Hepatolithiasis: Epidemiology, presentation, classification and management of a complex disease.

The term hepatolithiasis describes the presence of biliary stones within the intrahepatic bile ducts, above the hilar confluence of the hepatic ducts. The disease is more prevalent in Asia, mainly owing to socioeconomic and dietary factors, as well as the prevalence of biliary parasites. In the last century, owing to migration, its global incidence has increased. The main pathophysiological mechanisms involve cholangitis, bile infection and biliary strictures, creating a self-sustaining cycle that perpetuates the disease, frequently characterised by recurrent episodes of bacterial infection referred to as syndrome of "recurrent pyogenic cholangitis". Furthermore, long-standing hepatolithiasis is a known risk factor for development of intrahepatic cholangiocarcinoma. Various classifications have aimed at providing useful insight of clinically relevant aspects and guidance for treatment. The management of symptomatic patients and those with complications can be complex, and relies upon a multidisciplinary team of hepatologists, endoscopists, interventional radiologists and hepatobiliary surgeons, with the main goal being to offer relief from the clinical presentations and prevent the development of more serious complications. This comprehensive review provides insight on various aspects of hepatolithiasis, with a focus on epidemiology, new evidence on pathophysiology, most important clinical aspects, different classification systems and contemporary management.

Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

Immune-mediated cholangiopathies in children: the need to better understand the pathophysiology for finding the future possible treatment targets.

Cholangiopathies are defined as focal or extensive damage of the bile ducts. According to the pathogenetic mechanism, it may be immune-mediated or due to genetic, infectious, toxic, vascular, and obstructive causes. Their chronic evolution is characterized by inflammation, obstruction of bile flow, cholangiocyte proliferation, and progression toward fibrosis and cirrhosis. Immune-mediated cholangiopathies comprise primary sclerosing cholangitis (PSC), autoimmune cholangitis and IgG4-associated cholangitis in adults and biliary atresia (BA), neonatal sclerosing cholangitis (NSC) in children. The main purpose of this narrative review was to highlight the similarities and differences among immune-mediated cholangiopathies, especially those frequent in children in which cholangiocyte senescence plays a key role (BA, NSC, and PSC). These three entities have many similarities in terms of clinical and histopathological manifestations, and the distinction between them can be hard to achieve. In BA, bile duct destruction occurs due to aggression of the biliary cells due to viral infections or toxins during the intrauterine period or immediately after birth. The consequence is the activation of the immune system leading to severe inflammation and fibrosis of the extrahepatic biliary tract, lumen stenosis, and impairment of the biliary flow. PSC is characterized by inflammation and fibrosis of intra- and extrahepatic bile ducts, leading to secondary biliary cirrhosis. It is a multifactorial disease that occurs because of genetic predisposition [human leukocyte antigen (HLA) and non-HLA haplotypes], autoimmunity (cellular immune response, autoantibodies, association with inflammatory bowel disease), environmental factors (infections or toxic bile), and host factors (intestinal microbiota). NSC seems to be a distinct subgroup of childhood PSC that appears due to the interaction between genetic predisposition (HLA B8 and DR3) and the disruption of the immune system, validated by elevated IgG levels or specific antibodies [antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA)]. Currently, the exact mechanism of immune cholangiopathy is not fully understood, and further data are required to identify individuals at high risk of developing these conditions. A better understanding of the immune mechanisms and pathophysiology of BA, NSC, and PSC will open new perspectives for future treatments and better methods of preventing severe evolution.

The association between sonographic common bile duct dilatation and outcomes in emergency department patients with cholangitis.

BACKGROUND: The presentation of the patient with acute cholangitis (AC) ranges from mild illness to life-threatening shock. Therefore, prompt diagnosis and treatment are critical. Abdominal ultrasound (US) is the imaging of choice to locate bile duct dilatation. Other modalities include abdominal computed tomography (CT) or endoscopic retrograde cholangiopancreatography (ERCP). OBJECTIVES: To determine whether sonographic common bile duct dilatation in emergency department (ED) patients with AC predicts outcomes including sepsis, hospital length of stay (LOS), admission to the intensive care unit (ICU), time to ERCP, and mortality. METHODS: Electronic medical records of all patients hospitalized in a tertiary care medical center between July 2012-February 2021 with a discharge diagnosis of cholangitis were assessed. Patients were dichotomously classified as CBD dilated or CBD non-dilated based on ultrasound. Dilation was defined as CBD larger than 6 mm in patients younger than 60 or larger than 6 mm + 1 mm per decade in patients over 60. RESULTS: The study included 271 patients- 172 with CBD dilation versus 99 without. Mean LOS was 9.92 days for those with a dilated CBD versus 13.4 days without. The mean time to ERCP was 4.26 days for those with a dilated CBD versus 6.56 days without. Sepsis, mortality, and ICU admission were scarce and there was no statistically significant difference between the cohorts. CONCLUSION: Patients with a dilated CBD per the abdominal US performed during the patient's ED stay, underwent ERCP earlier, and were hospitalized fewer days than patients without CBD dilation.

[Cholangitis and cholecystitis: diagnostic criteria and management]. / Epeút- és epehólyag-gyulladás: diagnosztikus kritériumok és terápia.

In developed countries, diseases of the gallbladder and the biliary tract count as some of the most frequent gastrointestinal disorders. The inflammation of the gallbladder/biliary tree is a potentially severe, even lethal condition that requires rapid diagnosis and early multidisciplinary approach to be treated. Although the frequency of these diseases is high, the treatment is not unified in Hungary yet. The aim of the evidence-based recommendation is to clarify the diagnostic criteria and severity grading of these diseases and to highlight the indications and rules of proper application of the numerous available therapeutic interventions. The recent guideline is based on the consensus of the Board members of the Endoscopic Section of the Hungarian Gastroenterology Society in contribution with renown experts of surgery, infectology as well as interventional radiology and it counts as a clear and easy applicable guide during the all-day healthcare practice. Our guidelines are based on Tokyo guidelines established on the basis of the consensus reached in the International Consensus Meeting held in Tokyo which were revised in 2013 (TG13) and in 2018 (TG18). Orv Hetil. 2023; 164(20): 770-787.

Racial and Ethnic Disparities Among Patients Hospitalized for Acute Cholangitis in the United States.

GOALS: We sought to determine whether race/ethnicity is associated with hospitalization outcomes among patients admitted with acute cholangitis. BACKGROUND: Few studies have evaluated the association between race and outcomes in patients with acute cholangitis. STUDY: We analyzed United States hospitalizations from 2009 to 2018 using the Nationwide Inpatient Sample (NIS). We included patients 18 years old or above admitted with an ICD9/10 diagnosis of cholangitis. Race/ethnicity was categorized as White, Black, Hispanic, or Other. We used multivariable regression to determine the association between race/ethnicity and in-hospital outcomes of interest, including endoscopic retrograde cholangiopancreatography (ERCP), early ERCP (<48 h from admission), length of stay (LOS), and in-hospital mortality. RESULTS: Of 116,889 hospitalizations for acute cholangitis, 70% identified as White, 10% identified as Black, 11% identified as Hispanic, and 9% identified as Other. The proportion of non-White patients increased over time. On multivariate analysis controlling for clinical and sociodemographic variables, compared with White patients, Black patients had higher in-hospital mortality (adjusted odds ratio: 1.4, 95% confidence interval: 1.2-1.6, P <0.001). Black patients were also less likely to undergo ERCP, more likely to undergo delayed ERCP, and had longer LOS ( P <0.001 for all). CONCLUSIONS: In this contemporary cohort of hospitalized patients with cholangitis, Black race was independently associated with fewer and delayed ERCP procedures, longer LOS, and higher mortality rates. Future studies with more granular social determinants of health data should further explore the underlying reasons for these disparities to develop interventions aimed at reducing racial disparities in outcomes among patients with acute cholangitis.

Prognostic Scoring Systems in Primary Biliary Cholangitis: An Update.

Primary biliary cholangitis (PBC) is a complex, chronic disease with a heterogeneous presentation, disease progression, and response to therapy. Several prognostic models based on disease stage and/or treatment response enhance risk stratification and therapeutic management. Recent work on disease modeling proposed early prediction of outcomes at PBC onset, yet this has not been implemented in clinical practice. Although early stratification of patients based on their individual risk of developing end-stage liver disease may prove cost-effective and actually become matter of medical deontology to timely offer the best therapeutic option, given the forthcoming availability of novel, disease-modifying drugs. This review outlines established and novel prognostic systems in PBC and provides some perspectives on the potential role of omics-derived biomarkers in developing reliable risk prediction models and promoting the implementation of personalized medicine in PBC.

Optimal timing of biliary drainage based on the severity of acute cholangitis: A single-center retrospective cohort study.

BACKGROUND: Biliary decompression is well known to greatly decrease the risks of mortality in acute cholangitis (AC). Although early biliary drainage is recommended by the treatment guidelines for AC, the best time for performing this procedure is yet to be established. Furthermore, since the clinical outcomes of patients with severe AC vary dramatically, screening for patients that could benefit the most from early drainage would be more beneficial than the drainage performed based on the severity grade criteria. AIM: To investigate the optimal drainage timing for AC patients with each disease severity grade and organ dysfunction. METHODS: In this retrospective monocenter cohort analysis, we reviewed 1305 patients who were diagnosed with AC according to the Tokyo guidelines 2018 at a Chinese tertiary hospital between July 2016 and December 2020. Demographic characteristics including age and sex, clinical and laboratory characteristics, and imaging findings of each patient were obtained from electronic medical records. We investigated the all-cause in-hospital mortality (IHM), hospital length of stay (LOS), and hospitalization costs associated with the timing of biliary drainage according to the severity grading and different dysfunctioning organs and predictors [age, white blood cell (WBC) count, total bilirubin, albumin, lactate, malignant obstruction, and Charlton comorbidity index (CCI)]. RESULTS: Biliary drainage within 24 or 48 h in Grade III AC patients could dramatically decrease IHM (3.9% vs 9.0%, P = 0.041; 4% vs 9.9%, P = 0.018, respectively), while increasing LOS and hospitalization costs. Multivariate logistic analysis revealed that neurological, respiratory, renal, and cardiovascular dysfunctions, hypoalbuminemia, and malignant obstruction were significantly associated with IHM (odds ratio = 5.32, 2.541, 6.356, 4.021, 5.655, and 7.522; P < 0.001, P = 0.016, P < 0.001, P = 0.012, P < 0.001, and P < 0.001; respectively). Biliary decompression performed within 12 h of admission significantly decreased the IHM in AC patients with neurological dysfunction (0% vs 17.3%, P = 0.041) or with serum lactate > 2 mmol/L (0% vs 5.4%, P = 0.016). In the subgroup of AC patients with renal dysfunction, abnormal WBC count, hyperbilirubinemia, or hypoalbuminemia, early drainage (< 24 h) reduced the IHM (3.6% vs 33.3%, P = 0.004; 1.9% vs 5.8%, P = 0.031; 1.7% vs 5.0%, P = 0.019; 0% vs 27%, P = 0.026; respectively). The IHM was lower in patients with AC combined with hepatic dysfunction, malignant obstruction, or a CCI > 3 who had undergone biliary drainage within 48 h (2.6% vs 20.5%, P = 0.016; 3.0% vs 13.5%, P = 0.006; 3.4% vs 9.6%, P = 0.021; respectively). CONCLUSION: Biliary drainage within 12 h is beneficial for AC patients with neurological or cardiovascular dysfunction, while complete biliary decompression within 24 h of admission is recommended for treating patients with Grade III AC.

Practical management of primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease of autoimmune pathogenesis that mainly affects middle-aged women. Patients show elevated alkaline phosphatase and bilirubin levels as the disease progresses. The main symptoms of the disease are pruritus and fatigue, which interfere with the quality of life of patients. Progressive damage leading to end stage liver disease could require liver transplantation. Despite the efficacy of ursodeoxycholic acid (UDCA), the current standard of care for PBC, up to 40% of patients have an inadequate response to the treatment, requiring a second-line therapy. Obeticholic acid is the only second-line treatment approved for PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in patients intolerant to UDCA. Although different clinical guidelines for the diagnosis and management of PBC have been published, PBC is still challenging for many physicians. In this article we briefly review the main characteristics of the disease and include a practical user-friendly algorithm for the diagnosis and management of PBC developed by Spanish PBC experts and based on the European Association for the Study of the Liver recommendations. (AU)

[Guidelines on the diagnosis and management of primary biliary cholangitis (2021)].

In 2015, the Chinese Society of Hepatology and Chinese Society of Gastroenterology issued a consensus on the diagnosis and management of primary biliary cholangitis (PBC). In the past years, more clinical studies have been reported in the field of PBC. To provide guidance to the clinical diagnosis and management of patients with PBC, the Chinese Society of Hepatology invited a panel of experts to assess the new clinical evidence and formulated the current guidelines which comprises 26 clinical recommendations.

Liver cirrhosis is a risk factor for poor prognosis of acute cholangitis caused by choledocholithiasis.

INTRODUCTION AND OBJECTIVES: Acute cholangitis, which is characterized by biliary infection and acute liver injury, may impact cirrhosis prognosis. However, the prognosis itself remains unclear. MATERIALS AND METHODS: This multicenter retrospective cohort study compared the mortality and liver function change between patients with and without cirrhosis who underwent endoscopic treatment for acute cholangitis caused by choledocholithiasis between January 2004 and December 2019. RESULTS: We analyzed 699 patients, 44 of whom had cirrhosis. The cirrhotic group had a significantly higher 30-day mortality rate than the noncirrhotic group (14% vs. 1%; P < 0.001). The cirrhotic group also had significantly lower total bilirubin and albumin recovery. However, all patients with cirrhosis who survived achieved total-bilirubin recovery, and 91% achieved albumin recovery within 90 days. In multivariable Cox regression analysis, the independent risk factors for total-bilirubin recovery included cirrhosis (hazard ratio, 0.37; 95%CI, 0.24‒0.58; P < 0.001) and high total-bilirubin level (0.46; 95%CI, 0.34‒0.60; P < 0.001), whereas those for albumin recovery were cirrhosis (0.51; 95%CI, 0.33‒0.79; P = 0.002), high age (0.62; 95%CI, 0.47‒0.82; P < 0.001), organ dysfunction (0.62; 95%CI, 0.39‒0.96; P = 0.03), low albumin level (0.57; 95%CI, 0.36‒0.91; P = 0.02), and high C-reactive protein level (0.73; 95%CI, 0.56‒0.95; P = 0.02). CONCLUSIONS: Patients with cirrhosis complicated with acute cholangitis had poor prognosis. Recovery of liver function after endoscopic treatment was slow; nevertheless, most patients who survived could recover within 90 days.

Rare cause of obstructive haemobilia with recurrent biliopancreatic complications: a paradigmatic case.

Haemobilia is an unusual but significant cause of upper gastrointestinal bleeding. Two-thirds of haemobilia cases are secondary to invasive hepato-biliopancreatic procedures. Biliary angiodysplasia is exceptionally unusual, with only three cases reported. Herein, we report the case of an autonomous 80-year-old woman with a history of cholecystectomy 5 years ago and cardiovascular disease-hypertension, heart failure, acute myocardial infarction, stroke and non-valvular atrial fibrillation, anticoagulated with apixaban 2.5 mg two times per day. Since July 2019, she had four episodes of acute cholangitis of mild-to-moderate severity, having undergone broad spectrum antibiotics treatment and endoscopic retrograde cholangiopancreatography (ERCP), with sphincterotomy and bile sludge extraction. After 3 months, the patient presented with a new episode of acute cholangitis, this time with haemobilia (Quincke's triad). An abdominal CT angiography showed no evidence of active bleeding, with plastic biliary prosthesis left by ERCP. The patient continued presenting new episodes of acute cholangitis with haemobilia, some of them with associated pancreatitis. A cholangioscopy with Spyglass DS II was performed, showing an angiodysplasia occupying half of the luminal circumference of the middle choledoccus, without active haemorrhage. After a multidisciplinary meeting and given the high haemorrhagic/thrombotic risk (CHA2DS2-VASc 8), closure of the left atrial appendage was considered. However, relapse of the condition after beginning the antiaggregation protocol for cardiovascular intervention made it unfeasible. Another cholangioscopy with an ultra-thin endoscope for argon-plasma coagulation was attempted, without success. The abdominal CT angiography was repeated, this time with identification of dilated ramifications of the gastroduodenal and inferior pancreatic arteries. After embolisation of these aberrant vessels with microcoils, the patient went well, with no recurrence of bleeding or biliopancreatic complications. We present a case of obstructive haemobilia with multiple biliopancreatic complications, secondary to an extremely rare cause-choledochal angiodysplasia. Cholangioscopy had a decisive role in the diagnosis and therapeutic guidance. The diagnostic/therapeutic challenge associated with haemobilia stands out, with the need for a personalised and multidisciplinary approach.

Performance of diagnostic tools for acute cholangitis in patients with suspected biliary obstruction.

BACKGROUND: Acute cholangitis is an infection requiring endoscopic retrograde cholangiopancreatography (ERCP) and antibiotics. Several diagnostic tools help to diagnose cholangitis. Because diagnostic performance of these tools has not been studied and might therefore impose unnecessary ERCPs, we aimed to evaluate this. METHODS: We established a nationwide prospective cohort of patients with suspected biliary obstruction who underwent an ERCP. We assessed the diagnostic performance of Tokyo Guidelines (TG18), Dutch Pancreatitis Study Group (DPSG) criteria, and Charcot triad relative to real-world cholangitis as the reference standard. RESULTS: 127 (16%) of 794 patients were diagnosed with real-world cholangitis. Using the TG18, DPSG, and Charcot triad, 345 (44%), 55 (7%), and 66 (8%) patients were defined as having cholangitis, respectively. Sensitivity for TG18 was 82% (95% CI 74-88) and specificity 60% (95% CI 56-63). The sensitivity for DPSG and Charcot was 42% (95% CI 33-51) and 46% (95% CI 38-56), specificity was 99.7% (95% CI 99-100) and 99% (95% CI 98-100), respectively. CONCLUSIONS: TG18 criteria incorrectly diagnoses four out of ten patients with real-world cholangitis, while DPSG and Charcot criteria failed to diagnose more than half of patients. As the cholangitis diagnosis has many consequences for treatment, there is a need for more accurate diagnostic tools or work-up towards ERCP.

IgG4-related diseases of the digestive tract.

IgG4-related conditions affecting the digestive tract are part of a multi-organ fibro-inflammatory disorder termed IgG4-related disease (IgG4-RD), with autoimmune pancreatitis and IgG4-related cholangitis being the most prominent manifestations. Gastrointestinal symptoms include jaundice, weight loss, abdominal pain, biliary strictures, and pancreatic and hepatic masses that mimic malignant diseases. IgG4-RD manifestations occur less frequently elsewhere in the digestive tract, namely in the oesophagus, retroperitoneum or intestine. Evidence-based European guidelines frame the current state-of-the-art in the diagnosis and management of IgG4-related digestive tract disease. Diagnosis is based on histology (if available), imaging, serology, other organ involvement and response to therapy (HISORt criteria). Few biomarkers beyond serum IgG4 concentrations are reliable. The first-line therapy (glucocorticoids) is swiftly effective but disease flares are common at low doses or after tapering. Second-line therapy might consist of other immunosuppressive drugs such as thiopurines or rituximab. Further trials, for example, of anti-CD19 drugs, are ongoing. Although an association between IgG4-RD and the development of malignancies has been postulated, the true nature of this relationship remains uncertain at this time.

Practical management of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease of autoimmune pathogenesis that mainly affects middle-aged women. Patients show elevated alkaline phosphatase and bilirubin levels as the disease progresses. The main symptoms of the disease are pruritus and fatigue, which interfere with the quality of life of patients. Progressive damage leading to end stage liver disease could require liver transplantation. Despite the efficacy of ursodeoxycholic acid (UDCA), the current standard of care for PBC, up to 40% of patients have an inadequate response to the treatment, requiring a second-line therapy. Obeticholic acid is the only second-line treatment approved for PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in patients intolerant to UDCA. Although different clinical guidelines for the diagnosis and management of PBC have been published, PBC is still challenging for many physicians. In this article we briefly review the main characteristics of the disease and include a practical user-friendly algorithm for the diagnosis and management of PBC developed by Spanish PBC experts and based on the European Association for the Study of the Liver recommendations.