OBJECTIVE: To investigate the clinical and genetic features of a Chinese pedigree with Progressive familial intrahepatic cholestasis (PFIC) and explore its genotype-phenotype correlation. METHODS: A patient with PFIC diagnosed at Xinxiang Central Hospital in 2023 was selected as the study subject. The patient was subjected to abdominal magnetic resonance imaging (MRI) and painless gastroscopy. Peripheral blood samples were collected from the patient and his parents for the extraction of genomic DNA and trio-whole exome sequencing (trio-WES). Candidate variants were verified by Sanger sequencing. This study has been approved by the Medical Ethics Committee of Xinxiang Hospital (Ethics No. 2023-241). RESULTS: MRI scan showed that the patient had significantly enlarged liver and spleen. WES revealed that he has harbored compound heterozygous variants of the ATP8B1 gene, including a c.1710_1711insCCTC (p.A571Pfs*12) frameshifting variant in exon 16 and a c.2989G>A (p.V997M) missense variant in exon 24, which were respectively inherited from his father and mother, and rated as pathogenic (PVS1+PM2_Supporting+PM3+PP1) and likely pathogenic (PM2_Supporting+PM3+PP1) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). CONCLUSION WES can clarify the genetic etiology of patients with speed and accuracy, and facilitate clinical decision-making. The detection of pathogenic variants has provided a basis for clinical diagnosis and enriched the mutational spectrum of the ATP8B1 gene.
Humans ; Male ; Pedigree ; Cholestasis, Intrahepatic/diagnostic imaging* ; Adenosine Triphosphatases/genetics* ; Female ; Adult ; Exome Sequencing ; Mutation ; East Asian People

OBJECTIVE: To explore the clinical manifestations and genetic etiology of a child with Progressive familial intrahepatic cholestasis (PFIC2). METHODS: From April 2024 to June 2024, a child with jaundice, hepatomegaly and abnormal liver function who was repeatedly admitted to the First Department of Pediatrics of Qinzhou Maternal and Child Health Care Hospital was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples were collected from the child and her parents. Genomic DNA was extracted for trio-whole exome sequencing, the candidate variant was verified by Sanger sequencing and bioinformatic analysis using REVEL, BLAST/BLAT, Swiss-Model and Swiss-Pdb Viewer software. This study was approved by the Medical Ethics Committee of the Qinzhou Maternal and Child Health Care Hospital (Ethics No.: L20240116). RESULTS: The child was a 1.5-month-old female. Her main clinical manifestations included jaundice, hepatomegaly, brownish urine and earth-like stool. Laboratory examination showed increased levels of bilirubin, mainly direct bilirubin, increased aminotransferase, especially glutamic oxalacetic aminotransferase, accompanied by increased bile acid. Genetic testing revealed that the she has harbored a homozygous c.3410T>G (p.V1137G) variant of the ABCB11 gene, for which both of her parents were heterozygous carriers. The variant was unreported previously, and was predicted to be pathogenic based on REVEL. Prediction with BLAST/BLAT software showed that the amino acids were highly conserved among different species. Swiss-Pdb Viewer software predicted that the variant has resulted in changes in hydrogen bonds between amino acids. According to the guidelines from the American Collage for Medical Genetics and Genomics (ACMG), the variant was determined to be likely pathogenic (PM1+PM2_Supporting+PM3_Supporting+PP3_Moderate). CONCLUSION The homozygous variant of the ABCB11 gene may be the genetic cause of this child. Genetic testing is helpful for confirming the diagnosis and enrich the mutational spectrum of the ABCB11 gene.
Humans ; Cholestasis, Intrahepatic/genetics* ; Female ; Infant ; ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics* ; Homozygote ; Mutation

OBJECTIVE: To explore the clinical manifestation and genotype of a child with Progressive familial intrahepatic cholestasis 8 (PFIC8) due to variant of KIF12 gene. METHODS: A child diangosed with PFIC8 at Changzhou Children's Hospital in October 2017 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples (3 mL each) were collected from the patient, her parents and younger sister. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variants were validated using Sanger sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was classified. This study has been approved by the Medical Ethics Committee of Changzhou Children's Hospital (Ethics No.: 2023-002). RESULTS: The main clinical manifestations of the child included high GGT cholestasis, portal hypertension, splenomegaly, and abnormal liver enzymes. WES revealed that she has harbored compound heterozygous variants of the KIF12 gene, namely c.245G >A (p.Arg82Gln) and c.1291del (p.Ser431Valfs*13). Bioinformatics analyses showed that both variants were pathogenic. A total of 25 cases were reported in 7 English literature, including 13 males and 12 females. All patients had presented with high GGT cholestasis. Some had progressed to cirrhosis, and 3 cases also had renal lesions. No death was reported. Six children were treated with LTx. Nineteen children were found to harbor homozygous variants of the KIF12 gene, and the remaining six harbored compound heterozygous variants of the same gene. The most common mutation was c.655C>T (p.Arg219*). The mutation sites are mainly located in the Kinesin motor catalytic domain, with high GGT cholestasis as the main clinical feature. No correlation was found between the genotype and phenotype. CONCLUSION PFIC8 caused by KIF12 deficiency is mainly characterized by high GGT cholestasis, for which there is no effective treatment. The c.245G>A and c.1291del compound heterozygous variants of the KIF12 gene probably underlay the pathogenesis in this child.
Humans ; Kinesins/genetics* ; Female ; Cholestasis, Intrahepatic/genetics* ; Phenotype ; Heterozygote ; Child ; Mutation ; Child, Preschool ; Male ; Exome Sequencing

OBJECTIVE: To explore the clinical phenotype and genetic characteristics of a child with Progressive familial intrahepatic cholestasis type 8 (PFIC8). METHODS A child with PFIC diagnosed at Beijing Children's Hospital Affiliated to Capital Medical University in September 2025 was selected as the study subject. Peripheral venous blood samples were collected from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variants were validated by Sanger sequencing. The pathogenicity of the candidate variants was classified based on the guidelines from American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Beijing Children's Hospital Affiliated to Capital Medical University (Ethics No.: 2023-E-126-Y). RESULTS: The proband, a 2-month-old female infant, had manifested jaundice of the skin and sclera, and slightly distended abdomen. She had no visible abdominal wall varicose veins, soft abdomen, and no palpable masses. Biliary atresia was ruled out by intraoperative cholangiography. WES revealed that she has harbored compound heterozygous variants of KIF12 gene, namely c.809C>T (p.Ala270Val) and c.1313G>A (p.Arg438Lys), which were verified by Sanger sequencing to have derived from her mother and father, respectively. According to the ACMG guidelines, both variants were classified as variants of uncertain significance (VUS). Based on the pre-defined search strategy, 10 articles were retrieved, which involved 25 PFIC cases, including 5 from China. Together with the proband of this study, the 26 PFIC patients have primarily presented with high GGT cholestasis, with the genetic cause in all cases attributed to variants of the KIF12 gene. CONCLUSION The c.809C>T and c.1313G>A compound heterozygous variants of the KIF12 gene probably underlay the pathogenesis of cholestatic liver disease in this child. Above findings have enriched the mutational and phenotypic spectra of PFIC8.
Humans ; Kinesins/genetics* ; Female ; Cholestasis, Intrahepatic/genetics* ; Infant ; Heterozygote ; Mutation ; Exome Sequencing ; Male

Duplication of common bile duct is a rare anatomic congenital anomaly of the biliary tree that may present with many types. Such cases are usually clinically silent unless presented with other concomitant conditions that may also be symptomatic in normal variants. Obstruction of the duplicated common bile ducts due to bile duct stones or choledocholithiasis have also been seldom reported. Hence, we present a case of a 42-year-old female, presenting with abdominal pain and jaundice, with incidental finding of duplication of common bile duct Type IV, with choledocholithiases of duplicates on intra-operative cholangiogram. This will be the first in its kind to adequately document and report the intra-operative findings of this anatomic congenital anomaly in our locale.

Human ; Female ; Adult: 25-44 Yrs Old ; Choledocholithiasis ; Cholangiography ; Common Bile Duct ; Biliary Tract ; Bile Ducts ; Abdominal Pain ; Bile

Laparoscopic management of a giant choledochal cyst (CC) in an infant is a technically demanding surgical endeavor that requires specialized training and meticulous planning. Laparoscopic CC surgery presents unique challenges due to the limited operative space, delicate anatomy, and technical demands of the procedure, being both excisional and reconstructive. These challenges are magnified when presented with an infant with a giant CC. In this report, we are going to present the challenges encountered and share the various steps that allowed our team to overcome these challenges.

Our patient is an 11-month-old female, 8.6 kg female who presented to our institution with a RUQ mass, jaundice, and a CT scan showing a large type 1 saccular choledochal cyst. After careful review, our team attempted and successfully performed a laparoscopic cholecystectomy with en bloc excision of the CC and hepaticoduodenostomy reconstruction.

The main challenge is the limited operative space. Once addressed, we felt confident we could complete the procedure laparoscopically. Operative time was 270 minutes. Feeding was resumed at postoperative day 5. Patient was discharged on postoperative day 7. There were no reported intraoperative and postoperative complications. The child remained well with no issues on postoperative reviews. Laparoscopic excision of a giant choledochal cyst in an infant is feasible, effective and safe with good outcomes. Preoperative planning, creative port placement, use of multichannel port, gauze, bipolar shears and needle cyst decompression are key in the successful performance of this elusive and challenging operation.

Human ; Female ; Infant: 1-23 Months ; Choledochal Cyst ; Cholecystectomy, Laparoscopic ; Decompression ; Postoperative Complications ; Jaundice

OBJECTIVE

Phenobarbital is an inductor of microsomal hepatic enzyme and used as choleretic for cholestatic liver disease to enhance bile flow. It is also used as a premedication for hepatobiliary scintigraphy (HIDA) scan to improve diagnostic accuracy for an obstructive liver disease. We reviewed the available literature on the use of Phenobarbital for treatment of cholestasis and its utility as a premedication for HIDA scan.

METHODS

All published studies before June 30, 2023 that investigated the efficacy, effectiveness or safety of Phenobarbital in cholestatic jaundice and its effect on the accuracy of hepatobiliary scintigraphy in diagnosis of obstructive jaundice were included. Electronic databases were searched including MEDLINE via PubMed, Cochrane Library, medRxIV, BioRxIV, as well as the following registries for ongoing and completed trials: ClinicalTrials.gov (USA); ChiCTR.org. (China); and the WHO International Clinical Trials Registry Platform. We screened abstracts, reviewed full texts, and extracted relevant information on study design, settings, population and outcomes. There was no age and language restriction. Two reviewers independently rated the quality of included studies using: Joanna Briggs Institute critical appraisal tool for case reports, case series, and diagnostic accuracy; Newcastle – Ottawa Quality Assessment Scale for cohort studies, and Cochrane Risk of Bias for Randomized Trials. Risk of bias was appraised and GRADE certainty of evidence was judged. Pooled analysis was done using Stata 14 and reported as sensitivity and specificity.

RESULTS

Included were nine reports on Phenobarbital as treatment for cholestasis (one case report, five case series, one cohort and two randomized studies) and seven studies (four diagnostics, two cohorts, one randomized trial) on its use as a premedication for HIDA scan. The quality of case report and case series were considered fair; cohort studies as good; and diagnostic studies were included based on overall assessment. The randomized studies had some or high risk for bias due to concerns in randomization process, measurement of outcome, and risk in the selection of reported results.

There were 31 patients (16 adults and 15 children) from case reports and case series. Of the 16 adults, serum total bilirubin concentrations declined from 4 to 70% from baseline in 13 of 15 (87%) patients after Phenobarbital was given at 120 to 250 mg per day from 22 days to f ive months. Eleven of 14 with pruritus at onset also had improvement in intensity of itching. Of the 15 pediatric patients, ten (67%) showed a decrease from 10 to 60% of the baseline total bilirubin but not a normalization with Phenobarbital intake at a dose of 3 to 12 mg/kg/day from one to 21 months. Five of 14 children also had relief of itching after treatment.

Phenobarbital compared to Ursodeoxycholic acid had limited efficacy in reducing the bilirubin levels in neonates and young infants with cholestasis.

Phenobarbital compared to Ursodeoxycholic acid had limited efficacy in reducing the bilirubin levels in neonates and young infants with cholestasis.

Moderate certainty evidence showed that with Phenobarbital pretreatment, the hepatobiliary scan done on patients with neonatal cholestasis had 100% (CI 99.2, 100; I2 = 0.0%) sensitivity and 80.2% (CI 65.4, 92.1; I2 = 76.6%) specificity while no Phenobarbital pretreatment had 100% (94.9, 100; I2 = 0.0%) sensitivity and 89.5% (CI 77.0, 98.1; I2 = 11.4%) specificity. Adverse effects of Phenobarbital were drowsiness, lethargy, poor feeding, and irritability.

CONCLUSION

There was limited effectiveness of Phenobarbital in decreasing bilirubin levels in cholestatic liver disease. Moderate certainty evidence demonstrated that premedication with Phenobarbital did not improve the specificity of HIDA scan in the diagnosis of obstructive jaundice of infancy. Neurologic symptoms were observed with Phenobarbital intake.

Phenobarbital ; Cholestasis ; Scintigraphy ; Radionuclide Imaging ; Pruritus

Cholangiocarcinoma (CCA) is a malignant tumor originating from cholangiocytes. However, it remains unclear about the pathogenesis of this carcinoma, which may be related to multiple factors. Currently, CCA is mainly treated by surgery, chemotherapy, and radiotherapy. Among them, surgery is the only potentially curative option for CCA. Nevertheless, the high malignancy and asymptomatic nature of CCA may lead to poor treatment outcomes. It has been demonstrated that Chinese medicine (CM) plays a significant role in various antitumor applications. Meanwhile, CM exhibits fewer side effects and high availability. Moreover, the in vitro application of CM monomers has been explored in many domestic and foreign studies. This article mainly reviews the signaling pathways and molecular mechanisms of CM monomers in the treatment of CCA in recent years. These findings are expected to provide new insights into the treatment of CCA.
Cholangiocarcinoma/drug therapy* ; Humans ; Drugs, Chinese Herbal/pharmacology* ; Bile Duct Neoplasms/drug therapy* ; Medicine, Chinese Traditional ; Animals ; Signal Transduction/drug effects*

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder. Its occurrence secondary to hepatobiliary malignancies is even rarer, and without timely diagnosis and treatment, the mortality rate is extremely high. There is a need to raise awareness of this disease. This report describes a case of a 70-year-old female patient diagnosed with AHA 2 months after surgery for cholangiocarcinoma, admitted to the Second Affiliated Hospital of Bengbu Medical College in October 2022. The patient presented with subcutaneous hematoma in both lower limbs. Coagulation function tests showed a markedly prolonged activated partial thromboplastin time (APTT) of 74.5 seconds, with no correction in the APTT mixing test. Coagulation factor assays revealed a severely reduced coagulation factor VIII activity (FVIII:C) of 0.3%, and an inhibitor titer of 25.6 BU/mL was detected. After ruling out other potential causes, the patient was diagnosed with cholangiocarcinoma-associated AHA. With chemotherapy to control the primary tumor, alongside hemostatic and immunosuppressive therapy for inhibitor eradication, AHA was brought under control. The patient had no further coagulation abnormalities or bleeding, enabling timely and full-course chemotherapy for cholangiocarcinoma and significantly improving survival and quality of life. Therefore, in patients with malignancies who present with spontaneous bleeding or unusual bleeding following surgery, trauma, or invasive procedures, clinicians should be alert to the possibility of secondary AHA. Timely diagnosis and treatment can significantly improve prognosis.
Humans ; Cholangiocarcinoma/surgery* ; Female ; Hemophilia A/drug therapy* ; Aged ; Bile Duct Neoplasms/surgery* ; Factor VIII

OBJECTIVES: To study the therapeutic mechanism of Tuihuang Mixture against cholestasis. METHODS: Forty-eight Wistar rats were randomized equally into blank group, model group, ursodeoxycholic acid group and Tuihuang Mixture group. Except for those in the blank group, all the rats were given α‑naphthylisothiocyanate (ANIT) to establish rat models of cholestasis, followed by treatments with indicated drugs or distilled water. Serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL of the rats were determined, and hepatic expressions IL-1β, IL-18, FXR, NLRP3, ASC, Caspase-1 and GSDMD were detected using q-PCR, ELISA or Western blotting. Histopathological changes of the liver tissues were observed using HE staining. RESULTS: The rat models of cholestasis had significantly increased serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL with increased mRNA and protein expressions of IL-1β and IL-18, decreased protein and mRNA expressions of FXR, and increased protein expressions of NLRP3 and Caspase-1 and mRNA expressions of NLRP3, ASC, Caspase-1 and GSDMD in the liver tissue, showing also irregular arrangement of liver cells, proliferation of bile duct epithelial cells and inflammatory cells infiltration. Treatment of the rat models with Tuihuang Mixture significantly decreased serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL, lowered IL-1β and IL-18 and increased FXR protein and mRNA expressions, and reduced NLRP3, ASC, Caspase-1 and GSDMD proteins and NLRP3, ASC and Caspase-1 mRNA expressions in the liver tissue. Tuihuang Mixture also significantly alleviated hepatocyte injury, bile duct epithelial cell proliferation and inflammatory cell infiltration in the liver of the rat models. CONCLUSIONS Tuihuang Mixture can effectively improve cholestasis in rats possibly by inhibiting NLRP3 inflammatosome-mediated pyroptosis via regulating FXR.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein ; Rats ; Receptors, Cytoplasmic and Nuclear/metabolism* ; Cholestasis/drug therapy* ; Rats, Wistar ; Inflammasomes/metabolism* ; 1-Naphthylisothiocyanate ; Drugs, Chinese Herbal/therapeutic use* ; Male ; Interleukin-18/metabolism* ; Caspase 1/metabolism* ; Interleukin-1beta/metabolism* ; Liver/metabolism*