Clinical Characteristics Of Autoimmune Liver Diseases And The Serum Levels Of BAFF/APRIL In Patients With Primary Biliary Cirrhosis

Part I Clinical characteristcs of 55 patients with Autoimmune Liver DiseaseBackgroundAutoimmune liver disease (ALD) includes a spectrum of diseases such as autoimmue hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSD) and the overlap syndrome (OS). All of these dieseses have hepatitic or cholestatic damage which caused by excessive immune response to their own liver tissues. ALD was thought as a kind of rare disease previously. However, with in-depth research on these diseases and diagnostic technology advances, the incidence of these diseases increased year by year. And a part of previously unexplained hapatitis have been diagnosed with ALD now. Nonetheless, there is still a need of intensified research on these diseases. The detection of characteristic autoantibodies plays a major role in the diagnostic of ALD. However, the autoantibodies can express crosswise among different kinds of ALD and the titers of autoantibodies fluctuates during the different courses of diseases. Therefore, we can not decide whether one is a ALD patient or not only with a kind of autoantibody is negative, not to mention the distinguish of different kinds of ALD. In that case, misdiagnosis and escaped diagnosis is unavoidable. While in treatment, the clinical doctors often give hormone or UDCA treatmen without distinction, which will bring over economic burden to patients, even worse may delay the treatment of patients.ObjectiveTo improve the diagnosis and treatment about the different kinds of ALD, a retrospective study was carried out in 55 ALD patients admitted to Nanfang Hospital between 2004 and 2009.Methods66 patients diagnosed with ALD in Nanfang Hospital between 2004 and 2009 were enrolled in this study. Then they were re-assessed according to the diagnostic criteria and only 55 patients were confirmed the diagnosis of ALD, including 13 AIH patients,37 PBC patients,1 PSC patients and 4 AIH-PBC OS patients. The clinical data, biochemical parameters, autoantibodies and liver histopathological characteristics of the 55 ALD patients were collected and then retrospective analyzed.Results1. There were no significant differences among AIH, PBC, AIH-PBC OS on the profiles of age and gender(F=0.762, P=0.472;χ2=1.047, P=0.592).2. Generally, the ALT[217(103-304)U/L,74(48-112)U/L,388(150-811)U/L], AST[215(164-423)U/L,94(67-131)U/L,336(145-767)U/L, ALP[125(101-224)U/L, 354(219-612)U/L,647(168-863)U/L] and GGT[140(43-191)U/L,466(215-702)U/L, 526(125-1285)U/L] levels differed signifcanly among AIH, PBC, AIH-PBC OS (χ2=18.905, P<0.001;χ2=15.00, P<0.001;χ2=13.097, P=0.001). The interclass comparison found that the levels of ALT and AST in patients with AIH were significant higher than patients with PBC(Z=-3.617, P<0.001; Z=-3.318, P=0.001), while ALP and GGT levels were lower than PBC patients(Z=-3.639, P<0.001; Z=-3.859, P<0.001). The ALT and AST levels in AIH-PBC OS patients were higher than those in PBC patients (Z=-2.923, P=0.001; Z=-2.461, P=0.010).3. The autoantibodies ANA can be tested positively in 84.9% of AIH patients, while only 7.7% of AIH patients were positive for SMA. And all the autoantibodies were negative in one AIH patient. For the 37 PBC patients,64.9%,37.8% and 86.5% of them were positive for AMA, AMA-M2, and ANA, respectively. And there were 5 PBC patients were negative for both AMA and AMA-M2. All of the 4 AIH-PBC OS patients were ANA positive, and 3 of them were AMA positive, and 2 patients were AMA-M2 positive. The only one cases of PSC patient was negative for all the detected autoantibodies.4. AIH was generally charactrized by interface hepatitis and periportal infiltrate while PBC was characterized by destruction and proliferation of bile ducts. Both of the characteristics can appear in the AIH-PBC OS patients.Conclusion and Discussion1. With comparable demographic data (age and gender), the ALT, AST, ALP and GGT levels differed in AIH, PBC and AIH-PBC OS patients. The AIH patients were always with elevated ALT and AST levels, while the PBC patents were characterized by increased ALP and GGT levels. And both features appeared in AIH-PBC OS patients. However, with higer ALT and AST levels, the AIH-PBC OS patients sloped to AIH more.2. The detection of autoantibodies indicated that they were cross-expressed in AIH, PBC and AIH-PBC OS patients, and not all of the ALD patiens were positive for autoantibodies. Therefor, it's not reliable to diagnose ALD just with the detection of serum autoantibodies and that will lead to the misdiagnosis and escaped diagnosis. So a reasonable diagnosis should based on the comprehensive judgement including the manifestion, biochemical parameters, liver biopy and the autoantibodies, as well.3. The biochemical markers are consistent with the histological performance in patients with ALD. The pathohistological characteristic of AIH is interface inflammation and portal infiltration, which consistent with the high levels of ALT and AST. While PBC's histological change is mainly the damage of bile ducts, which is in according to the elevated levels of ALP and GGT. And both of these characteristics coexisted in AIH-PBC OS patients, though they sloped to AIH more. PartⅡElevated serum levels of BAFF and APRIL associated with the severity of Primary Biliary CirrhosisBackgroundThe pathogenesis of PBC remains completely unresolved, and the adaptive immune response was thought important previously. However, recent data suggest a significant role of innate immune response and co-stimulation mechanism in the pathogenesis of PBC. The disease is believed to be caused by a defect immunological tolerance, leading to autoreactive B cell activation and the production of autoantibodies. BAFF and APRIL are two members of TNF ligand superfamily. Studies on BAFF, APRIL and their receptors (TACI, BCMA and BAFF-R) have highlighted the importance of this system in regulating B-cell homeostasis, tolerance and malignacy. BAFF over-production can lead to autoimmunity. High levels of BAFF have been detected in patients with different kinds of autoimmune diseases, and BAFF levels corrlated with disease severity and the autoantibodies'titers.In 2007, a report from Japan suggested there was a higher serum level of BAFF in patients with AIH, and inhibited BAFF expression could significantly improve the biochemical and/or the histological changes. This indicated that BAFF/APRIL system may be associated with PBC, and BAFF/APRIL system inhibitor may be a potential therapeutic option for PBC patients.ObjectiveTry to find whether there is a correlation between BAFF/APRIL and PBC in the purpose of making a further study about the role of BAFF/APRIL system in the pathogenesis of PBC.MethodsInvestigate the serum levels of BAFF and APRIL among patients with PBC, CHB and HC, and the dynamic levels of BAFF in PBC patients during the different clinical course by ELISA, and then analyze the relationship between the serum levels of BAFF or APRIL and the biochemical indicators of PBC.Results1. Generally, the levels of ALT [52(44-60)U/L,73(25-118)U/L,19(15-27)U/L], AST[93(64-115)U/L,0(40-96)U/L,23(18-28)U/L], TB[45.5(14.2-131.9)μmol/L, 17.3(13.9-28.2)μmol/L,14.1(11.1-16.8)μmol/L], and DB[32.8(5.4-103.1)μmol/L, 5.9(4.3-16.4)μmol/L,4.2(3.5-6.7)μmol/L] differed in PBC, CHB patients, and HC(x2=27.53, P<0.001;χ2=35.069, P<0.001;χ2=10.731, P=0.005;χ2=11.019, P=0.004, respectively). And the multiple comparison found that the serum levels of ALT, AST, TB and DB in PBC patients were significantly higher than that in HC (Z=-5.102, P<0.001; Z=-5.358, P<0.001; Z=-2.976, P=0.002; Z=-3.017, P=0.002, respectively), but no significant differences achived between PBC and CHB patients(Z=-0.149, P=0.883; Z=-1.949, P=0.052; Z=-1.569, P=0.121; Z=-1.772, P=0.076, respectively).2. The levels of BAFF[763(595-1349)pg/ml,357(0-483)pg/ml,73(0-685)pg/ml, respectively] were significantly different in patients with PBC, CHB and HC (χ2=25.061, P<0.001). The interclass comparison showed tha the serum levels of BAFF in PBC patients were significantly higher than in patients with CHB(Z=-4.251, P<0.001) and HC controls(Z=-4.278, P<0.001).3. However, there was no significant difference among the three groups on the profile of APRIL levels(χ2=4.807, P=0.090).4. The level of BAFF in PBC patients increased gradually with disease progression, though there is no significant difference among the BAFF levels at different timepoints(χ2=9.426,P=0.093).5. There were significant correlations between serum BAFF levels and ALT (r=0.359, P=0.005), AST (r=0.550, P<0.001), TB (r=0.320, P=0.013) and DB (r=0.338, P=0.008). The APRIL level is positively correlated with AST(r=0.257, P=0.047) or DB(r=0.258, P=0.046). There was no other significant correlation between BAFF or APRIL levels and clinical parameters such as TP, ALB, GLB, and so on.Conclusion and Discussion1. With no significant difference of ALT, AST, TB and DB levels between PBC and CHB patients, the serum levels of BAFF elevated significantly in PBC patients, which indicates that BAFF plays different roles in various inflammatory disease. Though they both manifested chronic liver inflammation, the mechanisms are different between PBC and CHB. The liver injury of PBC is caused by the PDC-E2 autoantibodies against hepatocytes produced by self-reactive B cells, which leads to attack of liver cells by aotuimmune cells. However, the liver injury of CHB is caused by the clearing of HBV infected hepatocytes, which have nothing to do with autoimmunity. And the expression of BAFF was also upregulated in chronic hepatitis C patients, a disease accompanied with autoimmne response as reported, and this supports the role of BAFF in the pathogenesis of autoimmune disease.2. There was no significant difference in APRIL levels in PBC, CHB patients and HC, though with a decreasing trend. The possible reseason is that BAFF and APRIL play a different role in autoimmune disease. Because BAFF could combine to three recptors, BCMA, TACI and FAFF-R, while APRIL only combines to the former two recptors.3. Interestingly, with the treatment of UDCA, the serum BAFF remained high levels and even increased, though the biochemical markers of ALT, AST, TB, ALP and GGT levels decreased to nomal quikly. This hints that the treatment of UDCA can't stop the progression of the disease, and the efficacy of UDCA in PBC appeals for further studies. And this was in consistent with the big sample sized study of treating PBC with UDCA. So we have to seek new and effective drugs for PBC. Results from the clinical trial of BAFF inhibitor in the treatment of SLE indicate that BAFF and/or BAFF/APRIL system may be a potention target for PBC.4. The serum levels of BAFF are significantly elevated in patients with PBC, correlate to the levels of ALT, AST, TB and DB very well, which indicates that BAFF plays an important role in the pathogenesis of PBC and associates with the severity of disease.