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Cholecystocutaneous Fistula (CCF) is a type of external biliary fistula, which connects the gallbladder with the skin. Thilesus first described this phenomenon in 1670. There is usually a history of calculi in the gallbladder or neglected gallbladder disease. The incidence of CCF is rare, most patients are elderly females with the mean age of 72.8 years old. They usually present with chronic calculus cholecystitis or a history of a previous surgical intervention. US, CT, MRI, MRCP and (CT or X-ray) fistulogram are used to confirm the diagnosis. CT was more significant than US in identifying the track of the fistula and the fluid that runs throw it. CCF patients presented with systemic symptoms (fever, nausea and vomiting) or local symptoms. RUQ region is the most common site of external opening. Open cholecystectomy with excision of the fistulous tract is considered an acceptable option for treatment and it is curative in most cases. However, laparoscopic approach can be another option with experience surgeons., Highlights • Cholecystocutaneous Fistula (CCF) is a type of external biliary fistula, which connects the gallbladder with the skin. • Most patients present with chronic calculus cholecystitis or with a history of a previous surgical intervention. • Patients treated with conservative or surgical way. • We clarified, and in numbers, the possible pathogens that might be the main cause of the CCF. • A new comprehensive illustration of the CCF.

Background Liver biopsy is often necessary to obtain a diagnosis in dogs with hepatobiliary disease. Hemorrhage after biopsy is a concern. Objective To describe the extent of hemorrhage and incidence of complications after percutaneous ultrasound guided liver biopsy (PUGLB) in dogs and to examine risk factors for hemorrhage or complications. Animals One hundred two client owned dogs with suspected hepatobiliary disease that underwent PUGLB. Methods Medical records were retrospectively reviewed. Using human guidelines, major hemorrhage was defined as an absolute decrease in the PCV (ΔPCV) ≥ 6%. Complications were defined separately as clinically relevant physiologic compromise that necessitated intervention or death. The relationship between ΔPCV and the occurrence of complications and the initial PCV, coagulation variables, serum activity of liver-derived enzymes, serum bilirubin concentration, number of biopsies, biopsy needle gauge, radiologist experience, histological diagnosis, and ultrasound variables were compared. Results Before PUGLB, most aberrations in coagulation variables were mild. After biopsy a decrease in PCV occurred in 87/102 (85.3%) dogs. The mean ΔPCV was -7.2% ± 4.5%. Major hemorrhage occurred in 43/102 (42.2%) dogs and complications in 2/102 (1.9%). ΔPCV was significantly positively correlated with PCV before biopsy (r = .47, P = .004). There was no correlation between ΔPCV or complications with any of the variables examined. Conclusion and clinical importance Percutaneous ultrasound guided liver biopsy in the population of dogs in the current study, with normal or mild abnormalities in coagulation, results in a high incidence of clinically silent, major hemorrhage (42.5%), but few complications (1.9%).

BACKGROUND AND AIMS This study aimed to evaluate whether serum bilirubin levels were associated with cancer development in a population without liver disease. METHODS A retrospective longitudinal study was performed by including participants who underwent a health checkup at St. Luke's International Hospital in Tokyo from 2005 to 2019. We excluded those with liver diseases or prior history of cancer at baseline. All participants were classified into four groups according to their total bilirubin (T-Bil) level: very low (

Background: Conventionally it is assumed that raised level of CA 19-9 (Carbohydrate antigen 19-9) is related to malignancies of liver, pancreas and biliary tract. Through our early experience in Shaheed Suhrawardy Medical College Hospital we found that raised level of CA 19-9 is not associated only with malignancies but also with other benign disorders of HBS. The aim of this study was to explore the relationship of raised CA 19-9 with hepatobiliary disorders other than malignancies. Result: We encountered a total of 57 cases at our department of Hepatobiliary Surgery where patients presented with classical features of obstructive jaundice with pain, anorexia and vomiting. Routine investigations of USG and MRCP revealed stone disease in the CBD. Fiftyseven patients with obstructive jaundice were studied retrospectively. Serum CA19-9 levels and some additional biochemical parameters were evaluated before and after treatment. CA 19-9 levels were significantly elevated in most patients, along with levels of total bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGT), and 10 patients with benign disorders had extraordinarily high levels of these markers (> 1000 U/mL). The mean CA 19-9 level in the malignant group was greater than that in the benign group (826.83 ± 557.34 vs. 401.92 ± 483.92 U/mL, P = 0.005), and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for CA19-9 were 100%, 7.69%, 33.33% and 47.47%, respectively. CA19-9 levels in the whole cohort were correlated with ALP (r = 0.77, P < 0.001), GGT (r = 0.83, P < 0.001), bilirubin (r = 0.69, P < 0.001), and CRP (r = 0.37, P = 0.004). The reduction in serum level of CA19-9 after treatment in the malignant group was remarkably less than that observed in the benign group (97.26 ± 123.24 U/mL vs. 352.71 ± 397.29 U/mL, P < 0.001). CA 19-9 levels may not be sufficient to distinguish between malignant and benign obstructive jaundice diseases. So raised CA 19-9 can obviously denote any hepatobiliary disease other than malignancy that will start to decline 1 to 28 days later after extraction of stone. Conclusion: In conclusion, it is obvious that raised level of CA 19-9 is associated not only with malignancies but also with other benign disorders of HBS to a larger scale. J Shaheed Suhrawardy Med Coll, December 2019, Vol.11(2); 119-123

Cholangitis is a common cause of hepatobiliary disease in the cat. Feline cholangitis is characterized as neutrophilic (acute or chronic), lymphocytic, or caused by liver flukes. The neutrophilic form is caused by bacterial infection of the biliary system, and identification of the specific bacterial agent guides treatment. Bile is the sample of choice for cytology and bacterial culture in these cases, and percutaneous ultrasound-guided cholecystocentesis is used to obtain that sample. This review covers the literature that provides evidence for safety and usefulness of percutaneous ultrasound-guided cholecystocentesis as part of the diagnostic work-up of cats suspected of having hepatobiliary disease.

ObjectiveThere is limited prospective evidence on the association of physical activity with hepatobiliary cancer subtypes and other major hepatobiliary diseases, especially in China. We aimed to quantify the associations with risk of these diseases.MethodsThe study population involved 460 937 participants of the prospective China Kadoorie Biobank aged 30–79 years from 10 diverse areas in China without history of cancer or hepatobiliary disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HRs) for each disease associated with self-reported total and domain-specific physical activity (occupational and non-occupational, ie, leisure time, household and commuting).ResultsDuring ~10 years of follow-up, 22 012 incident cases of hepatobiliary diseases were recorded. The overall mean (SD) total physical activity was 21.2 (13.9) metabolic equivalent of task (MET)-hours/day, with 62% from occupational activity. Total physical activity was inversely associated with hospitalised non-alcoholic fatty liver disease (HR comparing top vs bottom quintile: 0.62, 95% confidence interval (CI) 0.53 to 0.72), viral hepatitis (0.73, 95% CI 0.62 to 0.87), cirrhosis (0.76, 95% CI 0.66 to 0.88) and liver cancer (0.81, 95% CI 0.71 to 0.93), as well as gallstone disease (0.86, 95% CI 0.81 to 0.90), gallbladder cancer (0.51, 95% CI 0.32 to 0.80) and biliary tract cancer (0.55, 95% CI 0.38 to 0.78). The associations for occupational physical activity were similar to those for total physical activity, but for non-occupational physical activity they differed by disease subtype. For leisure-time physical activity, there was an inverse association with liver cancer and an inverse trend for gallstone disease (HR comparing ≥7.5 MET-hours/day with none: 0.83, 95% CI 0.75 to 0.91 and 0.82, 95% CI 0.66 to 1.01).ConclusionAmong Chinese adults, high total physical activity, particularly occupational physical activity, was inversely associated with risk of major hepatobiliary cancers and diseases, including non-alcoholic fatty liver disease, cirrhosis and certain types of cancer.

Background The human liver fluke Opisthorchis viverrini is a food-borne trematode that causes hepatobiliary disease in humans throughout Southeast Asia. People become infected by consuming raw or undercooked fish containing metacercariae. Development of a vaccine to prevent or minimize pathology would decrease the risk of severe morbidity, including the development of bile duct cancer. Methods We produced an oral vaccine based on recombinant Bacillus subtilis spores expressing the large extracellular loop (LEL) of O. viverrini tetraspanin-2 (Ov-TSP-2), a protein that is abundant on the surface of O. viverrini secreted extracellular vesicles (EVs). Recombinant spores expressing Ov-TSP-2-LEL were orally administered to hamsters prior to challenge infection with O. viverrini metacercariae. Results Vaccinated hamsters generated serum IgG as well as bile IgG and IgA responses to Ov-TSP-2-LEL, and serum IgG from vaccinated hamsters blocked the uptake of fluke EVs by a human bile duct epithelial cell line. Vaccinated hamsters had 56% reductions in both adult flukes and fecal eggs compared to the control group. Conclusions These findings indicate that oral vaccination of hamsters with recombinant B. subtilis spores expressing Ov-TSP-2-LEL is efficacious at reducing infection intensity and could form the basis of a vaccine for control of carcinogenic liver fluke infection in humans.

Swertia mussotii Franch. has been widely used in Tibetan folk medicine as an important drug ingredient for the treatment of hepatitis and hepatobiliary disease and for homeopathic purposes. But the lacking natural resources of S. mussotii is becoming more obvious with increasing market demands. The main objective of this work was to examine genetic differentiation among S. mussotii populations from different geographical locations and use the knowledge gained to facilitate future selection of the species suitable for large-scale cultivation to meet the increasing demand for medicinal use of this plant. In this study, 68 S. mussotii Franch samples collected from Zhongda (16), Chengduo (16), and Xiewu (8) County in Qinghai Province, Xiaojin (14) and Jinchuan (14) County in Sichuan Province, China and 4 samples from related species, were genotyped using genotyping-by-sequencing (GBS) technique. GBS scored 4095 SNPs with a minor-allele frequency > 0.25 and an average read depth

Objective The purpose of this study was to evaluate the feasibility and safety in terms of prognostic significance and perioperative morbidity and mortality of cytoreduction in patients affected by advance ovarian cancer and hepato-biliary metastasis. Methods Patients with a least one hepatobiliary metastasis who have undergone surgical treatment with curative intent of were considered for the study. Perioperative complications were evaluated and graded with Accordion severity Classification. Five-year PFS and OS were estimated using the Kaplan–Meier curve. Results Sixty-seven (20.9%) patients had at least one metastasis to the liver, biliary tract, or porta hepatis. Forty-four (65.7%) and 23 (34.3%) patients underwent respectively high and intermediate complexity surgery according. Complete cytoreduction was achieved in 48 (71.6%) patients with hepato-biliary disease. In two patients (2.9%) severe complications related to hepatobiliary surgery were reported. The median PFS for the patients with hepato-biliary involvement (RT = 0 vs. RT > 0) was 19 months [95% confidence interval (CI) 16.2–21.8] and 8 months (95% CI 6.1–9.9). The median OS for the patients with hepato-biliary involvement (RT = 0 vs. RT > 0) 45 months (95% CI 21.2–68.8 months) and 23 months (95% CI 13.9–32.03). Conclusions Hepatobiliary involvement is often associated with high tumor load and could require high complex multivisceral surgery. In selected patients complete cytoreduction could offer survival benefits. Morbidity related to hepatobiliary procedures is acceptable. Careful evaluation of patients and multidisciplinary approach in referral centers is mandatory.

BackgroundFor many children with intrahepatic cholestasis and high-serum gamma-glutamyl transferase (GGT) activity, a genetic aetiology of hepatobiliary disease remains undefined. We sought to identify novel genes mutated in children with idiopathic high-GGT intrahepatic cholestasis, with clinical, histopathological and functional correlations.MethodsWe assembled a cohort of 25 children with undiagnosed high-GGT cholestasis and without clinical features of biliary-tract infection or radiological features of choledochal malformation, sclerosing cholangitis or cholelithiasis. Mutations were identified through whole-exome sequencing and targeted Sanger sequencing. We reviewed histopathological findings and assessed phenotypical effects of ZFYVE19 deficiency in cultured cells by immunofluorescence microscopy.ResultsNine Han Chinese children harboured biallelic, predictedly complete loss-of-function pathogenic mutations in ZFYVE19 (c.314C>G, p.S105X; c.379C>T, p.Q127X; c.514C>T, p.R172X; c.547C>T, p.R183X; c.226A>G, p.M76V). All had portal hypertension and, at liver biopsy, histopathological features of the ductal plate malformation (DPM)/congenital hepatic fibrosis (CHF). Four children required liver transplantation for recurrent gastrointestinal haemorrhage. DPM/CHF was confirmed at hepatectomy, with sclerosing small-duct cholangitis. Immunostaining for two primary-cilium axonemal proteins found expression that was deficient intraluminally and ectopic within cholangiocyte cytoplasm. ZFYVE19 depletion in cultured cells yielded abnormalities of centriole and axoneme.ConclusionBiallelic ZFYVE19 mutations can lead to high-GGT cholestasis and DPM/CHF in vivo. In vitro, they can lead to centriolar and axonemal abnormalities. These observations indicate that mutation in ZFYVE19 results, through as yet undefined mechanisms, in a ciliopathy.

Background: Antibiotics are most commonly used prophylactically in a surgical set up. Avoidance of infection helps in early wound healing. Various guidelines are available for the use of antibiotics for surgical prophylaxis. Indiscriminate use of wide spectrum, newer antibiotics has lead to the problem of antibiotic resistance. Our aim was to evaluate the gap between the guidelines and the choice of antibiotics in a tertiary care hospital located in the sub Himalayan area. Materials and Methods: Data of all the patients who underwent surgery was analysed. Results: Record sheets of total 746 cases were included in the study. 376 (50.4%) patients were males and 370 (49.6%) were females. Maximum numbers of patients were from age group 36-45 years. Mean age SD of patients was 40.57 17.46. 572 (76.6%) patients stayed in hospital for 2 to 10 days, 138(18.5%) for 11 to 20 days, 24(3.3%) for 21 to 30 days, 6(.8%) for 31 to 40 days and 6 (.8%) for>40 days. 274 (36.6%) patients suffered from Hepatobiliary diseases, appendicitis was in 99 (13.3%), gastro-intestinal diseases in 98 (12.2%), hernias in 93 (12.47%), urinary system diseases in 30 (4.21%), male genital system diseases in 28 (3.75%), breast diseases 27 (3.62%), rectal and peri-anal diseases in 25 (3.35%), spinal diseases 16 (2.12%), brain diseases 14 (1.88%) other diseases in 43 (5.76%). Commonest antibiotic used was cefuroxime. Conclusions: The hepatobiliary disease was the commonest reason to undergo surgery. Keywords: Surgical prophylaxis, Rational use of antibiotics.

Objective The aim of the study was to review the different etiologies and outcomes of patients with hepatic artery velocities greater than 200 cm/s. Methods This retrospective study included 88 hospitalized patients in whom angle-corrected proper hepatic artery flow velocities greater than 200 cm/s were obtained during an abdominal ultrasonographic examination. Peak systolic hepatic artery flow velocities, hepatic artery resistance index, and portal vein flow velocities were evaluated. The patients were then allocated to one of four groups based on their primary underlying diagnosis: structural liver disease, nonstructural liver disease, generalized infection, or miscellaneous. Results The median hepatic artery velocity was similar for all groups, ranging from 226 to 238 cm/s. The maximum portal venous velocities were not significantly different between groups. No lab values were statistically different between the groups, except total bilirubin that was greater in the nonstructural liver disease group (8 mg/dL). Overall, 9/88 (10.2%) of patients with elevated hepatic artery velocity died within 30 days of their ultrasonographic examination. Conclusion Elevated hepatic artery velocity greater than 200 cm/s in hospitalized patients is not specific to primary hepatobiliary disease but may indicate acute hepatic dysfunction from other causes such as infection or sepsis.

Primary sclerosing cholangitis (PSC) is a chronic, progressive, hepatobiliary disease characterized by inflammation and fibrosis of the intra- and extra-hepatic bile ducts. Its natural history is one that generally progresses towards cirrhosis, liver failure, cholangiocarcinoma, and ultimately disease-related death, with a median liver transplantation-free survival time of approximately 15-20 years. However, despite its lethal nature, PSC remains a heterogenous disease with significant variability in outcomes amongst different regions of the world. There are also many regions where the outcomes of PSC have not been studied, limiting the overall understanding of this disease worldwide. In this review, we present the geoepidemiologic variations in outcomes of PSC, with a focus on survival pre- and post-liver transplantation as well as the concurrence of inflammatory bowel disease and hepatobiliary neoplasia.

BACKGROUND & AIMS In about 20% of children with cholestasis and normal or low serum gamma-glutamyltransferase (GGT) activity, no aetiology is identified. We sought new genes implicated in paediatric hepatobiliary disease. METHODS We conducted whole-exome sequencing in 69 children evaluated at our centre from 2011 to 2018 who had low-GGT cholestasis and in whom homozygous/compound heterozygous predictedly pathogenic variants (PPVs) in ATP8B1, ABCB11, NR1H4, MYO5B or TJP2 were not found. Clinical records and findings on light microscopy and transmission electron microscopy of liver biopsy materials were reviewed. RESULTS In seven patients from seven unrelated families, biallelic PPVs (10 in total) were found in USP53, recently associated with intrahepatic cholestasis. Seven variants were classified as pathogenic: one canonical splicing, c.569 + 2T > C, and six nonsense or frameshifting: c.169C > T (p.Arg57Ter), c.581delA (p.Arg195GlufsTer38), c.831_832insAG (p.Val279GlufsTer16), c.1012C > T (p.Arg338Ter), c.1426C > T (p.Arg476Ter) and c.1558C > T (p.Arg520Ter). Three were likely pathogenic: c.297G > T (p.Arg99Ser), c.395A > G (p.His132Arg) and c.878G > T (p.Gly293Val). In all patients, jaundice began at age

There is limited literature on Gilbert’s syndrome (GS) in children with persistent unconjugated hyperbilirubinemia from Indian subcontinent. All patients (< 18 y of age) with genetically confirmed GS were included, and their profile was analysed. A total of 170 subjects were confirmed as having GS as per genetic analysis (133 with homozygous and 37 with heterozygous status). Majority were diagnosed in the adolescent age group (mean age 13.6 y). The median serum total bilirubin (TB) levels were around 3.3 mg/dl with maximum levels reaching upto 18 mg/dl. Around 15% subjects had an associated condition including hematological or hepatobiliary disease amongst others. GS is an important but under-recognised cause of unexplained unconjugated hyperbilirubinemia in Indian pediatric subjects. It may co-exist with other hematological and hepatobiliary disorders, and complicate the clinical/laboratory picture. Extent of hyperbilirubinemia may fluctuate to levels much higher than what is usually described in current world literature.

PURPOSE: To evaluate and compare the efficacy of intermittent needle aspiration and continuous catheter drainage in ultrasound-guided management of liver abscesses. METHODS: This was a prospective, randomised study conducted on 100 patients (88 males and 12 females; age range 22–74 years) with liver abscess(es) and having abscess size more than 5 cm, divided into two groups: Percutaneous needle aspiration (PNA) (n = 50) and percutaneous catheter drainage (PCD) (n = 50). Criteria of exclusion were: rupture of abscess before intervention; prior intervention; uncorrectable coagulopathy; concomitant biliary tract malignancy. In the PNA group, pus was aspirated by an 18-gauge needle using freehand technique and the number of aspirations was limited to two. Failure of abscess size to decline below 50% of the original diameter or of clinical improvement after second aspiration was considered as failure of aspiration. In the PCD group, drainage was done by 12-French catheters using Seldinger technique. Drainage was considered as failure if abscess cavity did not resolve and laparotomy was needed to evacuate the pus cavity. RESULT: The success rate in the PNA group was 88% and 92% in the PCD group; however, this difference was statistically not significant, suggesting that both are equally efficacious. The total duration of hospital stay (mean 6.8 days [PNA] vs 10.5 days [PCD]; p value: 0.011) and the average duration between intervention and discharge (5.9 days [PNA] vs 10.2 days [PCD]; p value:0.026) were significantly less in the PNA group. One major complication was seen in our study: peritonitis due to peri-catheter leak in PCD group. CONCLUSION: Both procedures are equally efficacious in the management of liver abscesses; however in view of less duration of hospital stay, patient safety and comfort, procedure simplicity, and the reduced cost, needle aspiration should be used as the first-line procedure in the treatment of liver abscess (even in abscesses more than 5 cm). Catheter drainage should be reserved for cases that do not respond to a second attempt of aspiration. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40477-020-00440-3) contains supplementary material, which is available to authorized users.

Objectives Vitamin D deficiency accompanies chronic cholestatic liver disease (CLD) in humans. The vitamin D status of cats with CLD is unknown. The objectives of this study were to describe serum vitamin D concentrations in cats with CLD and to determine if they correlated with indices of liver disease severity. Methods Thirty-six cats with CLD, defined by increases in serum bilirubin and serum alanine aminotransferase, and 23 sick cats with non-hepatobiliary diseases were prospectively enrolled. Serum 25-hydroxyvitamin D (25[OH]D), parathyroid hormone (PTH) and ionized calcium were measured. Signalment, clinical signs, comorbidities, diet history, serum bilirubin, liver enzyme activity, albumin, phosphorus, white blood cell count, prothrombin time and final hepatic cytologic/histopathologic diagnosis, when available, were recorded. Results Median serum 25(OH)D levels were similar in cats with CLD (89.5 nmol/l; range 21–112 nmol/l) and sick cats (89.0 nmol/l; range 49–115 nmol/l). Overall 12/36 (33%) cats with CLD and 4/23 (17%) sick cats had 25(OH)D levels below the lower limit of the reference interval (Conclusions and relevance Many cats with CLD have serum 25(OH)D concentrations below the lower limit of the reference interval. Further study is warranted to determine the clinical relevance and whether supplementation would provide benefits.

Highlights • Case of spontaneous bacterial peritonitis associated with E. tarda infection. • The patient had Child–Pugh A cirrhosis secondary to hepatitis C virus infection. • Surgical findings included redness and thickening of the cecal wall. • Purulent ascites without intestinal contents was observed. • E. tarda infection has a poor prognosis in patients with underlying disease., Introduction Edwardsiella tarda is a member of the Enterobacteriaceae family of gram-negative bacilli isolated from animals. Gastroenteritis is the most common manifestation of E. tarda infection. However, extraintestinal infections can occur in immunocompromised hosts as well as patients with hepatobiliary disease, malignancy, and/or diabetes mellites. The prognosis of sepsis caused by E. tarda is extremely poor, with a mortality rate of 38%. Here we report the occurrence of spontaneous bacterial peritonitis associated with E. tarda infection. Presentation of case An 87-year-old man with Child–Pugh A cirrhosis secondary to hepatitis C virus infection presented with diarrhea and sudden-onset pain in the abdomen. On arrival, guarding and rebound tenderness were observed over the entire abdomen. Computed tomography revealed circumferential thickening of the cecum and a small volume of ascites in the pelvic cavity. A diagnosis of peritonitis was made, and surgery was performed. Surgical findings included redness and thickening of the cecal wall and purulent ascites without intestinal contents. Peritoneal fluid culture revealed E. tarda as the sole pathogen. The abdominal cavity was washed, a drain was placed in the pelvic cavity, and postoperative intravenous antibiotic therapy was initiated. The postoperative course was uneventful. Discussion E. tarda infection in the presence of an underlying disease such as hepatobiliary disease, malignancy, and/or diabetes mellitus has a poor prognosis. Conclusion Although E. tarda infection is extremely rare, it is a life-threatening illness that can cause intestinal and extraintestinal infections. If necessary, early surgical intervention should be considered for cases of extraintestinal infection.

Background A distinct serum metabonomic pattern has been previously revealed to be associated with various forms of liver disease. Here, we aimed to apply mass spectrometry to obtain serum metabolomic profiles from individuals with cholangiocarcinoma and benign hepatobiliary diseases to gain an insight into pathogenesis and search for potential early-disease biomarkers. Methods Serum samples were profiled using a hydrophilic interaction liquid chromatography platform, coupled to a mass spectrometer. A total of 47 serum specimens from 8 cholangiocarcinoma cases, 20 healthy controls, 8 benign disease controls (bile duct strictures) and 11 patients with hepatocellular carcinoma (as malignant disease controls) were included. Data analysis was performed using univariate and multivariate statistics. Results The serum metabolome disparities between the metabolite profiles from healthy controls and patients with hepatobiliary disease were predominantly related to changes in lipid and lipid-derived compounds (phospholipids, bile acids and steroids) and amino acid metabolites (phenylalanine). A metabolic pattern indicative of inflammatory response due to cirrhosis and cholestasis was associated with the disease groups. The abundance of phospholipid metabolites was altered in individuals with liver disease, particularly cholangiocarcinoma, but no significant difference was seen between profiles from patients with benign biliary strictures and cholangiocarcinoma. Conclusion The serum metabolome in cholangiocarcinoma exhibited changes in metabolites related to inflammation, altered energy production and phospholipid metabolism. This study serves to highlight future avenues for biomarker research in large-scale studies.

Pyruvate kinase (PK) deficiency is a rare, congenital red blood cell disorder caused by a single gene defect. The spectrum of genotypes, variants, and phenotypes are broad, commonly requiring a multimodal approach including enzyme and genetic testing for accurate and reliable diagnosis. Similarly, management of primary and secondary sequelae of PK deficiency varies, mainly including supportive care with transfusions and surgical interventions to improve symptoms and quality of life. Given the risk of acute and long-term complications of PK deficiency and its treatment, regular monitoring and management of iron burden and organ dysfunction is critical. Therefore, all children and adolescents with PK deficiency should receive regular hematology care with visits at least every 6 months regardless of transfusion status. We continue to learn more about the spectrum of symptoms and complications of PK deficiency and best practice for monitoring and management through registry efforts (NCT03481738). The treatment of PK deficiency has made strides over the last few years with newer disease-modifying therapies being developed and studied, with the potential to change the course of disease in childhood and beyond.

IntroductionAs the main manifestation of gallstone disease, biliary colic (BC) is an episodic attack that brings patients severe pain in the right upper abdominal quadrant. Although acupuncture has been documented with significance to lead to pain relief, the immediate analgesia of acupuncture for BC still needs to be verified, and the underlying mechanism has yet to be covered. Therefore, this trial aims first to verify the immediate pain-alleviation characteristic of acupuncture for BC, then to explore its influence on the peripheral sensitised acupoint and central brain activity.Methods and analysisThis is a randomised controlled, paralleled clinical trial, with patients and outcome assessors blinded. Seventy-two patients with gallbladder stone disease presenting with BC will be randomised into a verum acupuncture group and the sham acupuncture group. Both groups will receive one session of immediate acupuncture treatment. Improvements in patients’ BC will be evaluated by the Numeric Rating Scale, and the pain threshold of acupoints will also be detected before and after treatment. During treatment, brain neural activity will be monitored with functional near-infrared spectroscopy (fNIRS), and the needle sensation will be rated. Clinical and fNIRS data will be analysed, respectively, to validate the acupuncture effect, and correlation analysis will be conducted to investigate the relationship between pain relief and peripheral–cerebral functional changes.Ethics and disseminationThis trial has been approved by the institutional review boards and ethics committees of the First Teaching Hospital of Chengdu University of Traditional Chinese Medicine, with the ethical approval identifier 2019 KL-029, and the institutional review boards and ethics committees of the First People’s Hospital of Longquanyi District, with the ethical approval identifier AF-KY-2020071. The results of this trial will be disseminated through peer-reviewed publications and conference abstracts or posters.Trial registration numberCTR2000034432.

IntroductionHepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF) is still a common type of liver failure in China. Therefore, we conduct this multicentre, non-blinded, randomised controlled clinical trial to investigate the efficacy and safety of combination treatment of double plasma molecular adsorption system (DPMAS) and low volume plasma exchange (PE) for patients with HBV related ACLF.Methods and analysisA total of 200 patients with HBV related ACLF in the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Eighth People’s Hospital, Nanfang Hospital of Southern Medical University, The Third People’s Hospital of Shenzhen, Xiangya Hospital of Central South University and The First Affiliated Hospital of Anhui Medical University, will be recruited into this trial. Eligible patients will undergo randomisation at a 1:1 ratio to two arms: the control group and the trial group. Patients in control group will receive comprehensive internal medical treatment. Patients in trial group will receive treatment of DPMAS and sequential low volume PE for three times, and comprehensive internal medical treatment. Clinical safety will be assessed by the analysis of adverse events (AEs) and laboratory tests. The primary efficacy outcome will be the incidence of unfavored events including death, liver transplantation and treatment abandonment. The secondary efficacy outcome will be the model for end-stage liver disease score variation. All evaluations will be performed at baseline, and 4, 8, 12, 24, 36, 48 weeks after enrolment. All AEs will be reported as soon as they are noted during the entire study procedure.Ethics and disseminationThis study was approved by Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (approval no. (2020)02-173-01). The results and conclusions of this clinical trial will be published at academic conferences or in journals.Trial registration numberNCT04597164.

ObjectivesBiliary atresia (BA) is regarded as a serious neonatal hepatobiliary disease, and its aetiology and pathogenesis remain unclear. Epidemiological studies are limited, especially for the data from China. This study aims to explore risk factors of BA and provide new evidence to improve understanding of its aetiology.DesignThis is a case–control study from 1 January 2015 to 31 December 2016.SettingCases were consecutively recruited from an urban tertiary care academic children’s hospital in Shanghai, China, while the controls were recruited from a community hospital in Shanghai through a random sampling system.Participants721 patients suspected for BA who planned to take the diagnostic surgery were enrolled preoperatively. 613 were diagnosed with BA and recruited into the case group. Meanwhile, 688 infants without any observed major congenital anomalies or jaundice were enrolled. Finally, 594 valid questionnaires from the case group and 681 from the control group were obtained.Primary and secondary outcome measuresStandardised questionnaires were used for data collection. Multivariate logistic regression analysis was performed to evaluate associations reported as ORs and precision, by adjusting covariates.ResultsAnxiety or stress during pregnancy was strongly associated with increased risk of BA (OR 8.36 (95% CI: 4.08 to 17.15); pConclusionsSocial factors including the educational and economic background and its related anxiety and stress during pregnancy might be noticed in the occurrence of BA. Maternal infections during pregnancy in the prevalence of BA were demonstrated.Trial registration numberChiCTR-IPR-15005885.

ObjectivesTo explore the prevalence and risk factors of metabolic-associated fatty liver disease (MAFLD) in Tianjin government employees of different genders.DesignCross-sectional study.SettingHealth Management Center of Tianjin Union Medical Center.Participants16 924 government employees (59.6% male).MeasuresUltrasound liver examination was performed to determine whether there is fat accumulation in the organ. Participants’ weight and height were measured, and body mass index (BMI) was calculated.ResultsThe overall prevalence of MAFLD in this population was 40.76%. The rates were significantly higher in men (49.42%) than in women (27.97%). The prevalence of MAFLD was highest in men aged 40–49 years (54.04%) and women aged 60–69 years (43.44%). In all BMI groups, the prevalence was higher in men than that in women. In both genders, higher BMI was associated with the risk of MAFLD, especially for BMI ≥31.9 kg/m2.ConclusionsThe prevalence of MAFLD in government employees in Tianjin was significantly higher than the average level in China. The prevalence varied by sex and age group, and those with high BMI were at the highest risk of developing MAFLD.

IntroductionLiver transplantation is a complex operation that can provide significant improvements in quality of life and survival to the recipients. However, serious complications are common and include major haemorrhage, hypotension and renal failure. Blood transfusion and the development of acute kidney injury lead to both short-term and long-term poor patient outcomes, including an increased risk of death, graft failure, length of stay and reduced quality of life. Octreotide may reduce the incidence of renal dysfunction, perioperative haemorrhage and enhance intraoperative blood pressure. However, octreotide does have risks, including resistant bradycardia, hyperglycaemia and hypoglycaemia and QT prolongation. Hence, a randomised controlled trial of octreotide during liver transplantation is needed to determine the cost-efficacy and safety of its use; this study represents a feasibility study prior to this trial.Methods and analysisWe describe a multicentre, double-blind, randomised, placebo-controlled feasibility study of continuous infusion of octreotide during liver transplantation surgery. We will recruit 30 adult patients at two liver transplant centres. A blinded infusion during surgery will be administered in a 2:1 ratio of octreotide:placebo. The primary outcomes will determine the feasibility of this study design. These include the recruitment ratio, correct administration of blinded study intervention, adverse event rates, patient and clinician enrolment refusal and completion of data collection. Secondary outcome measures of efficacy and safety will help shape future trials by assessing potential primary outcome measures and monitoring safety end points. No formal statistical tests are planned. This manuscript represents study protocol number 1.3, dated 2 June 2021.Ethics and disseminationThis study has received Research Ethics Committee approval. The main study outcomes will be submitted to an open-access journal.Trial sponsorThe Joint Research Office, University College London, UK.Neither the sponsor nor the funder have any role in study design, collection, management, analysis and interpretation of data, writing of the study report or the decision to submit the report for publication.Trial registrationThe study is registered with ClinicalTrials.gov (NCT04941911) with recruitment due to start in August 2021 with anticipated completion in July 2022.Clinical trials unitSurgical and Interventional Group, Division of Surgery & Interventional Science, University College London.

Liver blood tests (often also known as liver chemistries, liver tests, or the common misnomer liver function tests) are routinely used in diagnosis and management of hepatobiliary disease. Abnormal liver blood test results are often the first indicator of hepatobiliary disease and a common indication for abdominal imaging with US, CT, or MRI. Most of the disease entities can be categorized into hepatocellular or cholestatic patterns, with characteristic traits on liver blood tests. Each pattern has a specific differential, which can help narrow the differential diagnosis when combined with the clinical history and imaging findings. This article reviews the major liver blood tests as well as a general approach to recognizing common patterns of hepatobiliary disease within these tests (hepatocellular, cholestatic, acute liver failure, isolated hyperbilirubinemia). Examples of hepatobiliary disease with hepatocellular or cholestatic patterns are presented with characteristic test abnormalities and imaging findings. The commonly encountered scenario of chronic hepatitis with possible fibrosis is also reviewed, with discussion of potential further imaging such as elastography. The role of liver blood tests and imaging in evaluating complications of hepatic transplant is also discussed. Overall, integrating liver blood test patterns with imaging findings can help the radiologist accurately diagnose hepatobiliary disease, especially in cases where imaging findings may not allow differentiation between different entities. ©RSNA, 2021.

IntroductionLiver cirrhosis is a growing global healthcare challenge. Cirrhosis is characterised by severe liver fibrosis, organ dysfunction and complications related to portal hypertension. There are no licensed antifibrotic or proregenerative medicines and liver transplantation is a scarce resource. Hepatic macrophages can promote both liver fibrogenesis and fibrosis regression. The safety and feasibility of peripheral infusion of ex vivo matured autologous monocyte-derived macrophages in patients with compensated cirrhosis has been demonstrated.Methods and analysisThe efficacy of autologous macrophage therapy, compared with standard medical care, will be investigated in a cohort of adult patients with compensated cirrhosis in a multicentre, open-label, parallel-group, phase 2, randomised controlled trial. The primary outcome is the change in Model for End-Stage Liver Disease score at 90 days. The trial will provide the first high-quality examination of the efficacy of autologous macrophage therapy in improving liver function, non-invasive fibrosis markers and other clinical outcomes in patients with compensated cirrhosis.Ethics and disseminationThe trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by Scotland A Research Ethics Committee (reference 15/SS/0121), National Health Service Lothian Research and Development department and the Medicine and Health Care Regulatory Agency-UK. Final results will be presented in peer-reviewed journals and at relevant conferences.Trial registration numbersISRCTN10368050 and EudraCT; reference 2015-000963-15

ObjectiveConflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: Define complex interactions between resident microbes and their association in PSC patients by studying antibiotic-treated specific pathogen-free (SPF) and germ-free (GF) multi-drug-resistant 2 deficient (mdr2-/-) mice.DesignWe measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, fecal 16s rRNA gene profiling, and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients.ResultsGF mdr2-/- mice had exaggerated hepatic inflammation and fibrosis with 100% mortality by 8 weeks; early SPF autologous stool transplantation rescued liver-related mortality. Broad-spectrum antibiotics and vancomycin alone accelerated disease in weanling SPF mdr2-/- mice, indicating that vancomycin-sensitive resident microbiota protect against hepatobiliary disease. Vancomycin treatment selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased cytolysin-expressing E. faecalis and E. coli liver translocation; colonization of gnotobiotic mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated liver inflammation and mortality. Lachnospiraceae colonization of antibiotic pre-treated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, while Lachnospiraceae-produced SCFA decreased fibrosis. Fecal E. faecalis/ Enterobacteriaceae was positively and Lachnospiraceae was negatively associated with PSC patients’ clinical severity Mayo risk scores.ConclusionsWe identified specific functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical outcomes. These insights may guide personalized targeted therapeutic interventions in PSC patients.

Background: Necrotizing soft tissue infections (NSTIs) are rapidly progressing, life-threatening diseases associated with substantial morbidity and mortality, especially in patients 65 years or older. We aimed to evaluate clinical factors associated with mortality and discharge disposition after NSTIs in elderly patients. Patients and Methods: Retrospective data were obtained from the 2007-2017 American College of Surgeons-National Surgical Quality (ACS-NSQIP) database. Patients aged 65 years or older with a post-operative diagnosis of an NSTI (defined as gas gangrene, necrotizing fasciitis, or Fournier gangrene) were included. Univariable and multivariable analyses were performed to identify independent clinical and demographic factors associated with mortality and with discharge disposition. Results: A total of 1,460 patients were included. Median age was 71 years, 43% were females. Overall, 30-day mortality was 18.5% and 30-day morbidity was 63.6%. The most important predictors of mortality included pre-operative septic shock (odds ratio [OR], 6.36; 95% confidence interval [CI], 3.61-11.18), pre-operative dialysis dependence (OR, 2.99; 95% CI, 1.77-5.05), coagulopathy (international normalized ratio [INR], >1.5, OR, 2.25; 95% CI, 1.51-3.37), hepatobiliary disease (bilirubin >1.0 mg/dL; OR, 2.05; 95% CI, 1.38-3.04) and aged 80 years or older (OR, 3.36; 95% CI, 2.08-5.44). Patients without any of these risk factors had a mortality of 7.3%. Predictors of discharge to inpatient rehabilitation or skilled care included age 80 years or older (OR, 2.49; 95% CI, 1.44-4.30), American Society of Anesthesiologists (ASA) ≥3 (OR, 2.05; 95% CI, 1.03-4.05)] and amputation as opposed to debridement (OR, 2.53; 95% CI,1.48-4.32). Conclusions: We identified several pre-operative clinical factors that were associated with increased post-operative mortality and discharge to post-acute care. The next steps should focus on determining if optimization of modifiable predictors would improve mortality.

IntroductionA Low Glycaemic Index (LGI) diet is a proposed lifestyle intervention in non-alcoholic fatty liver diseases (NAFLD) which is designed to reduce circulating blood glucose levels, hepatic glucose influx, insulin resistance and de novo lipogenesis. A significant reduction in liver fat content through following a 1-week LGI diet has been reported in healthy volunteers. Changes in dietary fat and carbohydrates have also been shown to alter gut microbiota composition and lead to hepatic steatosis through the gut-liver axis. There are no available trials examining the effects of an LGI diet on liver fat accumulation in patients with NAFLD; nor has the impact of consuming an LGI diet on gut microbiota composition been studied in this population. The aim of this trial is to investigate the effects of LGI diet consumption on liver fat content and its effects on gut microbiota composition in participants with NAFLD compared with a High Glycaemic Index (HGI) control diet.Methods and analysisA 2×2 cross-over randomised mechanistic dietary trial will allocate 16 participants with NAFLD to a 2-week either HGI or LGI diet followed by a 4-week wash-out period and then the LGI or HGI diet, alternative to that followed in the first 2 weeks. Baseline and postintervention (four visits) outcome measures will be collected to assess liver fat content (using MRI/S and controlled attenuation parameter-FibroScan), gut microbiota composition (using 16S RNA analysis) and blood biomarkers including glycaemic, insulinaemic, liver, lipid and haematological profiles, gut hormones levels and short-chain fatty acids.Ethics and disseminationStudy protocol has been approved by the ethics committees of The University of Nottingham and East Midlands Nottingham-2 Research Ethics Committee (REC reference 19/EM/0291). Data from this trial will be used as part of a Philosophy Doctorate thesis. Publications will be in peer-reviewed journals.Trial registration numberNCT04415632.

Outpatient detection of total bilirubin levels should be performed regularly to monitor the recurrence of jaundice in hepatobiliary and pancreatic disease patients. However, frequent hospital visits for blood testing are burdensome for patients with poor medical conditions. This study validates a novel deep-learning-based smartphone application for the self-diagnosis of scleral jaundice in such patients. The system predicts total serum bilirubin levels using the deep-learning-based regression analysis of scleral photos taken by the smartphone’s built-in camera. Enrolled patients were randomly assigned to either the training cohort (n = 90, 1034 photos) or the validation cohort (n = 40, 426 photos). The intraclass correlation coefficient value for predicted serum total bilirubin (PSB) derived from the images repeatedly taken at the same time for the same patient showed good reliability (0.86). A strong correlation between measured serum total bilirubin (MSB) and PSB was observed in the subgroup with MSB levels ≥1.5 mg/dL (Spearman rho = 0.70, p &lt, 0.001). The receiver operating characteristic curve for PSB showed that the area under the curve was 0.93, demonstrating good test performance as a predictor of hyperbilirubinemia (p &lt, 0.001). Using a cut-off PSB ≥1.5, the prediction sensitivity of hyperbilirubinemia was 80.0%, with a specificity of 92.6%. Hence, the tool is effective for patient monitoring.

Macroenzymes are high molecular weight complexes that are formed by the binding of normal serum enzymes with circulating immunoglobulins - primarily IgG, IgA, and IgM. These high molecular weight complexes are difficult to clear through the kidneys, therefore they remain persistently elevated in the serum leading to inaccurate diagnoses and unnecessary workup. The prevalence of macroenzymes is relatively rare in the general population; however, it is an important phenomenon to be aware of when working up isolated elevations in serum enzymes. A quick and efficient test for the detection of macroenzymes is the polyethylene glycol precipitation test. Here, we present a case of macro-aspartate aminotransferase masquerading as an underlying hepatobiliary disease ultimately leading to an extensive evaluation before arriving at the correct diagnosis. This case highlights the importance of an accurate and efficient diagnosis of macroenzymes in the serum in order to prevent unnecessary healthcare utilization and also to decrease the psychological burden on the patient.