Overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis triggered by fluvastatin

Although statins are generally well-tolerated drugs, recent cases of autoimmune hepatitis (AIH) associated with their use have been reported. A 59-year-old Japanese man reported with liver damage, which appeared one month after beginning treatment with fluvastatin and continued after discontinuation of the drug. Although drug-induced liver injury was possible, positive autoantibody tests (antinuclear antibodies >1/1280, anti-mitochondrial M2 antibodies 21 index value) also suggested autoimmune liver disease. Liver biopsy findings were consistent with an overlap of autoimmune hepatitis and primary biliary cirrhosis. Treatment with prednisone and ursodeoxycholic acid led to a good response. In this patient, manifestation of AIH and primary biliary cirrhosis overlap syndrome was possibly triggered by statin use. Autoimmune liver disease should be considered as a possible diagnosis in patients with evidence of prolonged liver damage after discontinuation of statins.     

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 between autoimmune hepatitis and primary biliary cirrhosis complicated by hepatocellular carcinoma

The risk of hepatocellular carcinoma superimposed in the evolution of autoimmune hepatitis or primary biliary cirrhosis is low, even in patients with long-standing cirrhosis. We report a case of hepatocellular carcinoma occurring in a 46 year old woman with liver cirrhosis following overlap syndrome between autoimmune hepatitis and primary biliary cirrhosis, routinely followed while on the waiting list for liver transplantation. The patient had combined biochemical (elevated aminotransferases, alkaline phosphatase and gamma-glutamyl-transpeptidase in the range of 2-3 times above the upper limit of the normal) and serological (anti-smooth muscle antibody > 1/80 and anti-mitochondrial antibody anti-M2 > 1/40) criteria of autoimmune hepatitis and primary biliary cirrhosis. Hepatocellular carcinoma was diagnosed in the setting of chronic liver disease by the combination of two concordant imaging technics (Doppler ultrasound and magnetic resonance imaging) showing a hepatic nodule with arterial hypervascularization and elevated serum levels of alpha-fetoprotein up to 950 ng/ml. Liver transplantation is the best treatment both for the solitary nodule less than 5 cm and underlying autoimmune cirrhosis. Using the new Model for End-Stage Liver Disease allocation system our patient was placed in a prior position for liver transplantation (MELD 29). Unfortunately, a sudden fulminant liver failure complicated with intravascular disseminated coagulopathy was fatal for our patient while awaiting liver transplantation.     

PBC-AIH重叠综合征临床与病理特征:一项回顾性研究

目的 通过回顾性分析研究比较原发性胆汁性肝硬化(PBC)-自身免疫性肝炎(AIH)重叠综合征与单纯的PBC患者的临床、生化和免疫学指标以及组织学特征.方法 经我院诊断的PBC患者按目前的PBC诊断标准再评估,共计48例入选.同时用修订的国际自身免疫性肝炎协作组(International Autoimmune Hepatitis Group,IAIH-G)积分系统进行评估积分,对于AMA阳性且治疗前积分至少达到10分者,定义为PBC-AIH重叠综合征.对两组病人的临床表现、生化和免疫学指标以及组织学特征进行分析.结果 17例患者(女性占16例)为PBC-AIH重叠综合征,31例(女性占30例)不具有重叠AIH的特点为单纯PBC.PBC-AIH重叠综合征最常见的临床表现为乏力或疲劳(58.8%)、纳差(23.5%)及黄疸(23.5%).与PBC患者相比,重叠综合征患者在确诊时的平均年龄、免疫球蛋白IgM、血清ALP和GGT水平无统计学差异;而血清转氨酶水平(ALT和AST分别为:165.0±25.9 vs 87.1±8.7、177.5±32.3 vs 86.3±10.9,P均<0.01)、球蛋白和IgG水平显著升高.组织学分析提示,所有的重叠综合征患者存在中-重度界面性肝炎或碎屑样坏死,82.4%的患者存在肝细胞玫瑰花环样改变,64.7%的患者同时存在胆管病变.结论 PBC-AIH重叠综合征患者血清转氨酶水平和IgG水平明显高于单纯PBC患者,组织学主要特征为中.重度界面性肝炎、肝细胞玫瑰花环样改变以及同时伴有胆管病变.     

Overlap of autoimmune hepatitis and primary biliary cirrhosis: an evaluation of a modified scoring system

OBJECTIVE: The coexistence of autoimmune hepatitis (AIH) with primary biliary cirrhosis (PBC) as an overlap syndrome has been previously described. The ability to detect AIH overlap with a revised version of the International Autoimmune Hepatitis Group (IAHG) scoring system, however, remains unknown. Our specific aim was to evaluate the revised IAHG scoring system and its ability to identify AIH overlap in PBC. MErHODS: One hundred forty-one PBC patients with first-time visits to the Mayo Clinic from January 1, 1990 to December 31, 1992 were evaluated. The calculation of individual revised IAHG scores was performed and compared to original IAHG scores. RESULTS: Among 137 PBC patients with available liver histologies, use of the original IAHG scoring system detected "definite" and "probable" AIH overlap among 2.2% and 62% of cases, respectively. Application of the revised IAHG scoring system, however, revealed no individuals (0%) with definite AIH overlap (>15 points). Twenty-six subjects (19%) fulfilled IAHG criteria for probable AIH overlap (10-15 points). The presence of antinuclear antibody and/or smooth muscle antibody positivity (p = 0.05), other autoimmune disorders (p < 0.01), and total histological score (p < 0.001) were significantly greater in the PBC plus probable AIH group than in subjects with PBC alone. CONCLUSION: A reduction in the prevalence of definite 2.2% vs 0%) and probable (62% vs. 19%) AIH overlap among PBC subjects was observed with use of the revised IAHG coring system relative to the original criteria. Applicability of the revised IAHG scoring system, however, remains questionable, as nearly 20% of PBC patients will be classified with probable AIH overlap.     

Evolution from primary biliary cirrhosis to primary biliary cirrhosis/autoimmune hepatitis overlap syndrome

An asymptomatic 70-year-old Hispanic woman with type 2 diabetes was found in 2004 to have an AST of 132 U/L, ALT 146 U/L, alkaline phosphatase 1107 U/L, total serum bilirubin 3.5 mg/dL, and albumin 2.9 g/dL. Viral hepatitis testing was negative. Serum IgG, IgA, and IgM were all elevated, antimitochondrial antibody was weakly positive, and antinuclear antibody was negative. Liver biopsy was reported to show "evolving cirrhosis with marked lymphoid hyperplasia." Although the indication was nowhere stated, she was prescribed ursodeoxycholic acid 500 mg b.i.d, on which her biochemical tests initially improved. One year later she developed itching and jaundice. Imaging studies revealed multiple gallstones. An MRCP was suggestive of cirrhosis with a questionable common bile duct stricture, and she underwent ERCP with removal of gallbladder and common bile duct stones and placement of a biliary stent. A periampullary mass, which proved to be a somatostatinoma, was excised in 2006 via an open laparotomy, at which the stent was removed and a second liver biopsy performed. It was reported as showing chronic active hepatitis, activity stage 2, and fibrosis grade 3 with bridging. Her subsequent course was complicated by recurrent bleeding from small bowel arteriovenous malformations. Seen for the first time at Columbia University Medical Center in January 2007, she complained of continuing pruritus. AST was 69 U/L, ALT 43 U/L, alkaline phosphatase 491 U/L, and total bilirubin 3.3 mg/dL. Serum albumin was 2.6 g/dL. Antinuclear antibodies, negative in 2004, were now positive at 1:320, and antimitochondrial M2 antibodies were strongly positive. Serum IgG and IgA, but NOT IgM, were elevated. Review of her outside liver biopsies revealed features of primary biliary cirrhosis (PBC) in the first, and of both PBC and autoimmune hepatitis (AIH) in the second. The patient exhibits an overlap syndrome, in which both histologic and serologic features of AIH evolved in a setting initially most suggestive of PBC alone. The phenomenon of autoimmune overlap syndromes is discussed.     

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.     

Living-donor liver transplantation for autoimmune hepatitis and autoimmune hepatitis-primary biliary cirrhosis overlap syndrome

Aim: Recurrent autoimmune hepatitis (AIH) following liver transplantation has been reported in 20–30% of cases, mainly of Western populations. The aim of this study was to review our experience of living‐donor liver transplantation (LDLT) in Japanese patients with AIH. Methods: Among 375 adult (age ≥18 years) LDLT performed at our center between 1996 and 2010, 16 (4.2%) were for patients with AIH (n = 12) or AIH–primary biliary cirrhosis overlap syndrome (n = 4). The patient and donor characteristics and post‐transplantation course were reviewed. Results: All recipients were female with a median age of 48 years (range, 21–58). Low‐dose methylprednisolone and calcineurin inhibitors were continued in all patients. Acute cellular rejection occurred in 10 (63%), which was more frequent than in our overall series of 28.5% (107/375 cases). Overall survival rate was 81.2% at 5 years. At the end of the follow up (median, 6.0 years [range, 0.1–9.6]), 13 patients were alive with normal liver function tests (aspartate transaminase, 18 ± 5 IU/mL; alanine transaminase, 16 ± 8 IU/mL). None of the survivors exhibited liver function test results suspicious for recurrent AIH, which might indicate liver biopsy. Conclusion: Survival after LDLT for AIH and overlap syndrome was excellent and there was no evidence of clinical recurrence. The recurrence rate of AIH after liver transplantation may differ among countries, and requires further investigation.     

Overlap of primary biliary cirrhosis and autoimmune hepatitis: Characteristics,therapy, and long term outcomes

Background: Coexistence of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) is referred to as PBC‐AIH overlap. Pathogenesis of PBC‐AIH is not well understood and its diagnosis is challenging. We previously reported the clinical characteristics of 10 patients diagnosed with PBC‐AIH overlap. Aims: The aim of the study was extend the earlier series and evaluate the diagnostic criteria, biological characteristics, potential therapy, and long‐term outcomes of patients with PBC‐AIH overlap. Methods and Results: We retrospectively analyzed clinical, biochemical, and histological characteristics of 144 patients diagnosed with PBC and 73 diagnosed with AIH. We identified 16 cases of PBC‐AIH overlap, according to criteria established by Chazouillères et al. and other studies. PBC preceded AIH in 6 patients and both diseases occurred simultaneously in the remaining 10 patients. PBC‐AIH overlap has clinical, biochemical, and histological characteristics of both PBC and AIH. Thirteen patients treated with both ursodeoxycholic acid (UDCA) and immunosuppressive therapy responded well, with normal alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels. The remaining three patients treated with either prednisolone (PSL) or UDCA alone developed cirrhosis, varices, ascites, encephalopathy, or died of liver‐related causes at the 5, 12, and 14‐year follow up. Conclusions: PBC‐AIH overlap is not a rare entity; it was observed in 11% of PBC patients in this study. Further studies will be required to investigate whether PBC‐AIH overlap is distinct from the two individual diseases in terms of long‐term outcomes and therapeutic implications.     

Overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis in two cases

The overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis is a rare condition and only few cases have been published, partly associated with ulcerative colitis, but not with Crohn's disease. We report an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome in a female patient with Crohn's disease. In addition, a second case of overlap syndrome is reported in a man without inflammatory bowel disease. A 24-year-old woman was referred with a 10-month history of diarrhoea and biochemical changes including elevated serum levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and immunoglobulin G. Enzyme linked immunosorbent assay showed that antinuclear autoantibodies were elevated. Immunofluorescence for perinuclear-staining antineutrophil cytoplasmatic antibodies was positive. Diagnostic criteria of definite autoimmune hepatitis according to the International Autoimmune Hepatitis Group were fulfilled. Liver biopsy simultaneously showed criteria of autoimmune hepatitis and primary sclerosing cholangitis. Endoscopic retrograde cholangiography demonstrated features of primary sclerosing cholangitis. Colonoscopy and colonoscopic biopsies indicated an active Crohn's disease affecting the terminal ileum and the ascending and transverse colon. Furthermore, we report the case of a 28-year-old man with known primary sclerosing cholangitis for the previous 6 years, and who developed jaundice and a marked increase of aspartate aminotransferase, alanine aminotransferase and immunoglobulin G, leading to the diagnosis of definite autoimmune hepatitis. A review of the literature revealed only 16 cases of an autoimmune hepatitis/primary sclerosing cholangitis syndrome in patients without inflammatory bowel disease or in association with ulcerative colitis. We report two additional cases, one case showing an association with Crohn's disease.     

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.     

Overlap syndrome of primary sclerosing cholangitis and autoimmune hepatitis

We report a 46-year-old patient with the typical biochemical, histological and cholangiographic findings of primary sclerosing cholangitis (PSC) whose clinical and laboratory findings would also qualify her for the diagnosis of definite autoimmune hepatitis (AIH), according to the aggregate score of the International Autoimmune Hepatitis Group. We suggest that this patient may represent an example of the overlapping syndrome of PSC and AIH.     

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.     

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.     

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.     

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.     

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.