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.

A Unique Case of Caroli Disease in Kenya's Medical Landscape.

BACKGROUND If a young patient presents with fever, abdominal pain, jaundice and significant imaging abnormalities, especially dilation of the biliary system, it is usually due to obstruction from stones or strictures. However, on very rare occasions, it can be due to complications of congenital cystic dilatation of the biliary system, known as Caroli disease. We present such a patient and discuss the differential diagnosis and implications for long-term management. CASE REPORT A 14-year-old boy presented to the Emergency Department with a sudden onset of high-grade fever and abdominal pain for 2 weeks, accompanied by vomiting of blood. The patient had no relevant medical history. He was malnourished and had moderate pallor, jaundice, and right upper quadrant pain. Imaging revealed cystic dilatation of intrahepatic ducts and a central dot sign. There were no features suggesting advanced liver disease otherwise, and no tumors or cysts in the kidneys. A diagnosis of Caroli disease was made. The symptoms were ascribed to acute cholangitis and improved with antibiotics. He was discharged home 1 week later. No further blood loss was observed. CONCLUSIONS This case study describes a patient with ascending cholangitis, a complication of Caroli disease. This diagnosis should be considered in the differential diagnosis when a child or young adult presents with features of cholangitis, abnormal biliary imaging, and/or upper gastrointestinal bleeding, or portal hypertension. No prior cases of this disease have been encountered, documented, or published in Kenya. This case can increase awareness among primary care clinicians, including pediatricians.

Acute suppurative terminal cholangitis: Clinical characteristics of a new subtype of acute cholangitis.

BACKGROUND: Acute suppurative terminal cholangitis (ASTC) is rarer than acute obstructive cholangitis and is not well studied. To explore this subtype of acute cholangitis, we described our clinical experience with ASTC. METHODS: We performed a retrospective review of patients with ASTC admitted to our center from September 2014 to August 2020. We analyzed their clinical characteristics, including etiology, clinical manifestations, imaging features, treatment and prognosis. RESULTS: A total of 32 ASTC patients were included in the analysis. The majority of the patients had a history of biliary operations, and clinical manifestations were occult and atypical. The positive rate of bacterial culture was 46.9%. All the patients had typical imaging features on computed tomography and magnetic resonance imaging. Treatment with effective antibiotics was provided as soon as diagnosis was established. After treatment, most patients had a good outcome. Elevated levels of total bilirubin, aspartate aminotransferase, procalcitonin and gamma-glutamyltransferase were the characteristics of critically ill patients and were associated with relatively poor prognosis. CONCLUSIONS: Our results demonstrated that ASTC should be recognized as a new subtype of acute cholangitis, and that earlier diagnosis and more personalized treatments are needed.

The Use of Inflammatory Markers for Treatment Response Monitoring in Acute Cholangitis: A Retrospective Cohort Study.

INTRODUCTION: In acute cholangitis (AC), monitoring treatment response to antimicrobial therapy allows for making timely decisions on early biliary decompression. The aims of this study were to compare the discriminating powers of traditional blood inflammatory markers and propose new inflammatory markers that have a better ability to distinguish between patients with and without biliary tract infection. METHODS: This was a retrospective cohort study. Patients who underwent endoscopic retrograde cholangio-pancreaticography for AC and those without biliary tract inflammation were randomly selected in the 4:3 ratio of their hospital admissions from our hospital endoscopic retrograde cholangio-pancreaticography database. The exclusion criterion was the absence of C-reactive protein (CRP) measurements. RESULTS: The discriminating powers of the neutrophil count, lymphocytes, albumin, neutrophil-to-lymphocyte ratio, and CRP were superior to that of white blood cell (P1 < 0.005; P2 = 0.004; P3 < 0.0005; P4 < 0.0005; P5 < 0.0005). In monitoring treatment response in AC, lymphocyte count, albumin, neutrophil-to-lymphocyte ratio, and CRP were better than neutrophil count (P6 = 0.037, P7 < 0.005, P8, 9 < 0.0005). The area under the receiver operating characteristic curve (AUC) of CRP was higher than the AUC for lymphocytes, 96% (95% confidence interval [CI]: 94-98%) versus 81% (95% CI: 76-86%) (P < 0.0005), and larger than the AUC for albumin, 88% (95% CI: 84-92%) (P < 0.0005), indicating a greater discriminating power of CRP. However, the discriminating power of CRP-to-lymphocyte ratio (CLR) was more than that for CRP (P = 0.006) but equal to CRP-to-(lymphocytes∗albumin) ratio (CLAR) (P = 0.249). The AUCs of CLR and CLAR were both 98% (95% CI: 96-99%). CONCLUSIONS: CLR and CLAR have superior discriminating powers than traditional inflammatory markers used for monitoring treatment response in AC.

Lymphocyte count and NLR as predictive value for the severity of acute cholangitis.

OBJECTIVE: Acute cholangitis is a serious infectious condition in which systemic complications occur and can lead to mortality. In this study, we tried to elucidate the relationship between lymphocyte count and neutrophil-lymphocyte ratio (NLR) with disease severity in patients with acute cholangitis. PATIENTS AND METHODS: In this retrospective analysis, 633 patients who met the definitive diagnosis criteria for acute cholangitis were enrolled as the study group. In the same period, 155 patients without acute cholangitis who had normal inflammatory markers and underwent endoscopic retrograde cholangiopancreatography (ERCP) were included in the study as the control group. The lymphocyte count, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) of the acute cholangitis group, the control group, and the acute cholangitis group were compared according to the severity of cholangitis. RESULTS: There was a statistically significant correlation between the severity of cholangitis and the degree of lymphocytopenia (p<0.05). It was observed that as the disease severity increased, the proportion of patients with normal lymphocytopenia degree decreased, and abnormal findings increased. It was seen that the NLR and PLR results of the patients increased as the severity of cholangitis increased. CONCLUSIONS: As a result, one can conclude that the increase in the severity of cholangitis caused an increase in NLR and PLR and a decrease in lymphocytes. Although the increase in NLR and lymphocytopenia results were considered statistically significant, the increase in PLR was not at an acceptable level.

Sequence of events leading to primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that is observed more frequently in middle-aged women. This disorder is considered an autoimmune disease, since liver injury is sustained by the presence of self-directed antimitochondrial antibodies targeting the bile duct cells. The prognosis may vary depending on an early diagnosis and response to therapy. However, nearly a third of patients can progress to liver cirrhosis, thus requiring a liver transplant. Traditional immunosuppressive therapies, commonly employed for other autoimmune diseases, have limited effects on PBC. In fact, dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury. In this minireview, after a background on the disease and possible predisposing factors, the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail. The rise and maintenance of the autoimmune process, as well as the response of the biliary epithelia during inflammatory injury, are key factors in the progression of the disease. The so-called "ductular reaction (DR)", intended as a reactive expansion of cells with biliary phenotype, is a process frequently observed in PBC and partially understood. However, recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis, cell senescence, and loss of biliary ducts. All these issues (onset of chronic inflammation, changes in secretive and proliferative biliary functions, DR, and its relationship with other pathological events) are discussed in this manuscript in an attempt to provide a snapshot, for clinicians and researchers, of the most relevant and sequential contributors to the progression of this human cholestatic disease. We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.

Bioinformatic analysis identified novel candidate genes with the potentials for diagnostic blood testing of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune disorder characterized by intrahepatic bile duct destruction and cholestatic liver injury. Diagnosis of PBC is generally based on the existence of anti-mitochondrial antibody (AMA) in blood samples; however, some PBC patients are negative for serum AMA tests, and invasive liver histological testing is required in rare PBC cases. The current study seeks novel candidate genes that are associated with PBC status and have potentials for blood diagnostic testing. Human transcriptomic profiling data of liver and blood samples were obtained from Gene Expression Omnibus (GEO). Three GEO data series (GSE79850, GSE159676, and GSE119600) were downloaded, and bioinformatic analyses were performed. Various differentially expressed genes were identified in three data series by comparing PBC patients and control individuals. Twelve candidate genes were identified, which were upregulated in both liver tissues and blood samples of PBC patients in all three data series. The enrichment analysis demonstrated that 8 out of 12 candidate genes were associated with biological functions, which were closely related to autoimmune diseases including PBC. Candidate genes, especially ITGAL showed good potentials to distinguish PBC with other diseases. These candidate genes could be useful for diagnostic blood testing of PBC, although further clinical studies are required to evaluate their potentials as diagnostic biomarkers.

Intrahepatic Cholangiocarcinoma Arising from Biliary Hamartomas in Patients with Recurrent Acute Cholangitis: A Case Report and Literature Review.

Biliary hamartomas are tumor-like malformations of the liver. Biliary hamartomas are a type of fibrocystic disorder originating from ductal plate malformation and are typically considered benign, but with the risk of malignant transformation. In this case report, we present a rare occurrence of intrahepatic cholangiocarcinoma (ICC) that developed from biliary hamartomas, along with a literature review. A 76-year-old man with a diagnosis of biliary hamartomas had a history of recurrent cholangitis for 12 years, necessitating cholecystectomy, ERCP, and repeated antibiotic treatments. During his last episode, imaging studies revealed a hypervascular infiltrative mass in the right posterior liver segment. A liver biopsy confirmed adenocarcinoma and subsequent surgical pathology revealed ICC originating from biliary hamartomas. Chronic inflammation in the bile duct associated with biliary hamartomas may serve as a potential trigger for malignant transformation, as observed in this case. Therefore, close surveillance is essential for patients with biliary hamartomas presenting with infectious complications.

The Predictive Value of Different Laboratory Indicators Based on the 2018 Tokyo Guidelines for the Severity of Acute Cholangitis.

BACKGROUND: This study evaluated the predictive value of different laboratory indicators for the severity of acute cholangitis (AC) according to the 2018 Tokyo Guidelines. OBJECTIVES: We enrolled consecutive patients with a diagnosis of AC from June 2016 to May 2021. Serum procalcitonin (PCT) and C-reactive protein (CRP) levels, white blood cell counts, the neutrophil-lymphocyte ratio, and the platelet-lymphocyte ratio (PLR) were compared according to the severity of AC. RESULTS: In total, 293 patients were enrolled in this study (mild, n = 172; moderate, n = 68; severe, n = 53). In receiver operating characteristic analyses, CRP was the best biomarker for differentiating mild and moderate AC (area under the curve [AUC] 0.66, 95% confidence interval [CI] 0.58-0.74). PCT was the best biomarker for differentiating mild and severe AC (AUC 0.80, 95% CI 0.74-0.86). Blood culture was performed in 117 patients (39.93%), 53 of whom (45.30%) had positive results. Regarding blood culture positivity, PLR was most predictive (AUC 0.85, 95% CI 0.78-0.92). CONCLUSIONS: PCT can be used as a reliable predictor of severe AC. CRP was most predictive of moderate AC, whereas PLR was most predictive of blood culture positivity.

Primary biliary cholangitis: primary autoimmune disease or primary secretory defect.

INTRODUCTION: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by the immune-mediated destruction of small and medium intrahepatic bile ducts, involving predominantly females. PBC has long been described as an autoimmune liver disease, also because it is very often associated with many autoimmune conditions. More recently, another pathogenic mechanism exploring the damage of cholangiocytes has been hypothesized, i.e. a defect in the biliary umbrella which is physiologically responsible for the exchange of the ions Cl- and HCO3- and maintains the integrity of glycocalyx. To provide a state-of-the-art analysis of this topic, a systematic review of literature in PubMed, Scopus, and Science Direct was conducted (inclusive dates: 1986-2023). AREA COVERED: Although the etiology remains unknown, pathogenesis consists of a complex immune-mediated process resulting from a genetic susceptibility. PBC can be triggered by an immune-mediated response to an autoantigen, which leads to a progressive destruction of bile ducts and eventually to a progressive fibrosis with cirrhosis. The defect in the 'bicarbonate umbrella' acts as a protection against the toxic hydrophobic bile acids, leading to a toxic composition of bile. EXPERT OPINION: This review offers a summary of the current knowledge about the pathogenesis of PBC, indicating that this is probably based on the mutual relationship between the immune insult and the unbalanced secretory mechanisms.

Primary biliary cholangitis: Epidemiology, prognosis, and treatment.

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune liver disease characterized by a destructive, small duct, and lymphocytic cholangitis, and marked by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC vary widely in different regions and time periods, and although disproportionally more common among White non-Hispanic females, contemporary data show a higher prevalence in males and racial minorities than previously described. Outcomes largely depend on early recognition of the disease and prompt institution of treatment, which, in turn, are directly influenced by provider bias and socioeconomic factors. Ursodeoxycholic acid remains the initial treatment of choice for PBC, with obeticholic acid and fibrates (off-label therapy) reserved as add-on therapy for the management of inadequate responders or those with ursodeoxycholic acid intolerance. Novel and repurposed drugs are currently at different stages of clinical development not only for the treatment of PBC but also for its symptomatic management. Here, we summarize the most up-to-date data regarding the epidemiology, prognosis, and treatment of PBC, providing clinically useful information for its holistic management.

Diagnostic value of the serum lactate level as a predictor of bacteremia in patients with acute cholangitis.

BACKGROUND: Patients with acute cholangitis (AC) have increased mortality when associated with bacteremia. This study aimed to evaluate the predictive ability of serum lactate (Lac) for positive bacteremia in patients with acute cholangitis. METHODS: In this single-center, retrospective study, 138 consecutive patients with AC were analyzed. Their blood samples were collected and Lac was measured. RESULTS: A total of 50 patients showed grade I, 50 showed grade II, and 38 showed grade III severity according to the Tokyo Guidelines 2018. Positive bacteremia was observed in 71 patients, of which 15 showed grade I, 25 showed grade II, and 31 showed grade III severity. Logistic regression analysis showed that Lac was a significant predictor of bacteremia. The area under the curve of Lac and procalcitonin (PCT) for bacteremia were 0.737 and 0.780, respectively. The optimal cutoff values for bacteremia were 17 mg/dL and 2.8 ng/mL, with sensitivity of 69.0% and 68.3%, respectively. Sensitivity of Lac and PCT for bacteremia in grade I was 58.3% and 25.0%, respectively. Three patients died from AC, all of whom were positive for bacteremia and hyperlactatemia. CONCLUSION: Lac is useful for predicting bacteremia in patients with AC.

Anti-gp210-positive primary biliary cholangitis: The dilemma of clinical treatment and emerging mechanisms.

Anti-gp210 is the disease-specific anti-nuclear antibody (ANA) of primary biliary cholangitis (PBC). Anti-gp210-positive PBC patients have worse responses to ursodeoxycholic acid (UDCA) as compared with anti-gp210-negative patients. Moreover, anti-gp210-positive patients always present with more severe histopathologic features including lobular inflammation, interfacial hepatitis, and bile duct injury, and have a worse prognosis than their anti-gp210-negative counterparts. Previous studies have identified two antigenic epitopes recognized by anti-gp210. Although the pathogenetic mechanism of anti-gp210 production remains unclear, evidence suggests that the autoimmune response to anti-gp210 production might be due to molecular mimicry induced by bacteria or endogenous peptides. T cells and related cytokines play a critical role in the pathogenesis of PBC, however, the mechanism hasn't been fully understood. Thus, this review focuses on the clinicopathological characteristics of anti-gp210-positive PBC patients, the fundamental research of gp210 antigen, and the possible mechanism of anti-gp210 production to clarify the mechanism of anti-gp210-positive PBC and provide potential molecular targets for disease prevention and treatment in the future.

Influence of Frailty in Patients Undergoing Endoscopic Retrograde Cholangiopancreatography for Biliary Stone Disease: A Nationwide Study.

BACKGROUND AND AIMS: Pancreaticobiliary diseases are common in the elderly. To this end, frailty represents a state of vulnerability that should be considered when assessing the risks and benefits of therapeutic endoscopic procedures. We aim to determine the rate of readmissions and clinical outcomes using the validated Hospital Frailty Risk Score in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). METHODS: Using the National Readmissions Database, we identified patients with an admission diagnosis of cholangitis with obstructive stone from 2016 to 2019. Patients were determined to be of low frailty risk with a score of < 5, while patients of medium to high frailty risk had a score of > 5. RESULTS: During the study period, 5751 patients were identified with acute cholangitis with obstructing stone. Mean age of index admissions was 69.4 years and 51.8% were female. From the total cohort, 5119 (89.2%) patients underwent therapeutic ERCP, 38.0% (n = 1947) of whom were regarded as frail (risk score > 5). Following ERCP, frail patients had a less but statistically insignificant readmission rate compared to non-frail patients (2.76% vs 4.05%, p = 0.450). However, compared to non-frail patients, frail patients experienced higher post-ERCP complications (6.20% vs 14.63%, p < 0.001). Frail patients were more likely to have longer lengths of stay, higher hospital cost, and mortality risk. CONCLUSION: ERCP is not a risk factor for readmission among frail patients. However, frail patients are at higher risk for procedure-related complications, healthcare utilization, and mortality.

[Acute cholangitis secondary to periampullary duodenal diverticulum. Case report]. / Colangitis aguda severa secundaria a divertículo duodenal periampular. Reporte de un caso.

Background: Periampullary duodenal diverticula are rare and pancreaticobiliary complications infrequent, however, when they are diagnosed and associated with symptoms, they warrant urgent intervention. The aim of this article is to present a clinical case of severe cholangitis secondary to the presence of a periampullary diverticulum successfully treated endoscopically. Clinical case: A 68-year-old man with a history of diabetes and hypertension, was admitted to the emergency room with symptoms of abdominal pain, fever, and tachycardia. With acute kidney injury and alterations in liver function tests, ultrasound with dilated common bile duct and gallstones. Magnetic resonance cholangiography is performed, showing duodenal diverticulum and choledocholithiasis. Antibiotic management is given, and endoscopic retrograde cholangiopancreatography is decided, finding a duodenal diverticulum with stones and pus inside, sphincterotomy, transpapillary dilation and multiple sweeps are performed. Cholecystectomy was performed 7 days later, and the patient was discharged without complications. Conclusions: In patients with signs of severe cholangitis, it is important not to delay endoscopic retrograde cholangiopancreatography, even when infrequent associated pathologies are evidenced, such as a periampullary duodenal diverticulum, since this represents the diagnostic and therapeutic method of choice with high rates of resolution in the case of an obstructive pathology of the bile duct.

Introducción: los divertículos duodenales periampulares son raros y las complicaciones pancreaticobiliares infrecuentes; sin embargo, cuando se diagnostican y se asocian a sintomatología ameritan intervención urgente. El objetivo de este trabajo es presentar un caso clínico de colangitis severa secundaria a la presencia de un divertículo periampular tratado de manera exitosa por vía endoscópica. Caso clínico: hombre de 68 años con antecedentes de diabetes e hipertensión, quien acude al área de Urgencias con cuadro de dolor abdominal, fiebre y taquicardia. Se identifica lesión renal aguda y alteraciones en las pruebas de función hepática, ultrasonido con colédoco dilatado y litiasis vesicular. Se realiza colangioresonancia magnética que evidencia divertículo duodenal y coledocolitiasis. Se otorga manejo antibiótico y se decide colangiopancreatografía retrógrada endoscópica, encontrándose divertículo duodenal con litos y pus en su interior, se realiza esfinterotomía, dilatación transpapilar y múltiples barridos. Se realiza colecistectomía a los siete días y se egresa a domicilio por mejoría sin complicaciones. Conclusiones: en pacientes con datos de colangitis grave es importante no retrasar la colangiopancreatografia retrógrada endoscópica, aun cuando se evidencien patologías asociadas infrecuentes como un divertículo duodenal periampular, ya que esta representa el método diagnóstico y terapéutico de elección con tasas altas de resolución ante una patología obstructiva de la vía biliar.

Factors associated with clinical outcome in geriatric acute cholangitis patients.

OBJECTIVE: We aimed to determine the risk factors associated with the clinical outcome in cases of acute cholangitis among the geriatric age group. PATIENTS AND METHODS: Patients aged >65 years hospitalized with the diagnosis of acute cholangitis in an emergency internal medicine clinic were included in this study. RESULTS: The study population comprised 300 patients. In the oldest-old group, the rates of severe acute cholangitis and intensive care unit hospitalization (39.1% vs. 23.2%, p<0.001) were higher. The mortality rate was also higher in the oldest-old group (10.4% vs. 5.9%, p=0.045). The presence of malignancy, ICU hospitalization, decreased platelet levels, decreased hemoglobin levels, and decreased albumin levels were associated with mortality. In the multivariable regression model in which variables associated with Tokyo severity were included, the associated factors for membership in the severe risk group compared to the moderate risk group were decreased platelet count (OR: 0.96; p=0.040) and decreased albumin level (OR: 0.93; p=0.027). Increasing age (OR: 1.07; p=0.001), malignancy etiology (OR: 5.03; p<0.001), increasing Tokyo severity (OR: 7.61; p<0.001), and decreasing lymphocyte count (OR: 0.49; p=0.032) were determined to be associated with ICU admission. Decreasing albumin levels (OR: 0.86; p=0.021) and ICU admission (OR: 16.43; p=0.008) were determined to be factors associated with mortality. CONCLUSIONS: Worse clinical outcomes occur among geriatric patients with increasing age.