Advances in pharmacotherapy for primary biliary cirrhosis

Introduction: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive.

Areas covered: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids.

Expert opinion: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.     

Antibodies to carbonic anhydrase in patients with immune cholangiopathies

Bile duct epithelia contain an abundance of carbonic anhydrase. Antibodies to this enzyme have been described in autoimmune disorders. Serum from patients with immune-mediated liver diseases was studied to determine whether antibodies to carbonic anhydrase II and/or pyruvate dehydrogenase could distinguish autoimmune cholangitis as immunologically distinct from primary biliary cirrhosis. Antibody assays to carbonic anhydrase II (Western blot) and pyruvate dehydrogenase (flow cytometry) were performed on the sera of patients with autoimmune cholangitis (6), primary biliary cirrhosis (12), primary sclerosing cholangitis (12), autoimmune hepatitis (12), and control (Gilbert syndrome; 8). Reactivity to carbonic anhydrase II was detected in 5 of 6 patients with autoimmune cholangitis, 1 of 12 patients with primary biliary cirrhosis, 1 of 12 patients with autoimmune hepatitis, and no other patients. Individuals with autoimmune cholangitis were more likely than the other patients to be reactive to carbonic anhydrase II (P < 0.001). Patients with primary biliary cirrhosis were more reactive to pyruvate dehydrogenase compared with all other groups (P < 0.001). An antibody to human carbonic anhydrase II is frequently detected in the sera of patients with autoimmune cholangitis and is uncommon or not present in other cholangiopathies. These data provide evidence that autoimmune cholangitis and primary biliary cirrhosis represent distinct entities with unique patterns of immunoreactivity.     

Overlap syndromes among autoimmune liver diseases

The three major immune disorders of the liver are autoimmune hepatitis（AIH）,primary biliary cirrhosis（PBC） and primary sclerosing cholangitis（PSC）.Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis（AMA-negative PBC） overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.     

内镜治疗急性胆源性胰腺炎的临床疗效

目的探讨内镜治疗急性胆源性胰腺炎(ABP)的临床应用价值。方法整理经内镜治疗的48例及内科保守治疗的37例ABP患者的临床资料,分析内镜治疗对ABP的临床疗效和对ABP重症化的影响。结果内镜治疗ABP可明显缩短患者病程,加速患者恢复,降低患者住院费用并能减少ABP的重症化转化。结论内镜治疗ABP可加速患者恢复,缩短住院时间,同时可抑制ABP重症化转换并降低并发症发生率,是治疗ABP的一种安全、有效的方法。     

60例胆源性胰腺炎 MRCP 检查的临床应用研究

目的：探讨磁共振胰胆管成像（MRCP）诊断胆源性胰腺炎（BP）的临床价值。方法回顾性分析60例经临床证实的 BP 的 MRCP 表现。结果60例中,胰腺炎与胆囊结石或胆囊炎征像共存41例,胰腺炎和胆总管结石共存19例。胆管扩张23例,胰管扩张 9例,胆管扩张合并胰管扩5例。结论MRCP 可以明确显示 BP 的有关征象,具有较高的临床应用价值。     

Early Detection of High-grade Biliary Intraepithelial Neoplasia (BilIN-3) in the Cystic Duct Visualized by SpyGlass DS Cholangioscopy

An 84-year-old man was admitted with epigastralgia. Computed tomography showed contrast-enhanced wall thickness in the cystic duct. An endoscopic examination revealed short irregular stricture in the cystic duct, and per-oral cholangioscopy revealed a reddish papillary tumor at the stricture site. Surgical resection revealed high-grade biliary intraepithelial neoplasia (BilIN) at the stricture site of the cystic duct. To our knowledge, this is the first case of a solitary high-grade BilIN epithelium in the cystic duct detected by per-oral cholangioscopy.     

Surgical anatomy of hepatoduodenal ligament and hepatic hilus

The anatomical situation and variations of structures in the hepatoduodenal ligament and hepatic hilus are a legacy of their embryological development. The vascular, biliary, and lymphatic structures contribute to the functioning of blood and bile flow as well as lymph drainage of the liver. Connective tissue, fatty tissue, and the peritoneal sheet are enveloping underlying structures. Their position, shape, and relation to neighboring structures influence the situation during operative procedures. The cystic artery origin is variable, as is the number; and its recognition is important for safe cholecystectomy. Venous drainage of the gallbladder goes into the portal system of adjacent segments 4 and 5 and influences the spread of gallbladder pathology. There are some surgically important variations in the course and distribution of bile ducts and arteries in the hepatoduodenal ligament. The biliary anatomical variations significantly influence the incidence of bile ducts injuries during laparoscopic cholecystectomy. The arterial supply of extrahepatic bile ducts is delicate and variable and should be considered when trying to prevent ischemic injuries to the bile ducts. Inflammation and the combination of inflammation and anatomical variation are thought to contribute to a dangerous situation in regard to eventual injury to the bile ducts and vascular structures during operative procedures. This paper explores these questions.     

End-to-side choledochoduodenostomy: A widely applicable procedure for biliary reconstruction

End-to-side choledochoduodenostomy was originally used for reconstruction between the duodenum and the biliary tree in iatrogenic bile duct stricture. However, we believe the procedure could be applied for various biliary disorders. We have recently shown the high carcinogenicity of biliary epithelium in patients with pancreaticobiliary maljunction, and consequently we recommend excision of the bile duct, along with appropriate reconstruction of the biliary system to divert the flow of pancreatic juice from bile fluid, to prevent carcinoma in biliary epithelium even in patients without dilatation of the bile duct. The conditions causing primary or recurrent bile duct stones must be removed. We employed this procedure for biliary reconstruction in 42 patients with pancreatico-biliary maljunction and in 30 patients with various benign biliary diseases, such as bile duct stones and benign biliary stenosis. We also used the procedure for palliation in 6 patients with malignant tumors around the head of the pancreas. Among these 78 patients over 20 years, we experienced 5 cases of reflux cholangitis with anastomotic stenosis, for which conservative dilatation was required. This procedure of end-to-side choledochoduodenostomy could be widely applicable for biliary reconstruction in terms of its being simplicity, minimal invasiveness and the establishment of a single physiological route for bile flow into the duodenum.     

Primary biliary cirrhosis: lung involvement

Abstract: Sub-clinical lung impairment, mostly represented by a reduced diffusion of alveolar gases, is a recognised complication of advanced primary biliary cirrhosis. The aim of the study was to evaluate the prevalence and type of pulmonary involvement in primary biliary cirrhosis and the relationship between lung function abnormalities and selected epidemiological and clinical variables. Sixty-one patients with different stages of primary biliary cirrhosis consecutively seen in our outpatient clinic were evaluated. The advancement of primary biliary cirrhosis was characterised by the histological stage, the presence of signs of portal hypertension and the Mayo Risk Score: a Cox regression model using serum bilirubin and albumin levels, prothrombin time, age and degree of oedema as selected variables. We measured static and dynamic lung volumes, by means of a spirometer, and diffusing capacity for carbon monoxide. Rheumatological disorders were evaluated by an independent rheumatologist. No patient complained of respiratory symptoms. Airway obstruction was present in one patient. In 24 patients (39%) the alveolar diffusion capacity was reduced. We did not find any significant relationship between diffusing capacity and smoking habits, advancement of liver disease and concomitant Sjogren syndrome. Reduced diffusion capacity showed a significant correlation with the presence of complete or incomplete CREST syndrome (p<0.01) and with the presence of circulating anti-centromere antibodies (p<0.05). Alveolar diffusion capacity is frequently impaired in patients with primary biliary cirrhosis, usually in the absence of clinical manifestations. These alterations mostly affect patients with concomitant CREST syndrome. Prospective studies are needed to evaluate if these abnormalities will eventually lead to clinical symptoms and if their progression could be influenced by different therapeutic regimens for primary biliary cirrhosis.     

Indeterminate biliary strictures: a simplified approach

Introduction: Pre-operative evaluation of biliary strictures remains challenging. The dilemma that exists is how to balance the risk of failing to detect malignancy and the potential morbidity caused by unnecessary surgery in patients with benign etiologies. With emerging novel diagnostic modalities, this study aims to assess the efficacy of diagnostic techniques and facilitate a clinical approach to indeterminate biliary strictures.

Areas covered: Conventional imaging modalities are crucial in identifying the location of a stricture and are helpful for choosing further diagnostic modalities. Utilization of endoscopic techniques, including endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS), is key in establishing a diagnosis. The emergence of novel diagnostic modalities, such as fluorescence in-situ hybridization (FISH), peroral cholangioscopy (POC), intraductal endoscopic ultrasound (IDUS) and confocal laser endomicroscopy (CLE), enhance the diagnostic yield in the evaluation of indeterminate biliary strictures.

Expert commentary: More reliable and validated visual criteria for differentiating malignancy from benign biliary conditions, utilizing advanced imaging modalities such as POC and CLE, need to be established. It is of significance to further evaluate these novel diagnostic modalities through ongoing trials and to develop a diagnostic algorithm that reconciles cost-effectiveness with diagnostic accuracy.