Antibody-negative Primary Biliary Cirrhosis Research Articles

Long-term outcomes in antimitochondrial antibody negative primary biliary cirrhosis

abstractObjectives Antimitochondrial antibodies (AMA) are a sensitive and specific marker for primary biliary cirrhosis (PBC). AMAs are present in 95% of patients with PBC. However, 5% do not have AMAs and data on these patients is scarce. We aim to evaluate the long-term outcomes of patients with AMA negative PBC. Methods A retrospective chart review of 71 AMA negative PBC patients. Disease presentation, laboratory results, and clinical endpoints were recorded. AMA negative patients were matched on year of diagnosis to a control group of 71 AMA positive patients. Results Ninety-six percent of the AMA negative patients were of female gender with a median age at diagnosis of 55 years and a length of follow-up of 7.5 years vs. 86% females, a median age of 56 and a follow-up of 8.3 years in the control group. Mean total bilirubin and alkaline phosphatase levels were 0.7 mg/dL vs. 0.6 and 570 U/L vs 341, in AMA negative vs. AMA positive patients at presentation, respectively (p = NS). AMA negative patients did not differ in terms of age, serum IgM levels, ANA status, or length of follow-up. Notably, AMA negative patients had a significantly reduced survival free of liver-related complications including transplantation and death compared to AMA positive patients (p = 0.0182). Conclusion In this large experience, AMA negative PBC patients had a significantly worse prognosis compared to AMA positive PBC patients. The reason for the difference in prognosis is unclear, as it may be true difference or reflect delays in case detection among AMA negative patients.

Primary sclerosing cholangitis associated with CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly and telangiectasia) in an elderly woman: a case report

IntroductionCREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia) syndrome comprising calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia and primary sclerosing cholangitis are both chronic fibrotic diseases but the association between them is extremely rare. While primary sclerosing cholangitis has been associated with diffuse cutaneous scleroderma, the association with limited cutaneous scleroderma or CREST has not been previously reported in the literature. This case report illustrates the association between CREST and primary sclerosing cholangitis.Case presentationWe report the case of an 84-year-old Asian woman with a long history of CREST who was admitted with abdominal pain, fatigue and progressive derangement of her liver enzymes. This was initially thought to be secondary to her bosentan therapy for pulmonary hypertension but it persisted despite bosentan being ceased. Primary sclerosing cholangitis was subsequently diagnosed on magnetic resonance cholangiopancreatography and she was referred to a hepatologist for treatment.ConclusionsThis case highlights the need to consider primary sclerosing cholangitis in patients with CREST who present with abdominal symptoms and deranged liver enzymes when other causes have been excluded. Relevant differential diagnoses for this presentation, which can be difficult to exclude, include immunoglobulin G4-associated cholangitis and antimitochondrial antibody negative primary biliary cirrhosis. It is of particular significance to rheumatologists and gastroenterologists but has broader relevance to all medical specialists involved in the care of patients with CREST.

924 Long-Term Outcomes in Antimitochondrial Antibody Negative Primary Biliary Cirrhosis

were hazard ratios (HRs) for later hepatobiliary disease in women with ICP at ,1 year, 15 years, .5 years after delivery and odds ratios (ORs) for developing ICP in preexisting hepatobiliary disease. Risk estimates were calculated through Cox regression and logistic regression analysis. Results:Womenwith ICP were more often diagnosed with later hepatobiliary disease (HR 2.62; 95% CI 2.47-2.77; increment at 1% per year), hepatitis C or chronic hepatitis (HR 4.16; 3.14-5.51 and 5.96; 3.43-10.33, respectively), fibrosis/cirrhosis (HR 5.11; 3.29 -7.96), gallstone disease or cholangitis (HR 2.72; 2.55-2.91, and 4.22; 3.13-5.69, respectively) as compared to women without ICP (p,0.0001 for all HRs). Later ICP was more common in women with prepregnancy hepatitis C (OR 5.76; 1.30-25.44; p=0.021), chronic hepatitis (OR 8.66; 1.05-71.48; p=0.045), and gallstone disease, (OR 3.29; 2.025.36; p,0.0001). Conclusions: Women with ICP have substantially increased risk for later hepatobiliary disease. We found beyond gallstone-related morbidity a strong positive association between ICP and hepatitis C both before and after ICP diagnosis. Thus, we advocate testing for hepatitis C in women with ICP, in particular, since this potentially life-threatening infection can be treated successfully in the majority of patients.

Evaluation of Langerhans Cell Infiltrate by CD1a Immunostain in Liver Biopsy for the Diagnosis of Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is characterized by chronic nonsuppurative destructive cholangitis, which is considered to be a cell-mediated immune reaction. Antigen-presenting cells, including Langerhans cells and dendritic cells, have been found in portal tracts and in bile duct epithelium and may play a role in the pathogenesis of PBC, but the importance of identifying these cells for diagnosing PBC has not been studied yet. In this study, we sought to evaluate the importance of identifying Langerhans cells using a CD1a immunostain in the diagnosis of PBC. Liver biopsies from adult patients diagnosed with PBC (n=60), primary sclerosing cholangitis (n=29), obstructive cholangitis (n=13), chronic viral hepatitis B or C (n=19), autoimmune hepatitis (AIH, n=15), acute cellular rejection (n=11), and chronic rejection (n=10) at our institution were retrospectively reviewed. An immunohistochemical stain for CD1a was used to detect Langerhans cells, and the distribution of CD1a-positive Langerhans cell infiltrate was recorded as lobular, portal with bile duct sparing, and intraepithelial. Intraepithelial Langerhans cells were identified in 58% of PBC including antimitochondrial antibody-negative PBC and PBC-AIH overlap cases, 14% of primary sclerosing cholangitis, 15% of obstructive cholangitis, 9% of acute cellular rejection, 6% of AIH, and no cases of chronic viral hepatitis or chronic rejection. The number of intraepithelial Langerhans cells was significantly higher in PBC than in other conditions, with the mean number of CD1a-positive intraepithelial Langerhans cells per bile duct in PBC calculated as 2.2 compared with <1 per duct for the other control cases. Thirty-three of 60 (55%) PBC cases showed at least one bile duct containing ≥2 CD1a-positive Langerhans cells. This was statistically significant (P<0.01) when compared with control groups. The overall sensitivity and specificity of using ≥2 CD1a-positive Langerhans cells per bile duct as the diagnostic criteria for PBC were 55% and 96%. Given the heterogenous nature of liver involvement by PBC, a review of cases with morphologic features of duct damage yielded an increased sensitivity (79%) with no reduction in specificity. In conclusion, the detection of a Langerhans cell infiltrate of ≥2 cells by CD1a in a given bile duct on needle biopsy may be a valuable tool in the diagnosis of PBC.

Overcoming a “Probable” Diagnosis in Antimitochondrial Antibody Negative Primary Biliary Cirrhosis: Study of 100 Sera and Review of the Literature

Serum anti-mitochondrial antibodies (AMA) are the serological hallmark of primary biliary cirrhosis (PBC), yet up to 15% of PBC sera are AMA negative at routine indirect immunofluorescence (IIF) while being referred to as "probable" cases. The diagnostic role of PBC-specific antinuclear antibodies (ANA) remains to be determined. We will report herein data on the accuracy of new laboratory tools for AMA and PBC-specific ANA in a large series of PBC sera that were AMA-negative at IIF. We will also provide a discussion of the history and current status of AMA detection methods. We included IIF AMA-negative PBC sera (n=100) and sera from patients with other chronic liver diseases (n=104) that had been independently tested for IIF AMA and ANA; sera were blindly tested with an ELISA PBC screening test including two ANA (gp210, sp100) and a triple (pMIT3) AMA recombinant antigens. Among IIF AMA-negative sera, 43/100 (43%) manifested reactivity using the PBC screening test. The same test was positive for 6/104 (5.8%) control sera. IIF AMA-negative/PBC screen-positive sera reacted against pMIT3 (11/43), gp210 (8/43), Sp100 (17/43), both pMIT3 and gp210 (1/43), or both pMIT3 and Sp100 (6/43). Concordance rates between the ANA pattern on HEp-2 cells and specific Sp100 and gp210 ELISA results in AMA-negative subjects were 92% for nuclear dots and Sp100 and 99% for nuclear rim and gp210. Our data confirm the hypothesis that a substantial part of IIF AMA-negative (formerly coined "probable") PBC cases manifest disease-specific autoantibodies when tested using newly available tools and thus overcome the previously suggested diagnostic classification. As suggested by the recent literature, we are convinced that the proportion of AMA-negative PBC cases will be significantly minimized by the use of new laboratory methods and recombinant antigens.

Autoimmune liver disease: overlap and outliers

The three main categories of autoimmune liver disease are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC); all are well-defined entities with diagnosis based upon a constellation of clinical, serologic, and liver pathology findings. Although these diseases are considered autoimmune in nature, the etiology and possible environmental triggers of each remain obscure. The characteristic morphologic patterns of injury are a chronic hepatitis pattern of injury with prominent plasma cells in AIH, destruction of small intrahepatic bile ducts and canals of Hering in PBC, and periductal fibrosis and inflammation involving larger bile ducts with variable small duct damage in PSC. Serological findings include the presence of antimitochondrial antibodies in PBC, antinuclear, anti-smooth muscle, and anti-LKM antibodies in AIH, and pANCA in PSC. Although most cases of autoimmune liver disease fit readily into one of these three categories, overlap syndromes (primarily of AIH with PBC or PSC) may comprise up to 10% of cases, and variant syndromes such as antimitochondrial antibody-negative PBC also occur. Sequential syndromes with transition from one form of autoimmune liver disease to another are rare.

Antimitochondrial Antibody Negative Primary Biliary Cirrhosis in Japan: Utilization of Clinical Data When Patients Applied to Receive Public Financial Aid

BACKGROUNDWe examined patients who showed laboratory and histological evidence of primary biliary cirrhosis (PBC) in the absence of antimitochondrial antibody (AMA) to elucidate the characteristics of AMA negative PBC.METHODSFrom a total of 5,805 patients with symptomatic PBC, 2,419 cases (41.7%) were selected in the present study, who were diagnosed using the following criterion; chronic non-suppurative destructive cholangitis was histologically observed and laboratory data did not contradict PBC. The information collected from records included sex, age, symptoms, physical findings, and complicated autoimmune diseases. We then evaluated these data according to the positivity of AMA.RESULTSOf the total subjects, 470 cases (19.4%) were found to be negative for AMA. The proportion of female patients was higher among the AMA negative group than among the AMA positive one. Pruritus was found less frequently among patients with AMA negative PBC than among those with AMA positive PBC. Levels of alkaline phosphatase, γ-glutamyl transpeptidase, and IgM were significantly lower among patients with AMA negative PBC than among those with AMA positive PBC. Complications such as Sjögren’s syndrome, rheumatoid arthritis, and scleroderma, including CREST syndrome, were found with significantly higher frequency among patients with AMA negative PBC than among those with AMA positive PBC.CONCLUSIONConsidering serum level of IgM and frequencies of complicated autoimmune diseases, it is possible that Japanese patients with AMA negative PBC are consistent with the disease entity of autoimmune cholangitis reported in western countries.

Overlap Syndromes

In hepatology, the term overlap syndrome describes variant forms of the major hepatobiliary autoimmune diseases, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Patients with overlap syndromes present with both hepatitic and cholestatic biochemical and histological features of AIH, PBC, and/or PSC, and usually show a progressive course toward liver cirrhosis and liver failure without adequate treatment. AIH-PBC overlap syndromes have been reported in almost 10% of adults with AIH or PBC, whereas AIH-PSC overlap syndromes were found in 6 to 8% of children, adolescents, and young adults with AIH or PSC. A minority of patients may also show transition from stable PBC to AIH, AIH to PBC, or AIH to PSC, as documented by single case reports and small case series. Single cases of AIH and autoimmune cholangitis (antimitochondrial antibody-negative PBC) overlap have also been reported. Empiric medical treatment of AIH-PBC and AIH-PSC overlap syndromes includes anticholestatic therapy with ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine. In end-stage disease, liver transplantation is the treatment of choice.

Antibody to carbonic anhydrase II is present in primary biliary cirrhosis (PBC) irrespective of antimitochondrial antibody status.

Antibody to carbonic anhydrase II, an enzyme abundantly present in biliary epithelium, has been proposed as a diagnostic marker for antimitochondrial antibody-negative PBC. In this study we determine its prevalence and clinical significance in a large series of patients with antimitochondrial antibody-positive and -negative PBC. Reactivity to carbonic anhydrase II was sought by Western immunoblotting in sera from 215 consecutive patients with PBC (26 antimitochondrial antibody-negative), 13 with autoimmune hepatitis, 25 with primary Sjögren's syndrome (pSS), 12 with systemic sclerosis, 19 with systemic lupus erythematosus and 73 healthy subjects. The prevalence of antibody to carbonic anhydrase II (titre 1:100) in PBC was 8%. No specific reactivity to carbonic anhydrase II was found in antimitochondrial antibody-negative PBC (7% versus 8% in antimitochondrial antibody-positive PBC). Ascites (P = 0.006) and Sjögren's syndrome (SS) (P = 0.022) in PBC were significantly associated with presence of the antibody. In patients with SS associated with PBC, the prevalence (19%) was similar to that observed in pSS (16%). At a serum dilution of 1:40, the prevalence of positive sera in PBC rose to 27% but disease specificity was reduced. Our findings in a large population of PBC patients rule out a relation between presence of antibody to carbonic anhydrase II and lack of antimitochondrial antibody. The higher prevalence of ascites found in positive patients warrants further evaluation.

Primary biliary cirrhosis with features of autoimmune hepatitis.

The diagnosis of primary biliary cirrhosis (PBC) is made via a composite of clinical, laboratory, serologic, and histologic assessments, but within each parameter there exists a wide spectrum, so that the features of PBC are not always uniform. PBC is just one of several liver diseases thought to have an autoimmune basis. Therefore, it is not surprising, given the complexity of the immune response, that some patients thought to have PBC may have features of autoimmune hepatitis (AIH). Whether such patients have PBC with features of AIH, or antimitochondrial antibody-negative PBC, or another disease altogether, remains unclear.

Recent developments in autoimmune liver diseases.

Several diseases are regarded as autoimmune liver diseases. Apart from the cholestatic liver diseases, primary biliary cirrhosis, primary sclerosing cholangitis, these include autoimmune hepatitis, hepatitis as part of the autoimmune polyendocrine syndrome type 1 (APS-1) and particular overlap syndromes such as autoimmune cholangitis (also called antimitochondrial antibody negative primary biliary cirrhosis [PBC]), overlap syndrome chronic active hepatitis (CAH)/PBC and the overlap syndrome primary sclerosing hepatitis (PSC)/CAH. In addition, auto-antibodies may be observed during the course of chronic viral hepatitis, in particular chronic hepatitis C and D. Finally, a small number of drug-induced liver diseases is immune mediated. The following article will review our recent progress in the field of autoimmune hepatitis including APS-1 and autoimmunity in viral hepatitis and immune-mediated drug-induced liver disease.

抗ミトコンドリア抗体陰性原発性胆汁性肝硬変に合併し，各種薬剤治療を試みたＨｅｐａｔｏｐｕｌｍｏｎａｒｙ ｓｙｎｄｒｏｍｅの１例

症例は64歳, 男性. 糖尿病, アルコール性肝障害で外来通院中に胆道系酵素の著明な上昇と肝予備能の低下, 労作時呼吸困難を認め入院した. 著明な低酸素血症を認め, 呼吸機能検査では拡散障害を認めた. 心臓および肺に器質的異常はなかったが, 肺血流シンチグラフィーにて脳, 腎実質の描出があり, Hepatopulmonary syndromeと診断した. 基礎肝病変に関しては腹腔鏡, 肝生検にて胆汁性肝硬変と診断した. 内視鏡的逆行性胆管造影, 大腸内視鏡にて原発性硬化性胆管炎や炎症性腸疾患の所見はなく, 抗ミトコンドリア抗体陰性原発性胆汁性肝硬変と考えた. 低酸素血症に対してポリミキシンB, 塩酸ミドドリン, PGF2α, 酢酸オクトレオチドの投与を行ったが有意の改善はなく, 在宅酸素療法となった.

Abnormal expression of PDC-E 2 on the apical surface of biliary epithelial cells in patients with antimitochondrial antibody—negative primary biliary cirrhosis

The presence of antimitochondrial antibodies (AMA) is a major criterion for the diagnosis of primary biliary cirrhosis (PBC). Although it is not clear that AMA are involved in the pathogenesis of the disease, the study of these autoantibodies has enabled much information to be accumulated about the specificity of this response. The autoantigens have been identified as components of a functionally related enzyme family, the 2-oxo-acid-dehydrogenase complex. Within this complex, pyruvate dehydrogenase E 2 subunit (PDC-E 2) has been determined to be the immunodominant autoantigen. Using a panel of mouse monoclonal antibodies and human combinatorial autoantibodies, it has been demonstrated that patients with PBC, but not controls, have an abnormal expression of either PDC-E 2 or a cross-reacting molecule in the apical region of biliary epithelium. Others have shown a similar reaction using rabbit sera directed to PDC-E 2. Our previous studies have concentrated on AMA-positive patients. In this study, the presence of PDC-E 2, class II, immunoglobulin (Ig) A, and B7/BB1 in the bile duct epithelial cells of AMA-positive as well as AMA-negative patients is addressed. Most patients with AMA-negative PBC (seven of nine) react in a fashion similar to AMA-positive patients with intense staining of the apical region of the bile duct epithelial cells for “PDC-E 2,” increased IgA expression, and little major histocompatibility complex (MHC) class II staining in the early-stage patients. Interestingly, the two AMA-negative patients that did not express PDC-E 2 on the apical side of their biliary epithelium had anticentromere antibodies and Sjögren's syndrome. Based on these data, it can be concluded that the disease process for both AMA-positive and AMA-negative patients with PBC has a similar pathogenic mechanism, which is likely to involve the abnormal expression of PDC-E 2 or a molecular mimic of PDC-E 2, and does not require MHC class II expression.

“Atypical speckled” antinuclear antibodies in antimitochondrial antibody negative primary biliary cirrhosis

“Atypical speckled” antinuclear antibodies in antimitochondrial antibody negative primary biliary cirrhosis