Obstructive Cholestasis Research Articles

An Unusual Cause of a Cecal “Seesaw” and Pneumatosis Intestinalis

Question: A 66-year-old woman with history of stroke, previous hernia surgery with mesh placement, and obstructive cholestasis due to choledocholithiasis presented with 3 days of right-sided abdominal pain, 15-lb weight loss over 1 month, and 3 weeks of constipation with thin stools. Colonoscopy was normal a few months prior. Her prior episode of choledocholithiasis in 2017 led to endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and placement of a double pig-tail stent. She was recently admitted 1 month ago for jaundice and right upper quadrant (RUQ) pain at which time magnetic resonance cholangiopancreatography showed severe intrahepatic and extrahepatic biliary duct dilation but no liver or pancreatic lesions. The cecum was nonspecifically distended and fluid filled. Esophagogastroduodenoscopy revealed a benign-appearing intrinsic duodenal stricture felt to be related to scar tissue from the previous hernia mesh surgery. ERCP revealed an occluded biliary stent that had migrated to the major papilla and a severe burden of choledocholithiasis. The occluded stent was removed, and partial removal of stones was achieved via basket extraction. A new biliary stent was placed with a plan to follow up in 4 weeks for repeat ERCP for further stone extraction and stent removal. Before this appointment she was readmitted for worsening RUQ pain. A computed tomography scan revealed dilated loops of distal small bowel and a dilated cecum that had folded anteriorly and superiorly with extensive pneumatosis. The ascending colon was also dilated up to a decompressed hepatic flexure, where nonspecific bowel wall thickening was visualized, suggesting a transition point. No obvious mass or lesion was noted at the hepatic flexure (Figure A). Despite clinical improvement with conservative management, a lower gastrointestinal series performed a few days later showed persistent severe obstruction at the hepatic flexure with bird-beak appearance (Figure B). What is the most likely explanation for these imaging findings and how should it be managed? See the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. The patient’s imaging findings are consistent with cecal bascule (type III cecal volvulus). Cecal bascules are the rarest variant of cecal volvulus that involve upward folding of the cecum, without axial twisting or sigmoid involvement.1Rabinovici R. Simansky D.A. Kaplan O. et al.Cecal volvulus. Dis Colon Rectum. 1990; 33: 765-769Crossref PubMed Scopus (119) Google Scholar Bascule in French means “seesaw,” describing the pathophysiology of the cecal presentation. Surgical management was indicated given the persistent and severe hepatic flexure stricture seen on lower gastrointestinal series. Exploratory laparotomy revealed numerous omental nodules and a mass was discovered in the RUQ involving the gallbladder and liver that was causing extrinsic compression of the hepatic flexure. The largest nodule was excised and confirmed a diagnosis of metastatic cholangiocarcinoma. A distal loop ileostomy was created to decompress the colon and prevent ongoing colonic obstruction. No colonic resection was necessary. The patient began cancer staging and treatment planning, but unfortunately passed 1 month after diagnosis. This is a unique case of an extrinsic malignant obstruction causing cecal bascule. The development of a cecal bascule is usually attributed to an abnormally mobile cecum due to improper development and insufficient fixation of the mesentery to the posterior parietal peritoneum. A mobile cecum may also be acquired in pregnancy due to enlargement of the uterus or after abdominal surgery, such as open appendectomies, which require extensive division of peritoneal attachments to the cecum. Clinical presentation varies with abdominal pain, distention, and nausea being the most common symptoms but can progress to an acute abdomen and perforation.2Lung B.E. Yelika S.B. Murthy A.S. et al.Cecal bascule: a systematic review of the literature.Tech Coloproctol. 2018; 22: 75-80Crossref PubMed Scopus (14) Google Scholar Diagnosis of type III cecal volvulus requires computed tomography imaging confirming a distended cecum lying anterior to ascending colon. Treatment generally involves surgical resection of the affected bowel because colonoscopic detorsion may lead to recurrence.3Le C.K. Nahirniak P. Qaja E. Cecal volvulus. StatPearls Publishing. StatPearls Website, 2021Google Scholar

Systemic ASBT inactivation protects against liver damage in obstructive cholestasis in mice

Background & AimsNon-absorbable inhibitors of the apical sodium-dependent bile acid transporter (ASBT; also called ileal bile acid transporter [IBAT]) are recently approved or in clinical development for multiple cholestatic liver disorders and lead to a reduction in pruritus and (markers for) liver injury. Unfortunately, non-absorbable ASBT inhibitors (ASBTi) can induce diarrhoea or may be ineffective if cholestasis is extensive and largely precludes intestinal excretion of bile acids. Systemically acting ASBTi that divert bile salts towards renal excretion may alleviate these issues.MethodsBile duct ligation (BDL) was performed in ASBT-deficient (ASBT knockout [KO]) mice as a model for chronic systemic ASBT inhibition in obstructive cholestasis. Co-infusion of radiolabelled taurocholate and inulin was used to quantify renal bile salt excretion after BDL. In a second (wild-type) mouse model, a combination of obeticholic acid (OCA) and intestine-restricted ASBT inhibition was used to lower the bile salt pool size before BDL.ResultsAfter BDL, ASBT KO mice had reduced plasma bilirubin and alkaline phosphatase compared with wild-type mice with BDL and showed a marked reduction in liver necrotic areas at histopathological analysis, suggesting decreased BDL-induced liver damage. Furthermore, ASBT KO mice had reduced bile salt pool size, lower plasma taurine-conjugated polyhydroxylated bile salt, and increased urinary bile salt excretion. Pretreatment with OCA + ASBTi in wild-type mice reduced the pool size and greatly improved liver injury markers and liver histology.ConclusionsA reduced bile salt pool at the onset of cholestasis effectively lowers cholestatic liver injury in mice. Systemic ASBT inhibition may be valuable as treatment for cholestatic liver disease by lowering the pool size and increasing renal bile salt output even under conditions of minimal faecal bile salt secretion.Lay summaryNovel treatment approaches against cholestatic liver disease (resulting in reduced or blocked flow of bile) involve non-absorbable inhibitors of the bile acid transport protein ASBT, but these are not always effective and/or can cause unwanted side effects. In this study, we demonstrate that systemic inhibition/inactivation of ASBT protects mice against developing severe cholestatic liver injury after bile duct ligation, by reducing bile salt pool size and increasing renal bile salt excretion.

Karaciğer hastalıklarında kullanılan skorlamalar malign-benign kolestaz ayrımında kullanılabilir mi?

Giriş ve Amaç: Kronik safra yolu hastalıkları hepatositlerde bilirübin ve karaciğerden ekskrete edilen toksinlere daha uzun süre maruziyete neden olarak hepatosit fonksiyonlarını bozmaktadır. Ayrıca karaciğerin primer maligniteleri gibi safra yolu malignitelerinin de fibrotik karakterde olduğunu öne süren yayınlar vardır. Bu bilgiler ışığında kronik ve malign safra yolu tıkanıklığı oluşturan kolestatik hastalıkların, akut ve benign safra yolu tıkanıklığı oluşturan hastalıklara göre karaciğer fonksiyonlarını daha fazla bozduğu ve karaciğer fibrozisini artırdığı düşünülebilir. Çalışmamızda rutin testlerle ölçülebilen ve karaciğer hastalıklarında kullanılan skorlardan; R-faktör, son dönem karaciğer hastalığı modeli/sodyum, albümin-bilirübin skoru, albümin-alkalen fosfataz oranı, aspartat aminotransferaz-trombosit oran indeksi, dört faktörü temel alan fibrozis indeksi (fibrozis-4) ve gama glutamil transpeptidaz-trombosit oranı’ndan hangilerinin malign nedenli kolestaz tanısını koymakta yardımcı bir yöntem olarak kullanılabileceğinin araştırılması hedeflenmiştir. Gereç ve Yöntem: Ondokuz Mayıs Üniversitesi Tıp Fakültesi Gastroenteroloji Kliniği’nde Temmuz 2019- Temmuz 2021 tarihleri arasında obstrüktif kolestaz tanısı alan hastaların dosyaları retrospektif olarak tarandı. Akut ve benign nedenli kolestaz tanısı alan hastalar Grup 1, kronik ve malign nedenli kolestaz tanılı hastalar Grup 2 olarak sınıflandırıldı. Hastaların ilk başvuru zamanındaki laboratuvar değerleri kullanılarak; R-faktör, son dönem karaciğer hastalığı modeli/sodyum, albümin-bilirübin skoru, albümin-alkalen fosfataz oranı, aspartat aminotransferaz-trombosit oran indeksi, fibrozis-4 indeksi ve gama glutamil transpeptidaz-trombosit oranı skorları hesaplandı, tanıları ile tanı anındaki skorları arasındaki ilişki değerlendirildi. Bulgular: Çalışmaya 116’sı erkek (%57.4), 86’sı kadın (%42.6) toplam 202 hasta dahil edildi. Grup 1’de 92 (%45.5), Grup 2’de 110 (%54.5) hasta yer almaktaydı. Grup 1 ve Grup 2 arasında demografik özellikler açısından anlamlı fark görülmedi. Grup 1’de sık görülen hastalıklar kolanjit, koledokolitiazis ve safra çamuru ile biliyer pankreatit iken Grup 2’de ise pankreas başı karsinomuydu. Değerlendirilen laboratuvar parametrelerinden alkalen fosfataz, total ve direkt bilirübin maligniteye işaret eden en önemli testlerdi (p < 0.001). Karaciğer hastalığı skorlarından R-faktör (p < 0.001), son dönem karaciğer hastalığı modeli/sodyum (p < 0.001) ve albümin-bilirübin skoru (p = 0.023) Grup 2, albümin-alkalen fosfataz oranı (p < 0.001), aspartat aminotransferaz-trombosit oran indeksi (p < 0.001) ve fibrozis-4 indeksi (p < 0.001) Grup 1 lehine anlamlıydı ancak gama glutamil transpeptidaz-trombosit oranı için her iki grup arasında anlamlı fark yoktu (p = 0.242). Tanı konma süreçleri içinde Grup 1’deki hastaların nihai tanıları çoğunlukla ultrasonografi ile konmakta iken (p < 0.001), Grup 2’deki hastalar bilgisayarlı tomografi ile tanı almaktaydı (p < 0.001). Sonuç: Çalışmamız kronik karaciğer hastalıklarında kullanılan skorlardan R-faktör, son dönem karaciğer hastalığı modeli/sodyum ve albümin-bilirübin skoru malign nedenli kolestatik hastalıkların tanısında, albümin-alkalen fosfataz oranı, aspartat aminotransferaz-trombosit oran indeksi ve fibrozis-4 indeksinin benign nedenli kolestatik hastalıkların tanısında yardımcı bir yöntem olarak kullanılabileceğini, gama glutamil transpeptidaz-trombosit oranının ise bu ayırımda kullanılamayacağını göstermektedir. Bu tip öngörücü skorlar, anamnez ve muayene bulguları ile birlikte yorumlanarak hastaların tetkik ve tedavi planlarının daha hızlı sağlanmasını kolaylaştırabilir.

Obeticholic acid aggravates liver injury by up-regulating the liver expression of osteopontin in obstructive cholestasis

AimsObeticholic acid (OCA) was approved for the treatment of primary biliary cholangitis (PBC) patients, as it can significantly improve the level of serum alkaline phosphatase. However, OCA-induced liver injury in PBC patients puts them at risk of acute chronic liver failure, thus limiting the clinical application of OCA. Osteopontin (OPN), an extracellular cell matrix molecule, is highly induced in many cholestatic liver diseases. Herein we explored whether liver injury exacerbation by OCA was related to OPN. Main methodsBile duct ligation (BDL) mice were treated with OCA (40 mg/kg) to evaluate its effect on liver injury and OPN involvement. Enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and other assays were used to detect OPN levels in serum and liver. Immunohistochemistry, and immunofluorescence, among other assays, were used to evaluate the extent of ductular reaction. The extent of fibrosis was also determined using various assays, such as immunohistochemistry, quantitative real-time PCR (qPCR), and hydroxyproline assays. Key findingsOPN was overexpressed in the liver of BDL mice treated with OCA. OCA induced overexpression of OPN exacerbated ductular reaction, fibrosis, and liver inflammation, and reduced hepatocyte proliferation. SignificanceUpon liver injury, OCA upregulates the expression of OPN in the liver and accelerates disease progression. This mechanism helps explain the risk of liver damage associated with OCA.

Liver dysfunction and energy storage mobilization in traíra, Hoplias malabaricus (Teleostei, Erythrinidae) induced by subchronic exposure to toxic cyanobacterial crude extract.

Microcystins (MC) are hepatotoxic for organisms. Liver MC accumulation and structural change are intensely studied, but the functional hepatic enzymes and energy metabolism have received little attention. This study investigated the liver and hepatocyte structures and the activity of key hepatic functional enzymes with emphasis on energetic metabolism changes after subchronic fish exposure to cyanobacterial crude extract (CE) containing MC. The Neotropical erythrinid fish, Hoplias malabaricus, were exposed intraperitoneally to CE containing 100 μg MC-LR eq kg-1 for 30 days and, thereafter, the plasma, liver, and white muscle was sampled for analyses. Liver tissue lost cellular structure organization showing round hepatocytes, hyperemia, and biliary duct obstruction. At the ultrastructural level, the mitochondria and the endoplasmic reticulum exhibited disorganization. Direct and total bilirubin increased in plasma. In the liver, the activity of acid phosphatase (ACP) increased, and the aspartate aminotransferase (AST) decreased; AST increased in plasma. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were unchanged in the liver, muscle, and plasma. Glycogen stores and the energetic metabolites as glucose, lactate, and pyruvate decrease in the liver; pyruvate decreased in plasma and lactate decreased in muscle. Ammonia levels increased and protein concentration decreased in plasma. CE alters liver morphology by causing hepatocyte intracellular disorder, obstructive cholestasis, and dysfunction in the activity of key liver enzymes. The increasing energy demand implies glucose mobilization and metabolic adjustments maintaining protein preservation and lipid recruitment to supply the needs for detoxification allowing fish survival.

Acute Severe Hyperlipidemia Leading to a Diagnosis of Pancreatic Cancer in an Elderly Woman

There are multiple secondary causes of hyperlipidemia, including obstructive cholestasis. We present a patient case of a 72-year-old woman with controlled hyperlipidemia presenting for a routine primary care visit. Laboratory results showed marked hyperlipidemia. Subsequent evaluation revealed biliary obstruction resulting from pancreatic adenocarcinoma.

Biliary atresia-An experience from the first pediatric liver transplant center in Pakistan.

Biliary atresia (BA) is the most common cause of neonatal cholestatic syndrome. The true incidence of BA in Pakistan is largely unknown. This study aimed to report the clinical features, age at diagnosis and outcomes of biliary atresia from the first pediatric liver transplant center in Pakistan. The study was done in Shifa International hospital from 2013 to 2020. All babies who had biliary atresia confirmed by laboratory investigation were included. Demographic data, age of presentation, clinical presentation, supporting investigations like liver function tests, ultrasound abdomen, HIDA scan and liver biopsy were noted. Outcome related to Kasai portoenterostomy, liver transplant, complications and immunosuppressant agents were noted. A total of 42 children were included, 23 (54.7%) males and 19 (45.2%) were females. Jaundice was seen in all patients (100%) followed by acholic stools (81%). Associated malformations were noted in 6 (14.2%) patients. Liver function tests confirmed obstructive cholestasis (p 0.04). Kasai was done in 19 (45%) patients only, living donor liver transplant was performed in 6 (14%) patients. Age range of transplant patients was from 3months to 1year. Indication for liver transplant was failed Kasai in 1(16.7%) patient and chronic liver disease in 5 (83.3%) patients. LDLT survivors were 10months to 1year of age at the time of transplant, mean age was 10.6months. Maximum survival noted so far is 7 years. Acute complications seen post-transplant were sepsis (three patients), surgical site infections (two patients), biliary leaks and acute cellular rejection in one patient each. Chronic graft rejection, portal vein stricture needing stenting was done in one patient. All patients underwent LDLT from related donors wih no donor related mortality. All are deceased patients were yonger and had advanced disease. BA remains third most commo indication of transplant in our center. Liver transplant is the only lifesaving procedure after failed Kasai or as primary liver transplant due to advance liver disease. The advent of liver transplantation services offers survival and improving outlook of the disease.

Factors Predictive of an Obstructive Pathology among Filipino Infants with Neonatal Cholestasis

Objective. To determine factors predictive of obstructive neonatal cholestasis among Filipino infants and to describe their outcome.
 Methods. Jaundiced infants within the first eight weeks of life with liver biopsy were included. Excluded were cholestasis secondary to metabolic or infective causes. Retrospective chart review (2009-2012) and prospective recruitment of patients (2013) were done. A final diagnosis of non-obstructive or obstructive neonatal cholestasis was made on clinical, biochemical, ultrasonographic, and histologic findings, using histology and/or operative cholangiogram as the gold standard. The outcome was assessed on the 6th and 12th months from diagnosis. The crude odds ratio for obstructive jaundice was computed. Multiple logistic regression on significant variables (p-value <0.05) was done.
 Results. Two hundred sixty-three (263) patients were included: 161 with non-obstructive and 102 with obstructive cause. Mean age at first consult was higher in those with obstruction. On logistic regression, females (OR:2.3), absence of a family history of idiopathic neonatal hepatitis (OR:4), and persistently pale/acholic stools (OR:13) were predictive of obstruction. 85% of patients with a non-obstructive cause are alive and well, while 80% of patients with obstruction have died.
 Conclusion. Among jaundiced infants females, the absence of a family history of idiopathic neonatal hepatitis and persistently pale yellow/acholic stools were predictive of obstruction. The outcome was poor in patients with obstructive jaundice.

Pediatric Research Challenge, Alignment with the National Research Agenda

Pediatric Research Challenge, Alignment with the National Research Agenda

Bile acid-sensitive tuft cells regulate biliary neutrophil influx.

Inflammation and dysfunction of the extrahepatic biliary tree are common causes of human pathology, including gallstones and cholangiocarcinoma. Despite this, we know little about the local regulation of biliary inflammation. Tuft cells, rare sensory epithelial cells, are particularly prevalent in the mucosa of the gallbladder and extrahepatic bile ducts. Here, we show that biliary tuft cells express a core genetic tuft cell program in addition to a tissue-specific gene signature and, in contrast to small intestinal tuft cells, decreased postnatally, coincident with maturation of bile acid production. Manipulation of enterohepatic bile acid recirculation revealed that tuft cell abundance is negatively regulated by bile acids, including in a model of obstructive cholestasis in which inflammatory infiltration of the biliary tree correlated with loss of tuft cells. Unexpectedly, tuft cell-deficient mice spontaneously displayed an increased gallbladder epithelial inflammatory gene signature accompanied by neutrophil infiltration that was modulated by the microbiome. We propose that biliary tuft cells function as bile acid-sensitive negative regulators of inflammation in biliary tissues and serve to limit inflammation under homeostatic conditions.

Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease

Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease

Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis

Cholestasis is a common condition in which the flow of bile from the liver to the intestines is inhibited. It has been shown that organic anion–transporting polypeptide 3A1 (OATP3A1) is upregulated in cholestasis to promote bile acid efflux transport. We have previously shown that the growth factor fibroblast growth factor 19 and inflammatory mediator tumor necrosis factor α (TNFα) increased OATP3A1 mRNA levels in hepatoma peritoneal lavage cell/PRF/5 cell lines. However, the mechanism underlying TNFα-stimulated OATP3A1 expression in cholestasis is unknown. To address this, we collected plasma samples from control and obstructive cholestasis patients and used ELISA to detect TNFα levels. We found that the TNFα levels of plasma and hepatic mRNA transcripts were significantly increased in obstructive cholestatic patients relative to control patients. A significant positive correlation was also observed between plasma TNFα and liver OATP3A1 mRNA transcripts in patients with obstructive cholestasis. Further mechanism analysis revealed that recombinant TNFα induced OATP3A1 expression and activated NF-κB and extracellular signal–regulated kinase (ERK) signaling pathways as well as expression of related transcription factors p65 and specificity protein 1 (SP1). Dual-luciferase reporter and chromatin immunoprecipitation assays showed that recombinant TNFα upregulated the binding activities of NF-κB p65 and SP1 to the OATP3A1 promoter in peritoneal lavage cell/PRF/5 cells. These effects were diminished following the application of NF-κB and ERK inhibitors BAY11-7082 and PD98059. We conclude that TNFα stimulates hepatic OATP3A1 expression in human obstructive cholestasis by activating NF-κB p65 and ERK–SP1 signaling. These results suggest that TNFα-activated NF-κB p65 and ERK–SP1 signaling may be a potential target to ameliorate cholestasis-associated liver injury.

Corrosion Cast and 3D Reconstruction of the Murine Biliary Tree After Biliary Obstruction: Quantitative Assessment and Comparison With 2D Histology

Obstructive cholestasis can lead to significant alterations of the biliary tree depending on the extent and duration of the biliary occlusion. Current experimental studies reported about advanced techniques for corrosion cast and 3D reconstruction (3D-reco) visualizing delicate microvascular structures in animals. We compared these two different techniques for visualization and quantitative assessment of the obstructed murine biliary tree with classical 2D histology. Male mice (n= 36) were allocated to 3 different experiments. In experiments 1 and 2, we injected two different media (Microfil© for 3D-reco, MV; Batson's No.17 for corrosion cast, CC) into the extrahepatic bile duct. In experiment 3 we sampled liver tissue for 2D histology (HE, BrdU). Time points of interest were days 1, 3, 5, 7, 14, and 28 after biliary occlusion. We used different types of software for quantification of the different samples: IMALYTICS Preclinical for 3D scans (MV); NDP.view2 for the digital photography of CC; HistoKat software for 2D histology. We achieved samples in 75% of the animals suitable for evaluation (MV and CC, each with9/12). Contrasting of terminal bile ducts (4th order of branches) was achieved with either technique. MV permitted a fast 3D-reco of the hierarchy of the biliary tree, including the 3rd and 4th order of branches in almost all samples (8/9 and 6/9). CC enabled focused evaluation of the hierarchy of the biliary tree, including the 4th to 5th order of branches in almost all samples (9/9 and 8/9). In addition, we detected dense meshes of the smallest bile ducts in almost all CC samples (8/9). MV and CC allowed a quantitative assessment of anatomical details of the 3rd and 4th order branches of almost every sample. The 2D histology identified different kinetics and areas of proliferation of hepatocytes and cholangiocytes. Complementary usage of 3D-reco, corrosion casting and 2D histology matched dense meshes of small bile ducts with areas of intensive proliferative activity of cholangiocytes as periportal proliferative areas of 4th and 5th order branches (∼terminal bile ducts and bile ductules) matched with its morphological information the matching assessment of areas with increased proliferative activity (BrdU) and a partial quantification of the characteristics of the 4th order branches of the biliary tree. The 3D-reco and corrosion casting of the murine biliary tree are feasibleand provide a straightforward, robust, and reliable (and more economical) procedure for the visualization and quantitative assessment of architectural alterations, in comparative usage with the 2D histology.

Short-term preoperative drainage is associated with improved postoperative outcomes compared to that of long-term biliary drainage in pancreatic surgery

PurposeThe treatment of choice for patients presenting with obstructive cholestasis due to periampullary carcinoma is oncologic resection without preoperative biliary drainage (PBD). However, resection without PBD becomes virtually impossible in patients with obstructive cholangitis or severely impaired liver cell function. The appropriate duration of drainage by PBD has not yet been defined for these patients.MethodsA retrospective analysis was conducted on 170 patients scheduled for pancreatic resection following biliary drainage between January 2012 and June 2018 at the University Hospital Dresden in Germany. All patients were deemed eligible for inclusion, regardless of the underlying disease entity. The primary endpoint analysis was defined as the overall morbidity (according to the Clavien-Dindo classification). Secondary endpoints were the in-hospital mortality and malignancy adjusted overall and recurrence-free survival rates.ResultsA total of 170 patients were included, of which 45 (26.5%) and 125 (73.5%) were assigned to the short-term (< 4 weeks) and long-term (≥ 4 weeks) preoperative drainage groups, respectively.Surgical complications (Clavien-Dindo classification > 2) occurred in 80 (47.1%) patients, with significantly fewer complications observed in the short-term drainage group (31.1% vs. 52%; p = 0.02). We found that long-term preoperative drainage (unadjusted OR, 3.386; 95% CI, 1.507–7.606; p < 0.01) and periampullary carcinoma (unadjusted OR, 5.519; 95% CI, 1.722–17.685; p-value < 0.01) were independent risk factors for postoperative morbidity, based on the results of a multivariate regression model. The adjusted overall and recurrence-free survival did not differ between the groups (p = 0.12).ConclusionPBD in patients scheduled for pancreatic surgery is associated with substantial perioperative morbidity. Our results indicate that patients who have undergone PBD should be operated on within 4 weeks after drainage.

MiR-199a-5p inhibits the expression of ABCB11 in obstructive cholestasis

ATP-binding cassette, subfamily B member 11 (ABCB11) is an efflux transporter for bile acids on the liver canalicular membrane. The expression of this transporter is reduced in cholestasis; however, the mechanisms contributing to this reduction are unclear. In this study, we sought to determine whether miR-199a-5p contributes to the depletion of ABCB11/Abcb11 in cholestasis in mice. In a microRNA (miRNA) screen of mouse liver after common bile duct ligation (CBDL), we found that miR-199a-5p was significantly upregulated by approximately fourfold. In silico analysis predicted that miR-199a-5p would target the 3′-untranslated region (3′-UTR) of ABCB11/Abcb11 mRNA. The expression of ABCB11-3′-UTR luciferase construct in Huh-7 cells was markedly inhibited by cotransfection of a miRNA-199a-5p mimic, which was reversed by an miRNA-199a-5p mimic inhibitor. We also show treatment of mice after CBDL with the potent nuclear receptor FXR agonist obeticholic acid (OCA) significantly increased Abcb11 mRNA and protein and decreased miR-199a-5p expression. Computational mapping revealed a well-conserved FXR-binding site (FXRE) in the promoter of the gene encoding miR-199a-5, termed miR199a-2. Electromobility shift, chromatin immunoprecipitation, and miR199a-2 promoter-luciferase assays confirmed that this binding site was functional. Finally, CBDL in mice led to depletion of nuclear repressor NcoR1 binding at the miR199a-2 promoter, which facilitates transcription of miR199a-2. In CBDL mice treated with OCA, NcoR1 recruitment to the miR199a-2 FXRE was maintained at levels found in sham-operated mice. In conclusion, we demonstrate that miR-199a-5p is involved in regulating ABCB11/Abcb11 expression, is aberrantly upregulated in obstructive cholestasis, and is downregulated by the FXR agonist OCA.

Piezo1-Pannexin1 complex couples force detection to ATP secretion in cholangiocytes.

Cholangiocytes actively contribute to the final composition of secreted bile. These cells are exposed to abnormal mechanical stimuli during obstructive cholestasis, which has a deep impact on their function. However, the effects of mechanical insults on cholangiocyte function are not understood. Combining gene silencing and pharmacological assays with live calcium imaging, we probed molecular candidates essential for coupling mechanical force to ATP secretion in mouse cholangiocytes. We show that Piezo1 and Pannexin1 are necessary for eliciting the downstream effects of mechanical stress. By mediating a rise in intracellular Ca2+, Piezo1 acts as a mechanosensor responsible for translating cell swelling into activation of Panx1, which triggers ATP release and subsequent signal amplification through P2X4R. Co-immunoprecipitation and pull-down assays indicated physical interaction between Piezo1 and Panx1, which leads to stable plasma membrane complexes. Piezo1-Panx1-P2X4R ATP release pathway could be reconstituted in HEK Piezo1 KO cells. Thus, our data suggest that Piezo1 and Panx1 can form a functional signaling complex that controls force-induced ATP secretion in cholangiocytes. These findings may foster the development of novel therapeutic strategies for biliary diseases.

Pathological syndromes of the biliary tract decompression

Background: The increased incidence of cholelithiasis and tumoral lesions of the hepatopancreatoduodenal zone leads to an increase in the number of patients with obstructive cholestasis.&#x0D; Aims: To identify the spectrum of pathological conditions developing after decompression of the biliary tract in obstructive cholestasis and to develop an effective pathogenetically determined algorithm for treating patients.&#x0D; Methods: The results of the examination and treatment of 216 patients with obstructive cholestasis, who underwent various options for decompression of the biliary tract, were analyzed. Obstructive cholestasis of a tumor genesis was present in 112 (51.8%) patients, benign cholestasis in 104 (48.2%). The main group included 112 patients, the comparison group included 104 patients. A two-stage tactics was applied in 133 (61.6%) cases, 83 patients (38.4%) were operated in one stage. The treatment results were compared for the experimental group (n=112) in which a pathogenetically based algorithm was applied and for the control group (n=104) receiving a standard therapy.&#x0D; Results: Accelerated decompression syndrome developed in 31 (14.3%) cases, of those 26 in the comparison group, 5 in the main group. Disorders of the water and electrolyte balance occurred in 32 (46.4%) patients with complete external bile diversion. Digestion remodeling syndrome was present in 44 patients from 117 patients with external bile diversion.&#x0D; Conclusions: It has been shown that the pathogenetically based therapy after biliary decompression significantly reduces the number of complications in the postoperative period.

Liver Histopathological Analysis of 24 Postmortem Findings of Patients With COVID-19 in China.

Although the pathologic investigation of liver injury was observed in a couple of cases in China, the detailed description of liver histopathologic and ultrastructural changes in a relatively larger series of liver tissues from COVID-19 patients is lacking. Samples from the liver were obtained from 24 COVID-19 cases from February 1 to April 1, 2020. Light microscopy showed that all liver sections had different degrees of liver injury manifested as swelling of the hepatocytes, hepatocellular necrosis, steatosis, lobular inflammation, portal inflammation, dilatation of sinusoids, and so on. SARS-CoV-2 induced liver injury might be independent of pre-existing Schistosoma infection or obstructive cholestasis. Patients combined with respiratory failure had more severe hepatocellular necrosis and male patients were more susceptible to liver injury. Although coronavirus particles or viral inclusions were not detected in the liver tissues for all cases, vacuolar degenerations in hepatocytes, edematous of mitochondria with the disruption of cristae, and expansions of the endoplasmic reticulum were observed. In conclusion, pathologic changes of liver tissues provide us a further understanding of liver injury in COVID-19 patients. Changes in the liver seem to be related to the underlying diseases/conditions.

Effect of transient obstructive cholestasis on liver histology: a cross-sectional study.

The role of transient obstructive cholestasis on liver histology remains undetermined. To investigate whether transient cholestasis impairs liver histology. Cross-sectional study at a public university hospital (UNICAMP), Brazil. 169 individuals undergoing cholecystectomy, with or without cholestasis. were enrolled. Histopathological findings were correlated with clinical and biochemical characteristics. Biliary hepatopathy was more frequent in individuals with resolved cholestasis than in those with active obstruction or no jaundice (P < 0.01), as also were fibrosis and ductular proliferation (P = 0.02). Cholestasis was commoner in individuals with resolved obstruction than in those with no history (P < 0.01) or active cholestasis (P < 0.05). Biliary hepatopathy was associated with longer duration of cholestasis (P < 0.001) and higher bilirubin levels (P = 0.02) in individuals with active obstruction; with lower body mass index (P = 0.02) and longer cholestasis (P < 0.001) in individuals with resolved obstruction; and with longer cholestasis (P < 0.001) and longer interval between endoscopic retrograde cholangiopancreatography and surgery (P = 0.03) overall. In individuals with active obstruction, duration of cholestasis (R = 0.7; P < 0.001) and bilirubin levels (R = 0.6; P = 0.004) were independently correlated with cholestasis severity. Duration of cholestasis (R = 0.7; P < 0.001) was independently correlated with ductular proliferation severity. Transient cholestasis was associated with significant histopathological changes, even after its resolution. Longer duration of obstruction correlated with greater severity of histopathological changes, especially cholestasis and ductular proliferation. This emphasizes the need for early treatment of obstructive cholestasis.

The herbal medicines Inchinkoto and Saireito improved hepatic fibrosis via aquaporin 9 in the liver of a rat bile duct ligation model.

To determine if the administration of the Japanese herbal medicines Inchinkoto (ICKT) and Saireito (SRT) ameliorate hepatic fibrosis and derangement of hepatocyte aquaporins (AQPs) following bile duct ligation (BDL) in a rat model of obstructive cholestasis. Five groups of Wistar rats were used, and the groups included sham surgery (Sham group), BDL with no treatment (NT group), BDL plus ICKT (ICKT group), BDL plus SRT (SRT group), and BDL plus ICKT and SRT (SRT/ICKT group). Each herbal medicine was administered at 1g/kg/day on the first postoperative day. The serum levels and various clinical markers were measured with real-time polymerase chain reaction. Staining was used to evaluate the degree of fibrosis and the inflammatory responses. Serum aspartate aminotransferase and alanine aminotransferase in the ICKT and SRT/ICKT groups were significantly lower than those in the NT group. NF-κB mRNA expression was significantly decreased in the ICKT group and the SRT/ICKT group compared with the NT group. AQP9 mRNA expression was significantly increased in the ICKT group and the SRT/ICKT group compared with the NT group. The degree of Masson's trichrome staining in the SRT/ICKT group was significantly lower than that in the NT group. The degree of NF-κB staining in the SRT/ICKT group was significantly lower than that in the NT, ICKT, or SRT group. The postoperative administration of ICKT and SRT induced synergistic beneficial effects, resulting in the reduction of hepatic fibrosis via mechanisms involving the inhibition of NF-κB expression and the improvement of AQP9 downregulation.