Autoimmune diseases of the liver, autoimmune hepatitis and primary biliary cirrhosis: Unfinished business

Autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have attracted much attention since their discovery 50 years ago, but there remain items of unfinished business. These relate to disease susceptibility including genetic influences (HLA and non-HLA genes, genes associated with female predisposition, and others) and environmental influences (infections, chemicals, xenobiotics and medications). Also needed is better characterization of autoantigenic molecules, particularly the anti-F-actin specificity characteristic of AIH, shown here to have functional effects in vitro . Deeper analysis of T-lymphocyte function in AILD should reveal relative contributions of eachof the multiple subsets of T cells now being defined in studies on laboratory animals, CD4⁺, CD8⁺, Th1, Th2, Th17, memory subsets and regulatory subsets. Diagnostic immunology providers now offer high-performance assay formats that call for systematic clinical assessments to achieve standardization, calibration and optimal information.     

Clinicopathological study of primary biliary cirrhosis with interface hepatitis compared to autoimmune hepatitis

AIM:To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis(AIH)and primary biliary cirrhosis(PBC)with AIH features.METHODS:Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined.The activity of periportal and lobular inflammation was scored0(none or minimal activity)to 4(severe),and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3.The infiltration of mononuclear cells positive for CD20,CD38,CD3,CD4,and CD8 and positive for immunoglobulins(IgG,IgM,and IgA)at the periportal areas(interface hepatitis)and in the hepatic lobules(lobular hepatitis)were semiquantitatively scored in immunostained liver sections(score 0-6).Serum aspartate aminotransferase(AST),immunoglobulins,and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions.RESULTS:Lobular hepatitis,hepatitic rosette formation,and emperipolesis were more extensive and frequent in AIH than in PBC.CD3+,CD4+,and CD8+cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC.The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC,but to a lesser degree in AIH.CD20+cells were mainly found in the portal tracts and,occasionally,at the interface in both diseases.Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration,specifically CD38+cells in PBC.No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH.While most AIH cases were IgG-predominant at the interface,PBC cases were divided into IgM-predominant,IgM/IgGequal,and IgG-predominant types,with the latter sharing several features with AIH.CONCLUSION:These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical.     

Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis: a retrospective study of 115 cases of autoimmune liver disease

OBJECTIVE: The aim of this retrospective study was to compare clinical, biological, and histological features and treatment response in 115 patients with overlap syndrome (OS), autoimmune hepatitis (AIH) or primary biliary cirrhosis (PBC). METHODS: Consecutive patients with AIH, PBC or OS followed between 1984 and 2005 in five different centers were included. All data were re-evaluated using current diagnostic criteria of each disease. RESULTS: Fifteen patients had OS (13 females), 48 AIH (40 females) and 52 PBC (49 females). Patients with OS were significantly younger than patients with PBC (median age: 44 vs 59 years). Jaundice (20%) and pruritus (20%) were the main initial symptoms in OS. Patients with OS had serum transaminase and gammaglobulin levels significantly higher than patients with PBC; serum alkaline phosphatase, gamma-glutamyl-transpeptidase and IgM levels were significantly higher in OS than in patients with AIH. Histological analysis showed moderate or severe piecemeal necrosis in 86% and destructive cholangitis in 93% in OS group. Among 11 patients with OS treated with ursodeoxycholic acid (UDCA) or immunosuppressors alone, only 6 had a complete biochemical response. In contrast, all patients with OS receiving combined therapy, as first or second line, responded, 5 patients to the combination corticosteroids-azathioprine-UDCA and 2 to the combination cyclosporine-UDCA. CONCLUSION: OS is not rare and accounts for 13.9% of patients with autoimmune liver disease in our series. Combination of immunosuppressors and UDCA appears the most efficient treatment in these patients.     

自身免疫性肝炎和原发性胆汁性肝硬化患者自身免疫性甲状腺疾病流行率调查*

目的 调查自身免疫性肝病(AILD)患者自身免疫性甲状腺疾病(AITD)发病率情况。 方法 2018年6月～2020年12月我院诊治的自身免疫性肝炎(AIH)41例和原发性胆汁性肝硬化(PBC)患者45例,采用间接免疫荧光法或免疫印迹法检测血清抗核抗体(ANA)、抗线粒体抗体(AMA)或AMA-M2)、抗平滑肌抗体(ASMA)、抗双链DNA抗体(抗dsDNA)和抗着丝点抗体(ACA);采用ELISA法检测血清免疫球蛋白,包括IgG、IgM和γ-球蛋白。结果 在本组41例AIH患者中,合并HT患者12例,合并GD患者6例,在45例PBC患者中,合并HT患者8例,合并GD患者7例;AIH患者血清IgG水平为17.5(14.8,19.8)g/L,显著低于AIH合并HT组【21.6(17.5,29.0)g/L,P<0.05】或AIH合并GD组【22.4(20.2,26.4)g/L,P<0.05】,血清γ-球蛋白为22.2(19.3,25.6)%,显著低于合并HT组【26.5(22.2,32.2)%,P<0.05】或合并GD组【27.1(24.3,32.0)%,P<0.05】;PBC患者年龄为(55.2±1.1)岁,显著小于合并HT组【(62.4±1.6)岁,P<0.05】或合并GD组【(62.2±1.5)岁,P<0.05】,血清IgG水平为15.4(12.2,18.0)g/L,显著低于合并HT组【20.3(16.8,24.7)g/L,P<0.05】或合并GD组【21.3(16.8,25.6)g/L,P<0.05】,血清γ-球蛋白水平为21.2(17.8,25.6)%,显著低于合并HT组【26.7(21.7,30.4)%,P<0.05】或合并GD组【25.4(22.2,29.4)%,P<0.05】。结论 AILD合并AITD的发病率较高,合并AITD患者血清IgG和γ-球蛋白水平较高,其原因还有待于进一步研究。     

Features of hepatocellular carcinoma in cases with autoimmune hepatitis and primary biliary cirrhosis

AIM： To characterize the clinical features of hepatocellular carcinoma （HCC） associated with autoimmune liver disease, we critically evaluated the literature on HCC associated with autoimmune hepatitis （AIH） and primary biliary cirrhosis （PBC）. METHODS： A systematic review of the literature was conducted using the Japana Centra Revuo Medicina database which produced 38 cases of HCC with AIH （AIH-series） and 50 cases of HCC with PBC （PBC- series）. We compared the clinical features of these two sets of patients with the general Japanese HCC population. RESULTS： On average, HCC was more common in men than in women with AIH or PBC. While many patients underwent chemolipiodolization （CL） or transcatheter arterial embolization （TAE） （AIH-series： P = 0.048 （vs operation）, P = 0.018 （vs RFA, PEIT）; PBC-series： P = 0.027 （vs RFA, PEIT）, others refused therapeutic interventions [AIH-series： P = 0.038 （vs RFA, PEIT）; PBC-series： P = 0.003 （vs RFA, PEIT）].Liver failure was the primary cause of death among patients in this study, followed by tumor rupture. The survival interval between diagnosis and death was fairly short, averaging 14 ± 12 mo in AIH patients and 8.4 ± 14 mo in PBC patients. CONCLUSION： We demonstrated common clinical features among Japanese cases of HCC arising from AIH and PBC.     

Recurrence of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation

Liver transplantation (LT) is the standard therapeutic approach for the treatment of end-stage acute and chronic autoimmune liver disease as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Results of liver transplantation in these indications are good with a patient survival after LT at 5 years of 85%. However several series have reported a possible recurrence of primary autoimmune liver disease after liver transplantation. Concerning all these three autoimmune liver diseases, recurrence of the disease on the graft may have multiple clinical, biochemical, histological and radiological expression influenced by different factors as the diagnostic methods used, the degree of immunosuppression and the genetic background of the recipient. We would like with this overview to describe the different pattern of recurrence of these autoimmune liver disease, their potential influence on the liver graft and their therapeutic management.     

Polymyositis associated with autoimmune hepatitis,primary biliary cirrhosis,and autoimmune thrombocytopenic purpura

Abstract

We describe a 40-year-old woman with polymyositis (PM) who developed autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and autoimmune thrombocytopenic purpura (AITP) concurrently. About 4 years earlier, she suffered from muscle weakness probably due to PM. When she visited our hospital, she had polyarthritis, myalgia, symmetrical proximal limb-muscle weakness, elevated muscle enzymes, and myogenic abnormalities on electromyogram. Pathological findings obtained by muscle biopsy showed histological findings consistent with PM. Her serum liver enzymes were also elevated. The histology obtained by liver biopsy revealed the mixture findings of chronic active hepatitis and biliary cirrhosis. As antibodies to mitochondria M2 and liver/kidney microsome type 1 (LKM-1) were present, we concluded her liver disease was due to an overlap of AIH and PBC. Furthermore, purpura on the legs with thrombocytopenia appeared in parallel with liver dysfunction. She was diagnosed as having AITP by clinical and laboratory findings. Her serum showed a speckled pattern in immunofluorescence antinuclear antibody testing, but the antigen specificities were distinct from those of the known myositis-related autoantigens. This is a first case report of PM accompanied by AIH, PBC, and AITP. It was notable that there was an overlap of disease-associated immunological findings and immunogenetic backgrounds. This case provides a possible insight into the mechanisms and interplay of autoimmune diseases.     

Polymyositis associated with autoimmune hepatitis, primary biliary cirrhosis, and autoimmune thrombocytopenic purpura

We describe a 40-year-old woman with polymyositis (PM) who developed autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and autoimmune thrombocytopenic purpura (AITP) concurrently. About 4 years earlier, she suffered from muscle weakness probably due to PM. When she visited our hospital, she had polyarthritis, myalgia, symmetrical proximal limb-muscle weakness, elevated muscle enzymes, and myogenic abnormalities on electromyogram. Pathological findings obtained by muscle biopsy showed histological findings consistent with PM. Her serum liver enzymes were also elevated. The histology obtained by liver biopsy revealed the mixture findings of chronic active hepatitis and biliary cirrhosis. As antibodies to mitochondria M2 and liver/kidney microsome type 1 (LKM-1) were present, we concluded her liver disease was due to an overlap of AIH and PBC. Furthermore, purpura on the legs with thrombocytopenia appeared in parallel with liver dysfunction. She was diagnosed as having AITP by clinical and laboratory findings. Her serum showed a speckled pattern in immunofluorescence antinuclear antibody testing, but the antigen specificities were distinct from those of the known myositis-related autoantigens. This is a first case report of PM accompanied by AIH, PBC, and AITP. It was notable that there was an overlap of disease-associated immunological findings and immunogenetic backgrounds. This case provides a possible insight into the mechanisms and interplay of autoimmune diseases.     

增强MRI扫描在乙型肝炎肝硬化背景下对原发性肝癌的诊断价值分析*

目的 研究采用钆塞酸二钠(Gd-EOB-DTPA)增强磁共振成像(MRI)对乙型肝炎肝硬化背景下原发性肝癌(PLC)的诊断价值。方法 2018年12月～2020年12月我院收治的乙型肝炎肝硬化背景下肝脏局灶性病变患者147例,均行Gd-EOB-DTPA肝脏增强MRI扫描,观察病灶强化特点和各序列信号强度,包括T1加权像(T₁WI)、T2加权像(T₂WI)及动脉期、门脉期、肝胆特异期和磁共振弥散加权成像(DWI)病灶的信号强度。采用受试者工作特征(ROC)曲线下面积(AUC)分析上述信号特征对PLC的诊断效能。结果 在147例患者中,发现PLC者102例,病灶大小为0.9～2.9 cm,平均为(1.8±0.6)cm,肝脏异型性增生结节45例,病灶大小为0.8～2.5 cm,平均为(1.4±0.2)cm;增强MRI扫描显示,84例表现为动脉期病灶呈低或等强化,门静脉期或延迟期呈低强化,63例表现为动脉期明显强化,门静脉期或延迟期未廓清;PLC组病灶T₁WI低信号、T₂WI高信号、DWI高信号、动脉期高强化和肝胆期低信号表现占比分别为50.0%、79.4%、82.4%、52.9%和94.1%,显著高于非PLC组(20.0%、20.0%、26.7%、20.0%和20.0%,P＜0.05);ROC分析结果显示病灶T₁WI低信号(AUC=0.670,敏感度=0.451)、T₂WI高信号(AUC=0.817,敏感度=0.745)、DWI高信号(AUC=0.754,敏感度=0.863)、动脉期高强化(AUC=0.693,敏感度=0.520)和肝胆期低信号(AUC=0.891,敏感度=0.892)对PLC具有一定的诊断效能(P＜0.05)。结论 增强MRI扫描在乙型肝炎肝硬化背景下早期发现PLC具有重要的诊断价值,临床应不断总结其特点变化,提高早期诊断率。     

Development of autoimmune hepatitis following liver transplantation for primary biliary cirrhosis.

Two patients undergoing liver transplantation for classical end-stage primary biliary cirrhosis (PBC) are described, who went on to develop de novo autoimmune hepatitis (AIH) in the transplanted liver. The presentation, in both instances, was with malaise and lethargy. Markedly elevated serum transaminases were found, together with a raised serum IgG and/or globulin fraction and histological features on liver biopsy typical of AIH. Both cases had had changes in their immunosuppressive therapy before the onset of AIH episodes, and both rapidly responded to reinstitution of steroid therapy. The finding, in each case, of a coincidental multiple HLA class I allele match between the recipient and their liver donor suggests that HLA class I-restricted mechanisms may play an important role in the pathogenesis of AIH.     

Nodular regenerative hyperplasia of the liver,CREST syndrome and primary biliary cirrhosis: an overlap syndrome?

Nodular regenerative hyperplasia of the liver (NRHL) has been found in association with collagen vascular diseases, after drug therapy, with autoimmune disease, and with a variety of haematological disorders. The association of NRHL with the syndrome of Calcinosis cutis, Raynaud's phenomenon, oesophageal dysfunction, sclerodactyly and telangiectasia (CREST syndrome) has only been reported on two previous occasions. The liver disease usually associated with CREST syndrome is primary biliary cirrhosis (PBC) and recently nodular hyperplasia of the liver has been reported in patients with early stage PBC. We present a case of NRHL with CREST syndrome and serological and biochemical features of PBC, a newly recognised overlap syndrome.     

Nodular regenerative hyperplasia of the liver and primary biliary cirrhosis. A fortuitous association?

We report here in a case of primary biliary cirrhosis associated with nodular regenerative hyperplasia of the liver in a white woman revealed by digestive hemorrhage due to ruptured esophageal varices. The diagnosis of primary biliary cirrhosis was based on the following: elevated serum IgM, high titer of antimitochondrial antibody (anti M2), typical histopathological picture of stage I/II disease. The diagnosis of nodular regenerative hyperplasia was supported by the demonstration of disseminated small hepatic nodules without perinodular fibrosis. This association may be a supplementary argument in favor of a possible autoimmune origin of nodular regenerative hyperplasia of the liver.     

Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis

Primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome is a clinical entity characterized by the occurrence of both conditions at the same time in the same patient. In addition to PBC-AIH overlap syndrome, transitions from one autoimmune disease to another have been reported, but no systematic series have been published. We report a series of 12 patients with consecutive occurrence of PBC and AIH (i.e., PBC followed by AIH). Among 282 PBC patients, 39 were identified who fulfilled criteria for probable or definitive AIH. AIH developed in 12 patients (4.3%). The baseline characteristics of the patients were similar to those of patients with classical PBC. Time elapsed between the diagnosis of PBC and the diagnosis of AIH varied from 6 months to 13 years. Patients with multiple flares of hepatitis at the time of diagnosis of AIH had cirrhosis on liver biopsy. Ten patients were given prednisone +/- azathioprine; short-term as well as sustained remissions were obtained in 8 of these, while two had multiple relapses and eventually died 8 and 7 years after diagnosis of AIH. In conclusion, the development of superimposed AIH could not be predicted from baseline characteristics and initial response to UDCA therapy. If not detected early, superimposed AIH can result in rapid progression toward cirrhosis and liver failure in PBC patients.     

Recurrence of primary biliary cirrhosis and development of autoimmune hepatitis after liver transplant: A blind histologic study

Aim:  This long-term study aimed to evaluate recurrence and evolution of primary biliary cirrhosis (PBC) after orthotopic liver transplantation (OLT).
Methods:  We reviewed "blindly" allograft biopsy specimens of women who underwent transplantation for PBC ( n  = 84), and women who received a transplant for chronic hepatitis C virus infection (CHCV ) ( n  = 108). All needle liver biopsy specimens obtained more than 6 months post-OLT were examined, including 83 specimens from 44 PBC patients and 152 specimens from 58 CHCV patients.
Results:  Granulomatous destructive cholangitis was found in five biopsies from four PBC patients ( P  = 0.0048). Non-necrotizing epithelioid cell granulomas were present in four biopsies from four PBC patients, and in two biopsies from one CHCV patient. Piecemeal necrosis ( P  = 0.0002), lobular necroinflammatory activity ( P  < 0.0001), steatosis ( P  < 0.0001) and fibrosis ( P  < 0.0001) were more prevalent in CHCV patients than PBC patients. Four PBC patients developed histologic evidence of autoimmune hepatitis (AIH), at a mean time of 3.66 years post-OLT. One of these patients had histologic features of AIH/PBC overlap syndrome. All four patients developed bridging fibrosis ( n  = 2) or cirrhosis ( n  = 2). No other PBC patient had evidence of cirrhosis after OLT.
Conclusions:  Histologic findings indicative of recurrent PBC were present in 15.9% of the PBC patients undergoing biopsy in this series. However, this group of patients did not suffer significant bile duct loss or fibrosis, as compared to the control group, suggesting that recurrent PBC is a mild or slowly progressive disease. Histologic evidence of AIH was observed in allograft biopsies of some PBC patients.     

Overlap of autoimmune hepatitis and primary biliary cirrhosis: long-term outcomes

BACKGROUND: The coexistence of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) has been called "overlap syndrome," but diagnosis is challenging and the natural history of this syndrome has not been demonstrated. The importance of the diagnosis of PBC-AIH overlap is due to potential therapeutic options. Patients with PBC should receive ursodeoxycholic acid (UDCA); the role of and response to additional immunosuppressive therapy are unknown when AIH overlaps PBC. METHODS AND RESULTS: We reviewed 135 patients with PBC according to a revised scoring system proposed by the International Autoimmune Hepatitis Group (IAHG). Twenty-six patients had features of PBC-AIH overlap and 109 did not. Mean follow-up was 6.1 yr for overlap syndrome patients and 5.4 yr in PBC patients. There was a higher rate of portal hypertension (P=0.01), esophageal varices (P<0.01), gastrointestinal (GI) bleeding (P=0.02), ascites (P<0.01), and death and/or orthotopic liver transplantation (OLT) (P<0.05) in the overlap group. CONCLUSION: In conclusion, esophageal varices, GI bleeding, ascites, and death and/or OLT were more common in the overlap group. The higher risk of symptomatic portal hypertension and worse outcomes in patients with PBC overlap syndrome may justify the risks of immunosuppressive therapy. Large randomized studies are necessary to establish optimal therapeutic strategies.     

Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis with unusual initial presentation as fulminant hepatic failure

Autoimmune hepatitis and primary biliary cirrhosis are generally easy to discriminate on the basis of clinical, laboratory, and histological findings. The presence of anti-mitocondrial antibodies seropositivity and cholestatic clinical, laboratory, and/or histological features in patients with autoimmune hepatitis indicates the overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis. Fulminant hepatic failure is an unusual initial form of presentation of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome. We report the case of a 50-year-old woman with autoimmune hepatitis and primary biliary cirrhosis overlap syndrome who presented with fulminant hepatic failure. Fulminant hepatic failure has a high mortality rate and may require liver transplant. Our patient revealed a good response to corticosteroid and ursodeoxycholic acid therapy. It is important to identify and distinguish autoimmune hepatitis and variant syndromes from other forms of liver disease because of response to corticosteroid therapy.