NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

BACKGROUND: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. METHODS: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. RESULTS: Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. CONCLUSIONS: We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.

Percutaneous biliary stent removal for benign biliary stricture post hepaticojejunostomy.

This case report presents the percutaneous extraction of a biliary stent in a patient with a history of liver transplant and Whipple procedure, suffering from benign biliary stricture post hepaticojejunostomy. After failed management with conventional benign biliary protocol, a fully covered WallFlex biliary stent was percutaneously placed and later removed using a balloon catheter technique. The procedure demonstrated anastomosis patency without complications, providing a drain-free option for complex anatomy where endoscopic management was not feasible. This case contributes valuable insights to the limited literature on percutaneous stent removal for benign biliary strictures, emphasising the importance of considering alternative approaches in challenging clinical scenarios.

Loureirin B ameliorates cholestatic liver fibrosis via AKT/mTOR/ATG7-mediated autophagy of hepatic stellate cells.

AIM OF THE STUDY: Chronic cholestasis leads to liver fibrosis, which lacks effective treatment. In this study, we investigated the role and mechanisms of action of loureirin B (LB) in cholestatic liver fibrosis. MATERIALS AND METHODS: Bile duct ligation (BDL)-induced hepatic fibrosis mice were used as in vivo models. Transforming growth factor-ß1 (TGF-ß1)-pretreated HSC-T6 cells were used to explore the mechanism by which LB attenuates liver fibrosis in vitro. RNA sequencing, quantitative PCR (qPCR), western blotting, immunohistochemistry and immunofluorescence were performed to detect the fibrosis markers and measure autophagy levels. Flow cytometry, cell counting kit-8 (CCK-8) assay, and 5'-ethynyl-2'-deoxyuridine (EdU) assay were conducted to detect cell proliferation and viability. GFP-RFP-LC3 adenovirus, autophagy-related protein 7 (ATG7) siRNA, and bafilomycin A1 (BafA1) were used to verify autophagic flux. RESULTS: Our results showed that LB ameliorates liver injury, inhibits collagen deposition, and decreases the expressions of fibrosis-related markers in BDL-induced mouse livers. In vitro, we found that LB inhibited proliferation and migration, promoted apoptosis, and inhibited the activation of HSC-T6 cells pretreated with TGF-ß1. RNA sequencing analysis of HSC-T6 cells showed that LB treatment predominantly targeted autophagy-related pathways. Further protein analysis indicated that LB downregulated the expression of phosphorylated AKT (p-AKT) and phosphorylated mTOR (p-mTOR), and upregulated LC3-II, p62, and ATG7 both in vivo and in vitro. Intriguingly, ATG7 inactivation reversed the antifibrotic effects of LB on HSC-T6 cells. CONCLUSIONS: LB can improve BDL-induced liver fibrosis by inhibiting the activation and proliferation of HSCs and is expected to be a promising antifibrotic drug.

Complementary and alternative medicines and liver disease.

Complementary and alternative medicines (CAM) include conventional medical treatments. Patients worldwide use CAM at alarming rates; thus, reports of CAM-related DILI have been on the rise. The clinical presentations include asymptomatic liver test abnormalities, acute hepatitis with or without jaundice, acute cholestatic liver disease (bland or with hepatitis), acute liver failure, severe hepatitis with features of portal hypertension, and acute decompensation of known or unknown cirrhosis that can lead to acute-on-chronic liver failure. Acute hepatitis with or without necrosis, hepatocellular and canalicular cholestasis, herb-induced or CAM-triggered autoimmune hepatitis, granulomatous hepatitis, severe steatohepatitis, and vanishing bile duct syndrome are common liver biopsy findings in CAM-DILI. The presence of preexisting liver disease predicts severe liver injury, risk of progression to liver failure, and decreased transplant-free survival in patients with CAM-DILI. This review discusses global epidemiology and trends in CAM-DILI, clinical presentation, assessment and outcomes, commonly emerging threats in the context of hepatotoxic herbs, pragmatic assessment of "liver beneficial" herbs and health care myths, patient communication, regulatory framework, and future directions on research in CAM.

Discrimination of Etiologically Different Cholestasis by Modeling Proteomics Datasets.

Cholestasis is characterized by disrupted bile flow from the liver to the small intestine. Although etiologically different cholestasis displays similar symptoms, diverse factors can contribute to the progression of the disease and determine the appropriate therapeutic option. Therefore, stratifying cholestatic patients is essential for the development of tailor-made treatment strategies. Here, we have analyzed the liver proteome from cholestatic patients of different etiology. In total, 7161 proteins were identified and quantified, of which 263 were differentially expressed between control and cholestasis groups. These differential proteins point to deregulated cellular processes that explain part of the molecular framework of cholestasis progression. However, the clustering of different cholestasis types was limited. Therefore, a machine learning pipeline was designed to identify a panel of 20 differential proteins that segregate different cholestasis groups with high accuracy and sensitivity. In summary, proteomics combined with machine learning algorithms provides valuable insights into the molecular mechanisms of cholestasis progression and a panel of proteins to discriminate across different types of cholestasis. This strategy may prove useful in developing precision medicine approaches for patient care.

Clinical and genetic study of ABCB4 gene-related cholestatic liver disease in China: children and adults.

BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. CONCLUSION: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.

Mechanistic studies on the alleviation of ANIT-induced cholestatic liver injury by Polygala fallax Hemsl. polysaccharides.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygala fallax Hemsl. is a traditional folk medicine commonly used by ethnic minorities in the Guangxi Zhuang Autonomous Region, and has a traditional application in the treatment of liver disease. Polygala fallax Hemsl. polysaccharides (PFPs) are of interest for their potential health benefits. AIM OF THIS STUDY: This study explored the impact of PFPs on a mouse model of cholestatic liver injury (CLI) induced by alpha-naphthyl isothiocyanate (ANIT), as well as the potential mechanisms. MATERIALS AND METHODS: A mouse CLI model was constructed using ANIT (80 mg/kg) and intervened with different doses of PFPs or ursodeoxycholic acid. Their serum biochemical indices, hepatic oxidative stress indices, and hepatic pathological characteristics were investigated. Then RNA sequencing was performed on liver tissues to identify differentially expressed genes and signaling pathways and to elucidate the mechanism of liver protection by PFPs. Finally, Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to verify the differentially expressed genes. RESULTS: Data analyses showed that PFPs reduced the levels of liver function-related biochemical indices, such as ALT, AST, AKP, TBA, DBIL, and TBIL. PFPs up-regulated the activities of SOD and GSH, down-regulated the contents of MDA, inhibited the release of IL-1ß, IL-6, and TNF-α, or promoted IL-10. Pathologic characterization of the liver revealed that PFPs reduced hepatocyte apoptosis or necrosis. The RNA sequencing indicated that the genes with differential expression were primarily enriched for the biosynthesis of primary bile acids, secretion or transportation of bile, the reactive oxygen species in chemical carcinogenesis, and the NF-kappa B signaling pathway. In addition, the results of qRT-PCR and Western blotting analysis were consistent with those of RNA sequencing analysis. CONCLUSIONS: In summary, this study showed that PFPs improved intrahepatic cholestasis and alleviated liver damage through the modulation of primary bile acid production, Control of protein expression related to bile secretion or transportation, decrease in inflammatory reactions, and inhibition of oxidative pressure. As a result, PFPs might offer a hopeful ethnic dietary approach for managing intrahepatic cholestasis.

Multiscale X-ray phase-contrast CT unveils the evolution of bile infarct in obstructive biliary disease.

Bile infarct is a pivotal characteristic of obstructive biliary disease, but its evolution during the disease progression remains unclear. Our objective, therefore, is to explore morphological alterations of the bile infarct in the disease course by means of multiscale X-ray phase-contrast CT. Bile duct ligation is performed in mice to mimic the obstructive biliary disease. Intact liver lobes of the mice are scanned by phase-contrast CT at various resolution scales. Phase-contrast CT clearly presents three-dimensional (3D) images of the bile infarcts down to the submicron level with good correlation with histological images. The CT data illustrates that the infarct first appears on day 1 post-BDL, while a microchannel between the infarct and hepatic sinusoids is identified, the number of which increases with the disease progression. A 3D model of hepatic acinus is proposed, in which the infarct starts around the portal veins (zone I) and gradually progresses towards the central veins (zone III) during the disease process. Multiscale phase-contrast CT offers the comprehensive analysis of the evolutionary features of the bile infarct in obstructive biliary disease. During the course of the disease, the bile infarcts develop infarct-sinusoidal microchannels and gradually occupy the whole liver, promoting the disease progression.

Vertebral metastasis of hepatocellular carcinoma secondary to viral hepatitis B: case report of 2 patients.

Bone metastases from liver cancer are rare. We report two cases of bone metastases revealing HBV-induced HCC. A 26-year-old african man presented with 4 months of low back pain in the context of general deterioration. Examination revealed a lumbar spinal syndrome and hepatomegaly. Abdominal ultrasound revealed a multinodular liver, and a CT scan of the spine revealed osteolytic lesions. Biological tests revealed a hepatic cytolysis syndrome, hepatic cholestasis and hepatocellular insufficiency. Alpha foetoprotein levels were elevated and hepatitis B serology was positive. We adopted the diagnosis of HCC of viral B origin with bone metastasis. The second case involved a 44-year-old African man admitted for 10 days with back pain. Examination revealed a spinal syndrome, paraplegia and hepatomegaly. A thoracic-abdominal-pelvic CT scan revealed typical HCC lesions and osteolytic lesions on the ribs, pelvis and vertebrae. The biology revealed a biological inflammatory syndrome, hepatic cytolysis, a hepatocellular insufficiency syndrome and a cholestasis syndrome. Alfa-feto proteins were elevated and HBV serology was positive. The diagnosis of bone metastasis of HCC secondary to HBV infection was accepted.

Factors affecting survival in patients undergoing percutaneous transhepatic biliary drainage for malignant biliary obstruction.

OBJECTIVE: The general approach to malignant biliary obstruction (MBO) is to provide drainage in all patients with jaundice. However, the procedure is often palliative, and its contribution to survival is debated. This study aimed to investigate prognostic factors in patients undergoing percutaneous transhepatic biliary drainage (PTBD) for MBO. PATIENTS AND METHODS: All laboratory values were divided into two groups based on median values: low and high. Chi-square analysis was performed for dichotomous data. The time from the PTBD procedure to the date of death or last follow-up was considered overall survival (OS). Univariate and multivariate analyses were calculated using the Cox regression model. RESULTS: A total of 152 patients were included in the study, of whom 84 (55.3%) were male. The median OS was 71 ± 12.6 days (95% CI: 46.3-95.7). The 1, 3, 6, and 12-month OS rates were 74.3%, 45.2%, 29.2%, and 13%, respectively. In the multivariate analysis, comorbidity (p=0.029), Eastern cooperative oncology group performance status (ECOG PS) (p=0.007), pre-PTBD albumin (p=0.025), post-PTBD aspartate aminotransferase (p=0.025), chemo naive (p<0.001), and post-PTBD chemotherapy (CT) (p=0.01) were found to be independent prognostic factors. CONCLUSIONS: In patients with poor prognosis MBO, the decision for PTBD should be made multidisciplinarily, taking into consideration ECOG PS, comorbidities, albumin levels, and prior CT status.

Stauffer syndrome : a rare paraneoplastic complication of renal cell carcinoma to be kept in mind. Case report and literature survey.

The authors report the case of a 74-years-old woman treated by immunotherapy for a metastatic renal cell carcinoma and having developed an important cholestasis with thrombocytosis, increased CRP, leucocytosis and hypoalbuminemia. Liver remained free of metastases at medical imaging. The diagnosis of a Stauffer syndrome was confirmed by the hepatic biopsy. A complete response of liver disorders was obtained after nephrectomy. From literature survey, Stauffer syndrome should be kept in mind in cancer patients, especially those suffering from a renal cell carcinoma, presenting with cholestasis with no underlying cause.

[Choledochal cysts: surgical treatment in newborns and infants]. / Kisty kholedokha: osobennosti khirurgicheskogo lecheniya u detei pervykh trekh mesyatsev zhizni.

OBJECTIVE: To improve postoperative outcomes in newborns and infants with choledochal cysts and to determine the indications for surgery. MATERIAL AND METHODS: There were 13 children aged 0-3 months with choledochal cyst who underwent reconstructive surgery between 2019 and 2023. In all children, choledochal cyst was associated with cholestasis. Acholic stool was observed in almost half of the group (n=7). All children underwent cyst resection and Roux-en-Y hepaticoenterostomy. RESULTS: Symptoms of cholestasis regressed in all patients. Mean surgery time was 128±27 min. There were no complications. Enteral feeding was started after 1-2 postoperative days, abdominal drainage was removed after 6.2±1.6 days. Mean length of hospital-stay was 16±3.7 days. Adequate bile outflow is one of the main principles. For this purpose, anastomosis with intact tissues of hepatic duct should be as wide as possible. Roux-en-Y loop should be at least 40-60 cm to prevent postoperative cholangitis. CONCLUSION: Drug-resistant cholestasis syndrome and complicated choledochal cysts (cyst rupture, bile peritonitis) are indications for surgical treatment in newborns and infants. When forming Roux-en-Y hepaticoenterostomy, surgeon should totally excise abnormal tissues of the biliary tract to prevent delayed malignant transformation.

[Design of an improved percutaneous transhepatic cholangio drainage tube based on MRCP imaging data].

Objective: Quantified MRCP imaging data was used as a reference for design and preparation of a modified percutaneous transhepatic cholangio drainage (PTCD) tube. Methods: 3.0 T upper abdominal MR and MRCP imaging data of 2 300 patients treated from July 2015 to July 2020 at the Department of Radiology of the Affiliated Cancer Hospital of Zhengzhou University were screened and a total of 381 patients diagnosed with biliary duct structures were identified. Causative etiologies among these patients included pancreatic adenocarcinoma (pancreatic head), cholangiocarcinoma, ampullary carcinoma, as well as intrahepatic and/or extrahepatic bile duct dilation. An improved PTCD tube was designed based on MRCP quantification of left and right hepatic and common hepatic duct length. Results: In the setting of biliary obstruction caused by malignancy, the distance of the left hepatic duct from its origin to the point of left and right hepatic duct confluence was 15.9±3.8 mm, while the distance of the right hepatic duct from its origin to the point of left and right hepatic duct confluence was 12.4±3.2 mm; the length of the bile duct from its origin to the point of left and right hepatic duct confluence was 34.0±8.1 mm. The improved PTCD tube design incorporated an altered length of the drainage orifice. Conclusion: MRCP imaging of the biliary tract is effective for measuring biliary tract length in the setting of pathological dilation. Based on our biliary tract measurements, a modified PTCD tube was designed to more effectively meet drainage requirements and manage biliary obstruction caused by Bismuth-Corlette type Ⅱ and Ⅲ malignancies.