Primary Biliary Cirrhosis in China

Ｂａｃｋｇｒｏｕｎｄａｎｄａｉｍ :Ｐｒｉｍａｒｙ ｂｉｌｉａｒｙｃｉｒｒｈｏｓｉｓ(ＰＢＣ)ｉｓａｕｎｃｏｍｍｏｎｌｉｖｅｒｄｉｓｅａｓｅｉｎＣｈｉｎａ .ＯｎｌｙｓｏｍｅｓｐｏｒａｄｉｃｃａｓｅｓｗｅｒｅｒｅｐｏｒｔｅｄｉｎＣｈｉｎｅｓｅｍｅｄｉｃａｌｌｉｔ     

Treatment of Primary Biliary Cirrhosis: A new challenge?

Primary biliary cirrhosis (PBC) is characterized by unknown etiologies, anti-mitochondrial antibodies, injury of the biliary duct and the lack of a definite remedy. The etiologies of PBC have been well-discussed, including microorganisms and xenobiotics as the triggers for initiating the disease, and an abnormality of immune-tolerance. Recently, several animal models of PBC have been developed that may lead to the development of new therapies. Here, we reviewed the articles that address the etiology of PBC and the therapy for this disease for the confirmation of our current positions and future directions.     

Potential Roles for Infectious Agents in the Pathophysiology of Primary Biliary Cirrhosis: What’s New?

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease serologically characterized by the presence of high-titer antimitochondrial antibodies and, histologically by chronic nonsuppurative cholangitis and granulomata. The aetiology of the disease remains elusive, although genetic, epigenetic, environmental, and infectious factors have been considered important for the induction of the disease in genetically prone individuals. The disease shows a striking female predominance and becomes clinically overt at the fourth to sixth decade. These characteristics have prompted investigators to consider infections that predominate in women at these ages as the likely candidates for triggering the disease. Recurrent urinary tract infections due to Escherichia coli were the first infections to be considered pathogenetically relevant. Over the years, several other microorganisms have been linked to the pathogenesis of PBC owing to epidemiological, immunological, microbiological, or experimental findings in animal models. Recent studies have provided data supporting the pathogenic role of Novosphingobium aromaticivorans and betaretroviruses. Several reports have linked other organisms to the induction of the disease and/or the maintenance of the auto-aggressive responses that are perpetuated over the course of the disease. This review highlights the findings of the most recent studies investigating the link between infections and PBC. We also discuss the close interplay of the infectious agents with other environmental and genetic factors, which may explain the multifaceted nature of this puzzling disease.     

Antibodies Against Glycoprotein 2 Are Specific Biomarkers for Pediatric Crohn’s Disease

Background

Serological markers can assist in accurate differentiation between Crohn’s disease (CD) and ulcerative colitis (UC). One such marker is anti-glycoprotein 2 (anti-GP2) which was shown to be a specific marker for CD in adult patients. The aim of our study was to assess the utility of anti-GP2 and GP2 as biomarkers for pediatric CD, and determine whether they correlate with disease activity.

Methods

Serum samples were tested by ELISA for anti-GP2 isoform 4 IgG and IgA, and also for GP2. Results were correlated with demographic and clinical data.

Results

The cohort consisted of 53 pediatric patients with CD, 42 with UC, and 53 controls. Levels of anti-GP2 were significantly increased in pediatric patients with CD in comparison with patients with UC, and control subjects, with high positive predictive value for both IgG and IgA (97.9% and 82.6%, respectively). While specificity of anti-GP2 IgG and IgA was very high (98.7% and 90.0%, respectively), sensitivity was low (42.0% and 35.5% for IgG and IgA, respectively). In CD, anti-GP2 correlated with disease activity, and decreased in treatment-naïve patients following successful induction therapy. A higher IgA anti-GP2 was also demonstrated in patients with ileo-colonic involvement, and was associated with a younger age. Finally, positive GP2 level was identified in only 1/211 serum samples.

Conclusions

A positive anti-GP2 level is highly associated with CD, while a negative result does not exclude CD. Additional studies are required to determine whether these markers can be used in pediatric patients with CD for risk stratification.

     

Fibrates for Primary Biliary Cholangitis: What’s All the Hype?

Ursodeoxycholic acid is the first-line therapy for primary biliary cholangitis. However, a subset of patients fail to show biochemical response. For these patients, adjuvant therapies are warranted. Obeticholic acid was conditionally approved as a second-line drug. Evidence is building up in favor of fibrates, which are available for off-label use.     

Increased Risks of Spontaneous Bacterial Peritonitis and Interstitial Lung Disease in Primary Biliary Cirrhosis Patients With Concomitant Sj?gren Syndrome

The incidence of Sjögren syndrome (SS) in primary biliary cirrhosis (PBC) patients is high. The influence of SS on the clinical outcomes of PBC patients, however, remains unclear. Our study retrospectively collected data on PBC-only patients and PBC patients with concomitant SS (PBC-SS) to compare the clinical differences of long-term outcomes between them.A total of 183 patients were diagnosed with PBC from January 1999 to December 2014 at our hospital. Of these, the authors excluded patients with diabetes, hypertension, advanced liver cirrhosis at initial diagnosis of PBC (Child–Turcotte–Pugh classification score of ≥7) and other liver diseases (ie, alcoholic liver disease, alpha-antitrypsin deficiency, viral hepatitis, and primary sclerosing cholangitis), and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Of the remaining 125 patients, 77 (61.6%) were PBC-only and 48 (38.4%) were PBC-SS patients.The mean follow-up duration was 8.76 years. During the observation period, the incidence of interstitial lung disease was higher in the PBC-SS group than in the PBC-only group (P = 0.005). The occurrence of spontaneous bacterial peritonitis was significantly different in PBC-SS patients than in PBC-only patients (P = 0.002). The overall survival was lower in PBC-SS patients than in PBC-only patients (P = 0.033). Although the incidence of hepatocellular carcinoma, end-stage renal disease, variceal bleeding, and hypothyroidism were all higher in the PBC-SS group than in the PBC-only group, the differences were not significant.Our study suggests that PBC-SS patients have a higher risk of developing interstitial lung disease and spontaneous bacterial peritonitis and have a poor prognosis. Aggressive surveillance of thyroid and pulmonary functions should therefore be performed in these patients.     

Are the Echogenicities on Intraductal Ultrasonography Really Biliary Microlithiasis?

Background Intraductal ultrasonography (IDUS) is a useful procedure for diagnosing microlithiasis in the bile duct but it is not easy to differentiate between tiny echogenicity and real microlithiasis. We compared the echogenicity seen on IDUS and the findings of bile microscopy (BM) of bile that was collected in the common bile duct (CBD) to determine whether the echogenicity seen on IDUS is real microlithiasis. Methods This prospective study involved a total of 30 patients who experienced biliary pain (n = 11), acute cholecystitis (n = 11) or indeterminate pancreatitis (n = 8) without a filling defect or obstruction in the bile duct. IDUS was performed during endoscopic retrograde cholangiopancreatography (ERCP), followed by bile aspiration for BM. Endoscopic sphincterotomy (EST) was performed if definite echogenic materials were observed on IDUS. Results Of the 30 patients, 23 (77%) had echogenic materials visible in the CBD on IDUS. Of these 23 patients, 13 (57%) were found to have biliary crystals by BM. The size of the echogenic materials was the only significant factor associated with BM positivity. Using the receiver operating curve, the optimal size of the echogenicity to differentiate real microlithiasis was 1.4 mm. Conclusions Optimal concordance between IDUS and BM was observed when the size of the microlithiasis was greater than 1.4 mm; under these conditions the sensitivity and specificity were 71% and 75%, respectively. This information may be useful when deciding whether to perform endoscopic sphincterotomy.     

Chicken Egg Yolk Antibodies Specific for the γ Chain of Human Hemoglobin for Diagnosis of Thalassemia

Immunoglobulin Y (IgY) technology was used to generate anti-hemoglobin Bart's (Hb Bart's) IgY antibodies (Abs) for development into an enzyme-linked immunosorbent assay (ELISA) test for thalassemia diagnosis. Hb Bart's purified from the hemolysate of a patient with Hb Bart's hydrops fetalis (homozygous alpha-thalassemia) was used to immunize a chicken via the pectoralis muscle. After water dilution and sodium sulfate precipitation, 40 to 70 mg of IgY could be extracted from an egg. IgY, first detected in sera 2 weeks after immunization, reached the highest titer at week 4, and the titer remained stable for at least 2 weeks before declining. The pattern of Ab response in the yolk was the same as in the serum but was somewhat delayed. The IgY Abs produced reacted with gamma globin, Hb Bart's, Hb F, normal cord hemolysate (Hbs F plus A), and Hb Bart's hydrops fetalis (Hbs Bart's plus Portland) and to a lesser degree with beta globin, Hb A, Hb A2 and adult hemolysate (Hbs A plus A2), but the Abs did not react with alpha globin. Immunoaffinity purification with Hb A coupled to Sepharose was used to isolate an unbound IgY that reacted with Hb F, Hb Bart's, and gamma globin, and this IgY was used to develop an ELISA test for thalassemia diagnosis. The results of direct ELISA analyses of 336 hemolysate samples from individuals with various known thalassemia genotypes and phenotypes and from healthy individuals confirmed the specificity of the polyclonal Abs for Hbs containing Hb F and Hb Bart's. This specificity, which was due to the Abs' strong reactivity in cases of pathologic thalassemic diseases and weak reactivity in cases of nonpathologic thalassemic diseases, depended on the levels of Hb Bart's and Hb F.     

Are MADIT II Criteria for Implantable Cardioverter Defibrillator Implantation Appropriate for Chinese Patients?

MADIT II Criteria for Implantable Cardioverter. Background: MADIT‐II demonstrated that prophylactic implantation of an implantable cardioverter‐defibrillator (ICD) device prevents sudden cardiac death (SCD) in patients with myocardial infarction (MI) and impaired left ventricular ejection fraction (LVEF). It remains unclear whether the MADIT‐II criteria for ICD implantation are appropriate for Chinese patients. Methods and Results: We compared the clinical characteristics and outcome for a cohort of consecutive Chinese patients who satisfied MADIT‐II criteria for ICD implantation with the original published MADIT‐II population. Seventy consecutive patients who satisfied MADIT‐II criteria but did not undergo ICD implantation (age: 67 years, male: 77%) were studied. Their baseline demographics were comparable with the original MADIT‐II cohort with the exception of a higher incidence of diabetes mellitus. After follow‐up of 35 months, most deaths (78%) were due to cardiac causes (72% due to SCD). The 2‐year SCD rate (10.0%) was comparable with that of the MADIT‐II conventional group (12.1%), but higher than the MADIT‐II defibrillator group (4.9%). Similarly, the 2‐year non‐SCD rate was 3.0%, also comparable with the MADIT‐II conventional group (4.6%), but lower than the MADIT‐II defibrillator group (7.0%). Cox regression analysis revealed that advance NYHA function class (Hazard Ratio [HR]: 3.5, 95% Confidence Interval [CI]: 1.48–8.24, P = 0.004) and the lack of statin therapy (HR: 3.7, 95%CI: 1.35–10.17, P = 0.011) were independent predictors for mortality in the MADIT‐II eligible patients. Conclusion: Chinese patients who satisfy MADIT‐II criteria for ICD implantation are at similar risk of SCD and non‐SCD as the original MADIT‐II subjects. Implantation of an ICD in Chinese patients is appropriate. (J Cardiovasc Electrophysiol, Vol. 21, pp. 231–235, March 2010)     

Are Clinicians Ready for Safe Use of Stratified Therapy in Primary Biliary Cholangitis (PBC)? A Study of Educational Awareness

Background

Primary Biliary Cholangitis (PBC, formerly cirrhosis), is a chronic cholestatic liver disease which until spring 2016 had a single licensed therapy, Ursodeoxycholic acid (UDCA). Approximately 30% of patients do not respond to UDCA, and are high-risk for progressing to end stage liver disease, transplantation or death. A new era of stratified medicine with second-line therapies to treat high-risk disease is emerging, with the first such second-line agent obeticholic acid recently receiving FDA and EMA approval and entering practice. Recent experience in the USA of inappropriate use and associated deaths has highlighted concerns as to whether clinicians have the knowledge to implement second-line therapies appropriately and safely.

Methods

Online survey of knowledge regarding optimal PBC management in Gastroenterologists and Hepatologists in the USA; the first 100 completed responses from each group used for analysis.

Results

80% of Hepatologists felt they were highly competent in their understanding of the importance of early diagnosis and early UDCA therapy in PBC compared with 65% of gastroenterologists. However, only 36% of Hepatologists and 30% of gastroenterologists felt competent at assessing response to UDCA. Competence in knowledge (mode of action, efficacy, and side effects) of second-line therapies and enrollment into trials was low among both groups.

Conclusion

Significant knowledge gaps in clinicians managing PBC presents a problem in optimizing care. It is perhaps not surprising that knowledge of emerging second-line therapies is low, however more concerning is sub-optimal use of UDCA in real-life practice and the lack of confidence at assessing treatment response which should be a routine part of clinical practice to assess risk of disease progression and will be key in delivering stratified medicine.