Single or multiple dose ursodeoxycholic acid for cholestatic liver disease: biliary enrichment and biochemical response

Background: Ursodeoxycholic acid (UDCA) improves liver biochemistry in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Since UDCA acts partly by reducing the intestinal absorption of hydrophobic endogenous bile salts and is poorly absorbed from the intestine, a multiple dose regimen has been advocated. Single dose treatment, on the other hand, may improve compliance.Aim: The effects of a single or multiple dose regimen on liver enzymes and serum and biliary bile salts composition were evaluated.Methods: Twenty-seven patients (19 PSC, 8 PBC), most with early stage disease, received UDCA (10 mg kg⁻¹ day⁻¹) in a single dose at bed time (n=13) or in three divided gifts with meals (n=14) over 3 months. Five patients had both treatment regimens in random order with a 1-month wash-out period in between.Results: Liver biochemistry equally improved in both groups. Biliary enrichment (% UDCA of total bile salts, mean±SEM) was 40.1±2.4 in the single dose group vs 40.8±2.8 in the multiple dose group (p=NS) and was positively correlated with biochemical improvement (AP: r=0.47, p=0.02; GGT: r=0.58, p=0.002; ASAT: r=0.67, p=0.002; ALAT: r=0.52, p=0.01). Biochemical improvement was not correlated with the concentration or %UDCA in serum. Patients participating in the cross-over design had comparable biochemical response and biliary %UDCA during both regimens.Conclusion: Single and multiple dose UDCA have similar effects on liver biochemistry and biliary enrichment in cholestatic liver disease. Biochemical improvement appears to be related to biliary (but not serum) enrichment with UDCA.     

Liver transplantation for primary sclerosing cholangitis versus primary biliary cirrhosis: A comparison of complications and outcome

Abstract Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are the most common cholestatic disorders in adulthood requiring hepatic transplantation. Although they run similar courses, they may have different problems before and after transplantation. The aim of this study was to compare pre- and post-transplant complications and outcomes in these two similar but distinct patient groups. One hundred and seventeen adult patients underwent liver transplantation at our institution over a 6 year period, including 19 with PSC and 20 with PBC. Pre-transplant there were no significant differences in age, liver biochemistry, haematology or Child-Pugh scores between the two groups. The mean duration of disease before transplant was longer in PSC patients (11.7 vs 6.5 years; P < 0.05). The prevalence of septic cholangitis was greater in PSC (58 vs 5%; P < 0.01) as was the requirement for surgical or radiological interventional procedures, excluding cholecystectomy (53 vs 0%; P < 0.01). At transplantation, four patients with PSC had previously unrecognized cholangiocarcinoma. In the pre-transplant period these four patients had uncontrolled biliary sepsis at the time of transplant vs five of 15 PSC patients without cholangiocarcinoma. Postoperatively, PSC patients had a greater prevalence of intra-abdominal sepsis requiring surgical or radiological intervention (42 vs 5%; P < 0.05). In comparison, patients with PBC had a high prevalence of skeletal complications (30 vs 10%; P < 0.05) particularly avascular necrosis (15 vs 0%). The prevalence of chronic rejection was similar in both groups (15%). Overall survival was higher in PBC patients (85 vs 63%; P < 0.05). The prevalence of postoperative intra-abdominal sepsis requiring surgical or radiological intervention was higher in those patients with PSC who died (six of seven) compared to survivors (two of 12), (P < 0.001). Postoperative uncontrolled intra-abdominal sepsis directly contributed to more deaths in PSC patients (four of seven vs 0%). In conclusion, despite many similarities with PBC, PSC patients have higher prevalence of pre- and postoperative intra-abdominal sepsis that may contribute to poorer survival. In contrast PBC patients have excellent survival rates after a liver transplant, although bony complications are increased.     

Recent advances in the diagnosis and treatment of primary biliary cholangitis

Primary biliary cholangitis(PBC), formerly referred toas primary biliary cirrhosis, is an infrequent progressive intrahepatic cholestatic autoimmune illness that can evolve into hepatic fibrosis, hepatic cirrhosis, hepatic failure, and, in some cases, hepatocellular carcinoma. The disease itself is characterized by T-lymphocytemediated chronic non-suppurative destructive cholangitis and elevated serum levels of extremely specific antimitochondrial autoantibodies(AMAs). In this article, we will not only review epidemiology, risk factors, natural history, predictive scores, radiologic approaches(e.g., acoustic radiation force impulse imaging, vibration controlled transient elastography, and magnetic resonance elastography), clinical features, serological characteristics covering biochemical markers, immunoglobulins, infections markers, biomarkers, predictive fibrosis marker, specific antibodies(including AMAs such as AMA-M2), anti-nuclear autoantibodies [such as anti-multiple nuclear dot autoantibodies(anti-sp100, PML, NDP52, anti-sp140), anti-rim-like/membranous anti-nuclear autoantibodies(anti-gp210, anti-p62), anti-centromere autoantibodies, and some of the novel autoantibodies], histopathological characteristics of PBC, diagnostic advances, and antidiastole of PBC. Furthermore, this review emphasizes the recent advances in research of PBC in terms of therapies, including ursodeoxycholic acid, budesonide, methotrexate, obeticholic acid, cyclosporine A, fibrates such as bezafibrate and fenofibrate, rituximab, mesenchymal stem cells transplant, and hepatic transplant. Currently, hepatic transplant remains the only optimal choice with acknowledged treatment efficiency for end-stage PBC patients.     

微小RNA在胆道疾病中的研究进展

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2014年自身免疫性肝病诊疗进展

<正>自身免疫性肝病(Autoimmune liver diseases,AILD)是因免疫系统过度激活从而出现肝功能异常及相应临床综合征的一组疾病,可简单分为以肝炎为主型,即自身免疫性肝炎(Autoimmune hepatitis,AIH)及以胆管损害和胆汁淤积为主型,即原发性胆汁性肝硬化(Primary biliary cirrhosis,PBC)和原发性硬化性胆管炎(Primary sclerosing cholangitis,PSC)。此外,部分     

Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease

AIM:To assess the role of IgM and IgG immunohistochemistry(IHC) in the evaluation of autoimmune liver conditions-autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC),and primary sclerosing cholangitis(PSC).METHODS:Forty one biopsies from untreated patients diagnosed with autoimmune liver disease(AIH,n = 20;PBC,n = 13;PSC,n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected.IgM and IgG-positive plasma cells were counted in each sample.RESULTS:A predominance of IgG-positive plas...     

Hepatic copper content is normal in early primary biliary cirrhosis and primary sclerosing cholangitis

In previous studies, the majority of patients with the cholestatic liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), had increased hepatic copper (Cu) levels even in early stages of disease. We prospectively measured hepatic copper content by atomic absorption spectrophotometry in 55 patients with PBC, 6 patients with PSC, and 29 patients with other chronic noncholestatic liver diseases. Hepatic Cu content was normal in 22/61 (36%) of patients with PBC or PSC; 18 of the 22 did not have cirrhosis (82%). Hepatic Cu content increased with increasing stage of disease (r=0.61,P<0.001) and was positively correlated with serum total bilirubin (r=0.6,P<0.0001) and alkaline phosphatase (r=0.5,P<0.001). All patients with stage I and II disease had hepatic Cu<150 µg/g dry weight, and all patients with hepatic Cu>150 µg/g dry weight had stage III and IV disease. Hepatic Cu content is normal in early PBC and PSC. Copper accumulation in the liver in these cholestatic liver diseases is secondary to cholestasis rather than a primary phenomenon.Supported by General Research Center grant MOIRR0054 from the National Institutes of Health.     

Recurrence of primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation in Japan

Although there was some initial controversy, there is now a consensus that primary biliary cirrhosis (PBC) does indeed recur in both cadaveric and living donated allografts. Recurrence rate after deceased donor liver transplantation (LT) was reported to be 10.9–23% at 5 years. In the present study, we reviewed 221 PBC patients who underwent living-donor liver transplantation (LDLT) in Japan. The 5-year overall survival rate was 79%, and the rate of recurrence based on histological findings was 10% (7/70) after a median time of 36 months. Primary immunosuppression, withdrawal of corticosteroids and human leukocyte antigen matches were not associated with the recurrence. Recurrent PBC appears to have little impact on graft function and survival, but this may become a greater problem with longer follow up.
It is noteworthy that the 10-year survival of primary sclerosing cholangitis (PSC) patients who underwent LDLT wasfound to be only 39.1% in Japan, whereas that of PBC was 72.9%. Factors associated with the poor prognosis include biliary strictures, hepatobiliary and colorectal malignancies, and recurrence of PSC. In our study, we reviewed 66 patients with PSC who underwent LDLT in Japan. The 5-year survival rate was 72%, and the rate of recurrence diagnosed on histological and cholangiographic findings was 25% (11/44). Well-defined diagnostic criteria and longer studies are required to characterize the nature of recurrent PSC and its impact on graft survival in more detail.     

Magnetic resonance evaluations of biliary malignancy and condition at high-risk for biliary malignancy:Current status

Tumors of the biliary tree are relatively rare; but their incidence is rising worldwide. There are several known risk factors for bile duct cancers, and these are seem to be associated with chronic inflammation of the biliary epithelium. Herein, 2 risk factors have been discussed, primary sclerosing cholangitis and reflux of pancreatic juice into the bile duct, as seen in such as an abnor- mal union of the pancreatic-biliary junction because magnetic resonance imaging(MRI) is used widely and effectively in the diagnosis of these diseases. When biliary disease is suspected, MRI can often help dif- ferentiate between benignity and malignancy, stage tumors, select surgical candidates and guide surgical planning. MRI has many advantages over other modali- ties. Therefore, MRI is a reliable noninvasive imaging tool for diagnosis and pre-surgical evaluation of bile duct tumors. Nowadays remarkable technical advances in magnetic resonance technology have expanded the clinical applications of MRI in case of biliary diseases. In this article, it is also discussed how recent develop- ments in MRI contributes to the diagnosis of the bile duct cancer and the evaluation of patients with risk fac- tors affecting bile duct cancer.     

36例原发性胆汁性肝硬化的临床特征分析

目的探讨原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)患者的临床特征,以提高对PBC的诊断与治疗水平。方法对具有完整资料的36例PBC的一般资料、从出现症状或肝功改变到确诊的时间、临床表现、血清化学指标、免疫学、影像学、病理学改变及治疗转归等进行回顾性分析。结果本组36例PBC患者中女性33例(91.7%)。从出现症状或肝功改变至确诊的平均时间为18.95个月,最长82个月。临床表现主要为乏力(80.6%)、皮肤瘙痒(69.4%);最主要的体征为黄疸(61.1%)和脾大(61.1%);AMA/AMA-M2阳性率达91.67%;r-谷胺酰转肽酶(GGT)、总胆红素(TBIL)、直接胆红素(DBIL)和血清白蛋白(ALB)在不同的临床分期中差异有统计学意义(P<0.05)。肝硬化前期组经熊去氧胆酸(UDCA)治疗前后肝功的对比差异有统计学意义(P<0.05),而肝硬化期组此项对比差异无统计学意义(P>0.05)。结论 PBC以中年女性多见,高滴度AMA及AMA-M2亚型是诊断PBC的主要指标。肝硬化期GGT、TBIL和DBIL的水平明显高于肝硬化前期,而ALB水平反而明显降低。该病病程较长,在早期主要表现为原发性胆汁性胆管炎,需较长时间才发展为原发性胆汁性肝硬化。以UDCA为主的综合治疗能够明显改善早期患者的症状和血清胆汁淤积指标。因此早期发现、早期治疗效果较好。     

Recurrence of cholestatic liver disease after living donor liver transplantation

End-stage liver disease, due to cholestatic liver diseases with an autoimmune background such as primary biliary cirrhosis （PBC） and primary sclerosing cholangitis （PSC）, is considered a good indication for liver transplantation. Excellent overall patient and graft outcomes, based mostly on the experience from deceased donor liver transplantation （DDLT）, have been reported. Due to the limited number of organ donations from deceased donors in most Asian countries, living donor liver transplantation （LDLT） is the mainstream treatment for end-stage liver disease, including that resulting from PBC and PSC. Although the initial experiences with LDLT for PBC and PSC seem satisfactory or comparable to that with DDLT, some aspects, including the timing of transplantation, the risk of recurrent disease, and its long-term clinical implications, require further evaluation. Whether or not the long-term outcomes of LDLT from a biologically related donor are equivalent to that of DDLT requiresfurther observations. The clinical course following LDLT may be affected by the genetic background shared between the recipient and the living related donor.     

抗线粒体抗体与原发性胆汁性胆管炎临床血清学和肝硬化指标的相关性

目的探究首次就诊的抗线粒体抗体(AMA)阳性原发性胆汁性胆管炎(PBC)患者的AMA水平及其与临床指标的相关性。方法通过北京大学人民医院信息系统,收集2013年1月至2016年12月首次检测AMA和(或)M2型抗线粒体抗体(AMA-M2)阳性的1323例患者的临床资料,其中采用间接免疫荧光法183例、免疫印迹法431例、ELISA法709例;分为未诊断PBC组(973例)和新诊断PBC组(350例,其中非肝硬化者268例,肝硬化者82例)。709例采用ELISA法的患者中,未诊断PBC组567例,新诊断PBC组142例(PBC非肝硬化组115例,PBC肝硬化组27例)。183例采用间接免疫荧光法的患者中,未诊断PBC组118例,新诊断PBC组65例;其中AMA滴度为低滴度(1∶40~1∶80)者69例(未诊断PBC组53例,新诊断PBC组16例)、中滴度(1∶160~1∶320)者95例(未诊断PBC组59例,新诊断PBC组36例)、高滴度(≥1∶640)者19例(未诊断PBC组6例,新诊断PBC组13例)。比较各组患者的AMA水平,分析其与PBC临床指标免疫球蛋白(Ig)G、IgM、血小板计数、ALT、AST、GGT、ALP、血清总蛋白、TBil、总胆固醇,以及肝硬化指标天冬氨酸转氨酶与血小板比率指数(APRI)、基于四因子的纤维化指数(Fib-4)的相关性。统计学方法采用Mann-Whitney U检验、Kruskal-Wallis检验和线性回归分析。结果采用ELISA法检测的709例患者的AMA-M2滴度中位值为53 RU/mL,新诊断PBC组的血清AMA和AMA-M2中位水平均高于未诊断PBC组(1∶320比1∶80和180 RU/mL比47 RU/mL),差异均有统计学意义(χ^2=14.111,Z=-7.531,P均<0.01)。未诊断PBC组的AMA-M2值与年龄、IgG、IgM、AST、GGT、ALP、血清总蛋白、总胆固醇水平均呈正相关,均有统计学意义(Rho值=0.114、0.108、0.337、0.089、0.197、0.086、0.121、0.073,P均<0.05);新诊断PBC组的AMA-M2值与年龄、IgM、血清总蛋白、总胆固醇水平均呈正相关,与血小板计数呈负相关,均有统计学意义(Rho值=0.218、0.483、0.230、0.161、-0.183,P均<0.05);PBC非肝硬化组的血清AMA和AMA-M2中位水平均有低于PBC肝硬化组的趋势(1∶160比1∶320和174 RU/mL比495 RU/mL),但差异均无统计学意义(P均>0.05);PBC肝硬化组者组患者的AMA-M2值与IgM水平呈正相关(r=0.38,P=0.039),但与APRI、Fib-4均无明确相关性(P均>0.05)。采用间接免疫荧光法检测的183例患者的AMA滴度中位值为1∶160;未诊断PBC组中AMA低滴度、中滴度和高滴度者的IgM中位水平逐渐升高(分别为1.2、1.7和1.8 g/L),新诊断PBC组中AMA低滴度、中滴度和高滴度者的IgM、GGT、ALP的水平均逐渐升高(中位水平分别为1.5、3.7和4.1 g/L,144、182和317 U/L,137、168和221 U/L),差异均有统计学意义(χ^2=6.260、7.081、8.030、15.226,P均<0.05)。总体中未诊断PBC组男性的血清AMA-M2中位水平低于女性(41 RU/mL比50 RU/mL),差异有统计学意义(Z=-2.945,P=0.003);新诊断PBC组男性的血清AMA-M2中位水平有低于女性的趋势(113 RU/mL比206 RU/mL),但差异无统计学意义(P=0.257)。结论血清AMA水平与诸多临床指标有一定的相关性,并可能与PBC患者的疾病严重程度相关。     

原发性胆汁性胆管炎患者血清甲状腺激素水平和抗甲状腺抗体阳性率变化*

目的 探讨原发性胆汁性胆管炎(PBC)患者血清甲状腺激素水平和抗甲状腺抗体阳性率变化。方法 2018年1月～2020年1月我院收治的PBC患者94例,其中肝硬化50例(Child-Pugh A级29例,B级15例,C级6例)和胆管炎44例,另选择同期于我院健康体检者60名,采用化学发光免疫法测定血清游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)和促甲状腺激素(TSH)水平及血清甲状腺过氧化物酶抗体(TPOAb)和甲状腺球蛋白抗体(TGAb)。结果 胆管炎患者血清FT3、FT4和TSH水平分别为(2.4±0.5)ng/L、(1.4±0.2)ng/L和(8.9±2.3)ng/L,血清TPOAb和TGAb阳性率分别为77.3%和81.8%,肝硬化患者血清FT3、FT4和TSH水平分别为(1.9±0.3)ng/L、(1.0±0.1)ng/L和(19.7±4.9)ng/L,血清和TPOAb和TGAb阳性率分别为70.0%和64.0%,而健康人血清FT3、FT4和TSH水平分别为(2.8±0.8)ng/L、(1.8±0.3)ng/L和(3.4±1.2)ng/L,血清TPOAb和TGAb阳性率均为0.0%,肝硬化和胆管炎患者血清FT3和FT4水平显著低于,血清TSH水平显著高于健康人(P＜0.05),而肝硬化患者血清FT3和FT4水平显著低于,血清TSH水平显著高于胆管炎患者(P＜0.05),肝硬化和胆管炎患者血清TPOAb和TGAb阳性率比较,无统计学差异(P＞0.05);在肝硬化患者中,Child-Pugh A级患者血清FT3和FT4水平显著高于,血清TSH水平显著低于Child-Pugh B级或C级患者(P＜0.05),而Child-Pugh B级患者血清FT3和FT4水平显著高于,血清TSH水平显著低于Child-Pugh C级患者(P＜0.05),不同肝功能分级的肝硬化患者血清TPOAb和TGAb阳性率比较,无统计学差异(P＞0.05)。结论 原发性胆汁性肝硬化和胆管炎患者血清FT3、FT4和TSH水平显著不同于健康人,血清TPOAb和TGAb阳性率较高,其临床意义值得进一步观察和研究。     

A case of coexisting primary biliary cirrhosis and primary sclerosing cholangitis: a new overlap of autoimmune liver diseases

Although the etiology of AIH, PBC, and PSC remains unknown, it is apparent that these autoimmune liver diseases share many common features and can coexist in the same patient. Our patient had features of PBC and later clearly developed a picture of PSC. This case suggests that PBC, PSC, AIH, and autoimmune cholangitis are part of a spectrum of chronic autoimmune liver disease that develop in response to some yet unidentified antigen.     

Autoimmune liver serology：Current diagnostic and clinical challenges

Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases（AiLD）,namely autoimmune hepatitis types 1 and 2（AIH-1 and 2）,primary biliary cirrhosis（PBC）,and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody（ANA） and smooth muscle antibody（SMA）.AIH-2 is specified by antibody to liver kidney microsomal antigen type-1（anti-LKM1） and anti-liver cytosol type 1（anti-LC1）.SMA,ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.PBC is specified by antimitochondrial antibodies（AMA） reacting with enzymes of the 2-oxo-acid dehydrogenase complexes（chiefly pyruvate dehydrogenase complex E2 subunit） and disease-specific ANA mainly react-ing with nuclear pore gp210 and nuclear body sp100.Sclerosing cholangitis presents as at least two variants,first the classical primary sclerosing cholangitis（PSC） mostly affecting adult men wherein the only（and non-specific） reactivity is an atypical perinuclear antineutro-phil cytoplasmic antibody（p-ANCA）,also termed perinuclear anti-neutrophil nuclear antibodies（p-ANNA） and second the childhood disease called autoimmune sclerosing cholangitis（ASC） with serological features resembling those of type 1 AIH.Liver diagnostic serology is a fast-expanding area of investigation as new purified and recombinant autoantigens,and automatedtechnologies such as ELISAs and bead assays,become available to complement（or even compete with） traditional immunofluorescence procedures.We survey for the first time global trends in quality assurance impacting as it does on（1） manufacturers/purveyors of kits and reagents,（2） diagnostic service laboratories that fulfill clinicians＇ requirements,and（3） the end-user,the physician providing patient care,who must properly interpret test results in the overall clinical context.     

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.     

Clinical analysis of liver transplantation in autoimmune liver diseases

Background: Autoimmune liver diseases(ALDs) consist of autoimmune hepatitis(AIH), primary biliary cirrhosis(PBC), primary sclerosing cholangitis(PSC), Ig G4-associated cholangitis and overlap syndromes.Patients with these diseases may gradually progress to end-stage liver diseases and need liver transplantation. The present study aimed to explore the prognosis of patients with ALDs after liver transplantation.Methods: The clinical data of 80 patients with ALD(24 cases of AIH, 35 of PBC, 15 of PSC and 6 of AIHPBC overlap syndromes) who underwent liver transplantation in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2004 to September 2016 were collected retrospectively. The causes of death were analyzed and the postoperative cumulative survival rate was estimated by the Kaplan–Meier method. Recurrence and other complications were also analyzed.Results: Of the 80 patients, 18 were males and 62 were females. The average age was 50.5 years and the average Model for End-stage Liver Disease(MELD) score was 14.1. After a median follow-up of 19.8 months, 8 patients died. The 1-, 3-and 5-year cumulative survival rates were all 89.0%. Three cases of recurrent ALDs were diagnosed(3.8%) but they were not totally consistent with primary diseases. Biliary tract complication occurred in 10 patients(12.5%). The new onset of tumor was observed in 1 patient(1.3%). De novo HBV/CMV/EBV infection was found in 3, 8 and 3 patients, respectively.Conclusion: Liver transplantation is an effective and safe treatment for end-stage ALD.