range of etiologies and pathogenesis (e.g., inherited disorders, autoimmune disorders, infections, drug-induced, ischemia, and unknown etiology), all share the common pathogenetic target-the biliary epithelial cell (cholangiocyte). For the most part, the pathogenesis of these diseases is poorly understood, which correspondingly has restricted clinicians to nonspecific and usually ineffective therapies for these disorders. Nevertheless, significant advances toward the understanding of the mechanisms involved in cholangiocyte-directed inflammation, biliary fibrosis, cholangiocyte death, and cholangiocarcinoma have unfolded over the past 15 years that may provide us new hopes and schemes for treatment of these disorders.

Novel interaction of bile acid and neural signaling in the regulation of cholangiocyte function

Cholangiocytes, the epithelial cells that line the intrahepatic biliary tree, are the target of cholangiopathies, a wide array of chronic disorders that are characterized by the progressive vanishing of bile ducts, leading to ductopenia and liver failure. The loss of bile ducts is a consequence of cholangiocyte death by apoptosis and impaired proliferative response of these cells to injury. The factors that regulate cholangiocyte proliferation and survival are poorly understood. In this regard, a major role is played by the interaction between bile acids and the autonomic nervous system. It has been shown that adrenergic and cholinergic denervation of the liver results in the induction of cell death and impaired proliferative responses of the biliary epithelium to cholestasis. In addition,bile acids have been shown to enter cholangiocytes through the apical, Na(+)-dependent bile acid transporter, ASBT, which has a marked impact on cholangiocyte pathobiology. Recent evidence shows that bile acids and autonomic innervation interact in modulating cholangiocyte response to liver injury. In this review, we describe the recent advances in understanding the molecular mechanisms by which such events occur.

Primary Sclerosing Cholangitis Is a More Common Indication for Orthotopic Liver Transplantation among African American Than Non-African American Patients

Purpose: Primary sclerosing cholangitis (PSC) is a progressive, incurable condition of unknown etiology, characterized by inflammation, fibrosis, destruction and loss of interlobular-sized bile ducts, leading to biliary cirrhosis and liver failure. Orthotopic liver transplantation (OLT) is the only life-extending intervention for patients with end-stage PSC. Recent US Scientific Registry of Transplant Recipients (SRTR) data indicate that among patients with PSC being added to the United Network for Organ Sharing (UNOS) waiting list the proportion of African Americans (AA) was greater than non-AAs, compared to other disease indications. This suggests that PSC may run a more aggressive clinical course. It was our aim to determine whether the proportion of AA patients with PSC undergoing OLT per unit time was different from the proportion of non-AA patients undergoing OLT for PSC. Methods: The SRTR was reviewed between 1998 and 2002 inclusive for all adults (18 – 80 years) who were added to the UNOS waiting list for OLT. The proportions of AA and non-AA patients undergoing OLT for PSC within 1 year, 1–2 years, 2–3 years, and > 3 years of being added to the waiting list were calculated, and compared using the Chi-square test. Results: From 1998 to 2002 inclusive 39,878 patients were added to the UNOS waiting list for OLT. 2173 (5.45%) had PSC. Of these, 262 (12.1%) were AA. The proportions of AA patients with PSC who underwent OLT within 1 year, 1–2 years, 2–3 years, and >3 years of being added to the waiting list were: 28.2% (74/262), 13.7% (36/262), 8.8% (23/262) and 5.7% (15/262). 114/262 (43.5%) AA patients with PSC did not undergo OLT during the study period. The proportions of non-AA patients with PSC who underwent OLT within 1 year, 1–2 years, 2–3 years, and > 3 years of being added to the waiting list were: 33.5% (640/1911), 11.5% (220/1911), 4.7% (89/1911) and 4.9% (93/1911). 869/1911 (45.5) non-AA patients with PSC did not undergo OLT during this period. Except for the period < 1 year from the time of OLT listing, the proportion of AA patients with PSC undergoing OLT was significantly greater than the porportion of non-AA patients with PSC who underwent OLT (P= 0.026). Conclusion: These outcomes for AA patients with PSC suggest that their disease course may be more agressive, given that patients underwent OLT sooner from the time of listing than did non-AA patients. An alternative explanation is that AA patients with PSC were simply sicker than non-AA patients at the time of listing for OLT.