Evaluation of nail fold capillaroscopy findings in patients with primary biliary cirrhosis.

AIM: Some patients with primary biliary cirrhosis (PBC) experience Raynaud's phenomenon. The objective of this study was to clarify the relationships between nail fold capillaroscopy findings and clinical presentations of PBC. METHODS: A total of 70 patients with PBC and 57 patients with non-PBC liver diseases, including 44 patients with chronic viral hepatic disease, eight with autoimmune hepatitis and five with non-alcoholic fatty liver disease, were included in this study. Nail fold capillaroscopy findings were classified as normal or abnormal and were further graded as mild, moderate or severe, and the relationships between frequency of abnormal blood vessel and their clinical presentations were examined. RESULTS: The frequency of abnormal nail fold capillaroscopy findings was significantly higher in PBC patients (54.3%) than in patients with non-PBC liver disease (13.8%) (P < 0.01). These abnormal findings observed in PBC patients were graded as mild in 15 patients, moderate in 18 patients and severe in five patients. Significantly more PBC patients with abnormal capillaroscopy findings (19/38, 50%) were positive for anticentromere antibody than were those with normal capillaroscopy findings (3/32, 9.4%) (P < 0.01). CONCLUSION: PBC patients had significantly higher frequency of abnormal nail fold capillaroscopy findings than did patients with non-PBC liver disease.

Anti-nucleosome autoantibodies as markers for autoimmune hepatitis and their correlation with disease activity.

AIM: To assess the prevalence of autoantibodies against nucleosomes (anti-nucleosome Ab) in patients with autoimmune hepatitis (AIH), examine the correlation between anti-nucleosome Ab and disease activity, and evaluate the effectiveness of anti-nucleosome Ab in predicting relapse. METHODS: We analyzed serum anti-nucleosome Ab levels in 38 patients with AIH by enzyme-linked immunosorbent assay, and assessed their correlation with clinical characteristics. RESULTS: Anti-nucleosome Ab levels were significantly higher in AIH, but not in patients with chronic hepatitis B (n = 20) or chronic hepatitis C (n = 20), compared to healthy controls (n = 15). The positive prevalence of anti-nucleosome Ab was 71.1% in AIH. Anti-nucleosome Ab levels were significantly lower during remission compared to that during flares within the same patients with AIH. Total bilirubin levels were significantly higher in patients with anti-nucleosome Ab levels of 53.7 U/mL or more compared to those with less than 53.7 U/mL at disease onset. Analysis of the reduction in anti-nucleosome Ab by immunosuppressive therapy in 16 AIH patients revealed that age at disease onset was significantly lower and IgG levels and relapse rates were significantly higher in patients with a reduction rate of less than 35% compared to those with a reduction rate 35% or more. The International Autoimmune Hepatitis Group score and γ-globulin levels were also higher in patients with reduction rates of less than 35% (borderline significance). CONCLUSION: Anti-nucleosome Ab in AIH patients may be useful markers not only for disease diagnosis, but also for activity assessment and relapse prediction.

Liver dysfunction in patients with systemic lupus erythematosus.

OBJECTIVE: We aimed to define the clinical features of liver dysfunction in patients with systemic lupus erythematosus (SLE). METHODS: The frequency and causes of liver dysfunction were examined in 206 patients with SLE. RESULTS: Liver dysfunction was evident in 123 (59.7%) of the 206 patients. Liver dysfunction in patients with SLE can be drug-induced (30.9%) or caused by SLE itself (28.5%), fatty liver (17.9%), autoimmune hepatitis (AIH) (4.9%), primary biliary cirrhosis (2.4%), cholangitis (1.6%), alcohol (1.6%) or viral hepatitis (0.8%), and it tends to be mild except when caused by AIH. Values for aminotransferase were significantly increased when AIH was the cause, whereas alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GTP) were significantly increased when AIH or drugs were the cause. The liver was already dysfunctional at the time of SLE onset in 56 (45.5%) of 123 patients with liver dysfunction. Neurological involvement was more common among patients with than without liver dysfunction, whereas SLE activity and prognosis did not significantly differ between the two groups. CONCLUSION: Liver dysfunction in the presence of SLE can be caused by many factors, but when extant at the time of SLE onset, either SLE itself or drugs can be the cause. Autoimmune hepatitis should be considered when liver dysfunction is relatively severe.

Case of idiopathic portal hypertension complicated with autoimmune hepatitis.

We report a case of idiopathic portal hypertension (IPH) complicated with autoimmune hepatitis. A 60-year-old woman was admitted to our hospital with esophageal and gastric varices in February 2010. Abdominal ultrasonography and computed tomography showed splenomegaly and collateral veins without evidence of liver cirrhosis. Laboratory examinations and liver biopsy indicated that the esophageal and gastric varices were caused by IPH. She underwent endoscopic injection sclerotherapy and partial splenic embolization. Two years after these therapies, laboratory examinations showed liver dysfunction with elevated levels of aspartate aminotransferase (180 IU/L), alanine aminotransferase (190 IU/L), γ-glutamyl transpeptidase (159 IU/L) and immunoglobulin G (2609 mg/dL). The titer of antinuclear antibodies was 1:320 and its pattern was homogeneous and speckled. Histological examination revealed plasma cell/lymphocyte infiltration and interface hepatitis in the portal tract. Based on these findings, a diagnosis of autoimmune hepatitis accompanied by IPH was made. After treatment with prednisolone (20 mg/day), liver functions were normalized immediately. Overlapping of IPH and AIH is extremely rare, but the present case is interesting considering the etiology of IPH because an autoimmune mechanism is thought to be involved in the pathogenesis of IPH.

Autoantibodies by line immunoassay in patients with primary biliary cirrhosis.

OBJECTIVES: We attempted to measure multiple autoantibodies simultaneously using line immunoassay (LIA) in patients with primary biliary cirrhosis (PBC) with or without anti-mitochondrial antibody (AMA) and patients with PBC-autoimmune hepatitis (AIH) overlap, and we examined the clinical significance of measuring these autoantibodies. METHODS: The study population consisted of 80 patients with PBC (including 12 AMA-negative patients), 16 patients with PBC-AIH overlap and 40 patients with AIH as controls. Nine antibodies (AMA-M2, M2-3E, Sp100, PML, gp210, Ro-52, LKM-1, LC-1 and SLA/LP) were detected by LIA, and AMA-M2 and anti-centromere antibody (ACA) were detected by ELISA. We examined the relationship between these autoantibodies and clinical findings. RESULTS: The positive prevalence of each autoantibody and ACA in the PBC group, as determined by LIA, was as follows: 13.8% for anti-Sp100, 8.7% for anti-PML, 40% for anti-gp210 and 27.5% for anti-Ro-52 antibodies and 32.5% for ACA. In the PBC-AIH overlap group, the prevalence of anti-gp210 antibody (68.7%) and that of anti-Ro-52 antibody (81.2%) were significantly higher than those in the PBC and AIH groups. Only a few patients were positive for 2 or more autoantibodies. Nine patients were determined to be negative for all autoantibodies by LIA, of whom 7 were positive for ACA. Patients positive for anti-gp210 antibody included more patients classified as stage 4 on histology than did the negative group. Those positive for ACA included more patents with varices than did the negative group. CONCLUSION: LIA can measure multiple autoantibodies simultaneously and thus is considered useful in diagnosing PBC and PBC-AIH overlap. In addition, ACA is a useful marker for identifying AMA-negative PBC.

Centrilobular necrosis in acute presentation of Japanese patients with type 1 autoimmune hepatitis.

AIM: To compare clinicopathological features of acute presentation of type 1 autoimmune hepatitis (AIH) with or without centrilobular necrosis (CN). METHODS: Our study comprised 41 patients with biopsy-proven acute presentation (acute exacerbation phase 36, acute hepatitis phase 5) of type 1 AIH at our hospital from 1975 to 2009. Elevated serum alanine aminotransferase (ALT) (> 5x upper limit of normal) identified acute presentation of the disease. We compared clinicopathological features of these AIH patients with or without CN. The data used for analysis included patient background (age, sex, type of disease, presence of complications with other autoimmune diseases, human leukocyte antigen, and International Autoimmune Hepatitis Group score), clinical parameters at presentation (ALT, alkaline phosphatase, IgG, anti-nuclear antibodies, and anti-smooth muscle antibodies), histology and therapy. RESULTS: CN was found in 13 (31.7%) patients with acute presentation (acute exacerbation phase 10, acute hepatitis phase 3) of AIH. Serum IgG levels of patients with CN were significantly lower than those of patients without CN (mean: 2307 mg/dL vs 3126 mg/dL, P < 0.05), while antinuclear antibody-negative rates were significantly higher (30.7% vs 3.5%, P < 0.05). However, other clinical features were similar between the two groups. The frequency of advanced fibrosis in patients with CN was significantly lower than in patients without CN (F0-2: 84.6% vs 35.7%, F3-4: 15.4% vs 64.3%, P < 0.05). Other histological features were similar between the two groups. Although there was no significant difference between groups when evaluated using the revised original score (12 vs 14), the simplified AIH score of patients with CN was significantly lower (6 vs 7, P < 0.05). Frequency of DR4 was similar between patients with and without CN. CONCLUSION: CN is observed in both Japanese patients with acute hepatitis phase and acute exacerbation phase of type 1 AIH, although AIH with CN often shows clinical features of the genuine acute form.

Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

A case of peripheral T-cell lymphoma presenting with acute liver failure.

A 68-year-old woman was evaluated by her primary physician for swelling and pain in the right neck. Treatment with antibiotics failed to achieve any improvement. Two weeks later, she was hospitalized to the gastroenterology department because of liver dysfunction and pneumonia. Disseminated intravascular coagulation (DIC) was diagnosed, and protease inhibitor and steroid pulse therapy were started. She was transferred to our department for further evaluation the following day. Bone marrow examination revealed hemophagocytosis and infiltration of CD3-positive cells. Multiple masses were identified in the liver. Her prothrombin time was 35.7% of the standard value 17 days from disease onset, despite improvement of DIC. She was diagnosed with acute liver failure based on the Japanese diagnostic criteria. Her general condition worsened quickly, which prevented use of chemotherapy, and she died after a total course of 19 days. Autopsy revealed atypical lymphocytes in the liver. The diagnosis was peripheral T-cell lymphoma.

Case of primary biliary cirrhosis-autoimmune hepatitis overlap which manifested after delivery.

A 34-year-old woman showed liver dysfunction for the first time at 3 months after delivery. Two years later, she was referred to our department with continued liver dysfunction. She fulfilled the criteria for primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap. Liver dysfunction improved after administration of ursodeoxycholic acid and bezafibrate. To the best of our knowledge this represents the second report of PBC-AIH overlap after delivery and we discuss immunological changes during the perinatal period.

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.

A case of advanced intrahepatic cholangiocarcinoma successfully treated with chemosensitivity test-guided systemic chemotherapy.

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare and highly fatal neoplasm that arises from the biliary epithelium. Prognosis is generally poor and survival is limited to a few months. Here we present a case of advanced ICC successfully treated by chemosensitivity test-guided systemic chemotherapy combining S-1 and cisplatin (CDDP). A 65-year-old woman with a liver tumor was referred to our hospital on November 21, 2007. Abdominal ultrasonography and computed tomography (CT) showed low-density masses of 50 and 15 mm in diameter, respectively in segment VIII of the liver and in the enlarged lymph node in the para-aorta. Ultrasonography-guided fine needle biopsy diagnosed the tumors as ICC. Since the patient was inoperable for lymph node metastasis, she underwent systemic chemotherapy with gemcitabine. Six months after initiation of chemotherapy, CT revealed ICC progression in the liver and pleural dissemination with pleural effusion. The patient was admitted to our hospital for anticancer drug sensitivity testing on June 9, 2008. Based on the sensitivity test results, we elected to administer systemic chemotherapy combining S-1 and CDDP. Two months into the second chemotherapy treatment, CT revealed a reduction of the tumors in the liver and lymph node and a decrease in pleural effusion. After eight cycles of the second chemotherapy, 17 mo after ICC diagnosis, she is alive and well with no sign of recurrence. We conclude that chemosensitivity testing may effectively determine the appropriate chemotherapy regimen for advanced ICC.

Development of autoimmune hepatitis type 1 after pulsed methylprednisolone therapy for multiple sclerosis: a case report.

A 43-year-old woman with multiple sclerosis (MS) was treated with pulsed methylprednisolone and interferon beta at a hospital. Four weeks after initiating treatment, liver dysfunction occurred and she was referred and admitted to our hospital. Clinical and laboratory findings were consistent with and fulfilled the criteria for drug-induced hepatitis, but not for autoimmune hepatitis (AIH). She was successfully treated with corticosteroids. As ataxia developed after 1 year, she was treated with pulsed methylprednisolone for 3 d, then readmitted to our hospital when liver dysfunction occurred. Clinical and laboratory findings led to the diagnosis of AIH. To the best of our knowledge, this is the second case of AIH developed after pulsed methylprednisolone for MS.

Primary biliary cirrhosis complicated by polymyositis and pulmonary hypertension.

A 68-year-old woman was admitted to a hospital with pulmonary hypertension (PH) in August 2006. Perfusion scintigraphy of the lung was normal and showed no interstitial change. Liver dysfunction was noted and antinuclear antibodies (x1,280) were positive. In November 2006, muscle pain and weakness gradually developed in the brachial muscle and a quadriceps. She was referred and admitted to our hospital for elevated CPK and liver dysfunction in March 2007. She was diagnosed with polymyositis (PM) on the basis of the histological findings of muscle biopsy and treated with prednisolone. In addition, because anti-centromere antibodies and anti-mitochondrial M2 antibodies were positive with high titers, she was also diagnosed with primary biliary cirrhosis (PBC). Although PBC is often associated with other autoimmune diseases, there have been no reports of PBC complicated by PM and PH.

Autoimmune hepatitis complicated by late-onset systemic lupus erythematosus.

A 69-year-old man with autoimmune hepatitis (AIH) was admitted to hospital with high fever and cough. Chest roentgenogram and computed tomography showed pleural and pericardial effusion. Serological tests showed a high titer of antinuclear antibodies and positive anti-DNA antibody and lymphocytopenia. He fulfilled the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). After administration of corticosteroids, his symptoms and liver dysfunction improved. To the authors' knowledge, this is the first male case of overlap between AIH and late-onset SLE.

Two cases of primary biliary cirrhosis complicated by acute leukemia.

Case 1 was a 43-year-old woman, who was diagnosed as having PBC. After one month, she was hospitalized owing to sudden temporary unconsciousness. She was diagnosed as having acute lymphoid leukemia (ALL) by bone marrow examination. Chemotherapy was done, but she died after 6 months. Case 2 was a 54-year-old woman, who was diagnosed as having PBC with CREST syndrome. Seven years later, she was diagnosed as having acute promyelocytic leukemia (APL) by bone marrow examination. Chemotherapy was continued, and her symptoms are at present, stable. To date, there have been no reports of PBC complicated by acute leukemia.

[A case of hepatocellar carcinoma associated with mixed connective tissue disease].

A 79-year-old woman, who had been treated because of mixed connective tissue disease (MCTD), was admitted to the hospital for the intensive examination of a hepatic tumor that was unexpectedly found on computed tomography. The hepatic tumor was approximately 40 mm in diameter. Her transaminase levels were slightly elevated but hepatic virus markers were negative. However, a liver aspiration biopsy revealed moderately differentiated hepatocellular carcinoma (HCC). In the surrounding non-tumor area, nonspecific reactive hepatitis was detected. MCTD associated with HCC has not yet been reported in the past. This case appears to be very interesting in terms of the etiology of HCC.

[Case of acute hepatitis associated with Basedow's disease].

A 20-year-old woman given a diagnosis of hyperthyroidism (Basedow's disease) had been subsequently treated with methimazole since 1999. As she could not be made euthyroid, surgery was planned to relieve the symptoms. Because of liver dysfunction after discontinuation of methimazole and administration of iodine, she was admitted to the hospital. She was negative for hepatitis A, B and C virus serologies, but positive for anti-nuclear antibodies. A liver biopsy, which showed features of chronic active hepatitis, led to the diagnosis of autoimmune hepatitis (AIH). Interestingly, normalization of serum T4 correlated with improvement of serum aminotransferases. This leads us to speculate that this patient's liver dysfunction may have been AIH exacerbated by the liver dysfunction of hyperthyroidism rather than acute deterioration of AIH itself.

Breakthrough of immune self-tolerance to calreticulin induced by CpG-oligodeoxynucleotides as adjuvant.

Reportedly, bacterial DNA containing unmethylated cytosine-guanosine dinucleotide motif-containing oligodeoxynucleotides (CpG-ODNs) can induce Th1-type adjuvant effects. We produced autoantibodies and induced hepatitis in mice using extracted proteins from human hepatocytes with CpG-ODNs as adjuvant. Western blot analysis was performed of sera from immunized mice and two patients with autoimmune hepatitis (AIH). When a common band was detected, N-terminal amino acid sequencing was performed to determine its site. For detection of antibodies against the identified protein (calreticulin), ELISA was performed of sera of 50 patients with AIH: 45 with primary biliary cirrhosis (PBC), 24 with chronic hepatitis C (CH), and 24 healthy controls. Mice were immunized with calreticulin protein with CpG-ODNs as adjuvant. Several reacted bands were detected in their sera; in addition, a common band to the sera of patients with AIH was detected at 60 kDa. Subsequent N-terminal amino acid sequencing revealed that the protein was human calreticulin. ELISA showed that, of patients with AIH, PBC, and CH, 30.0% (15/50), 17.8% (8/45), and 12.5% (3/24), respectively, were positive for anti calreticulin antibodies. Splenocytes from immunized mice produced IFN-gamma after they were pulsed with calreticulin protein. Histological analyses of liver specimens taken from mice immunized with calreticulin protein together with CpG-ODNs showed spotty and focal necrosis. Immunofluorescence analysis showed increased expression of calreticulin in the liver treated with CpG-ODNs. These results suggest that a breakthrough of immune self tolerance to calreticulin is induced with CpG-ODNs as adjuvant and that calreticulin protein might be a target antigen in this model.

A recovery case of acute-onset autoimmune hepatitis presenting as fulminant hepatic failure [corrected], who received living donor-liver transplantation.

A 23-year-old woman was admitted to our hospital with jaundice and hepatic coma. She had taken a weight-loss supplement for one month before admission. Her clinical and laboratory findings were consistent with fulminant hepatic failure and fulfilled the criteria of autoimmune hepatitis. Despite corticosteroid pulse therapy and plasma exchange, her symptoms and laboratory findings deteriorated. Her condition improved after she received a living donor-liver transplant from her sister. Autoimmune hepatitis usually follows a chronic course, but it should be considered a type of fulminant hepatic failure and treated promptly.

Expression of human glucocorticoid receptor beta of peripheral blood mononuclear cells in patients with severe autoimmune hepatitis.

We evaluated the expression of human glucocorticoid receptor beta (hGRbeta) in patients with severe autoimmune hepatitis (AIH). The subjects were 27 patients with AIH, including 6 with severe type (prothrombin time [PT] < 40%) and 21 with non-severe type (PT>40%). Total RNA extracted from peripheral blood mononuclear cells (PBMCs) was reversed using reverse transcriptase. The resultant complementary DNA was amplified by reverse transcription polymerase chain reaction (RT-PCR) using specific primers for hGR alpha and beta. The six patients with severe AIH were female; three presented fulminant hepatic failure with hepatic encephalopathy. In all patients with AIH, hGR a was detected. The incidence of hGR beta expression in patients with non-severe type was 42.9% (9/21) ; it was 100% (6/6) in those with severe type. The positive ratio was significantly higher in severe-type patients. These results suggest that hGR beta expression in PBMCs is a novel predictor of AIH severity.