Onset Of Autoimmune Hepatitis Research Articles

妊娠中に発症し胎児に腹水を認めた自己免疫性肝炎の1例

症例は31歳女性．第2子の妊娠14週頃に皮膚搔痒感と不眠を自覚し始めた．妊娠20週に同僚から皮膚および眼球結膜の黄染を指摘され，近医を受診したところ，肝障害（黄疸）を指摘された．肝庇護剤の投与が開始されたが，黄疸はさらに増強した．この時点では抗核抗体は陰性であった．当院産婦人科での入院精査では，母体肝機能の低下に加え，胎児腹水の貯留も認められた．しかし胎児胸水は認められず，典型的な胎児水腫とは異なる病像であった．本人および家族の希望により，妊娠21週6日目に人工妊娠中絶が施行された．人工妊娠中絶後，肝機能は速やかに改善傾向を示したものの，中絶後2週目に再び増悪してきたため，原因精査のため当科にて肝生検をおこなった．その結果，リンパ球を主体とした高度炎症細胞浸潤やロゼット様構造など自己免疫性肝炎（AIH）に特徴的な組織学的所見が得られた．この時点で陽性化していた抗核抗体およびHLA-DR4陽性などの血清学的所見を加味し，「definite AIH（国際診断基準）」と診断した．診断後直ちにステロイドの内服を開始した結果，肝機能は改善した．

Autoimmune acute liver failure: an emerging etiology for intractable acute liver failure.

Diagnosis of acute onset autoimmune hepatitis (AIH) is the most challenging task because of atypical clinicopathological features. We examined the nature of acute onset AIH consisting of nonsevere, severe, and fulminant AIH based on our published data and other published papers, and propose how to diagnose and treat this intractable hepatitis. We analyzed clinical, biochemical, immunological, radiological, and histological features of acute onset AIH. Thirty percent of fulminant hepatitis was due to AIH and autoimmune acute liver failure (ALF) was not rare. The important characteristic of acute onset AIH is its histological, radiological, and clinical heterogeneity. Sometimes acute onset AIH develops into ALF in a sub-acute clinical course without appropriate diagnosis and treatment, and becomes resistant to immunosuppressive therapy and has poor prognosis. Unenhanced computed tomography (CT) often shows heterogeneous hypoattenuation in autoimmune ALF. The revised original scoring system (1999) performed better in patients with acute onset AIH than the simplified scoring system (2008). Liver regeneration from periportal progenitor cells to mature hepatocytes was impaired in ALF, resulting in resistance to immunosuppressive therapy. Precise histological evaluation (the presence of centrilobular necrosis/collapse) along with the revised original scoring system and CT findings of heterogeneous hypoattenuation after systematic exclusion of other causes 36 plays an important role in the diagnosis. The most important strategy for autoimmune ALF is to diagnose and treat acute onset AIH before its development into ALF. Liver transplantation should be considered before the occurrence of infectious complications in the case of fulminant liver failure.

Autoimmune hepatitis in the postpartum period

Autoimmune hepatitis (AIH) presenting primarily in the postpartum period has rarely been reported. The medical data of 58 female patients diagnosed with AIH was assessed. In the study population, three (5.1%) patients were diagnosed postpartum. Based on clinical, laboratory and liver biopsy findings, two of these patients were considered to have subclinical AIH and were diagnosed by disease flare after delivery. The remaining patient was considered as new onset of AIH in the postpartum period. AIH can present in the postpartum and should be actively considered among the differential diagnosis if liver dysfunction is observed after delivery.

Importance of computed tomography imaging features for the diagnosis of autoimmune acute liver failure

The diagnosis of acute liver failure due to autoimmune hepatitis is often difficult because of atypical clinicopathological features. Patients with autoimmune acute liver failure are sometimes resistant to immunosuppressive therapy and have poor prognosis. Although their survival rates are especially poor (5-20%) without liver transplantation in Japan, their clinicopathological features have remained uncertain. A major problem is that there is no gold standard for making the diagnosis of acute onset autoimmune hepatitis. If there are diagnosing tools supporting clinicopathological features, they are of benefit to the patients. We examined computed tomography (CT) imaging features of autoimmune acute liver failure to clarify the usefulness of imaging for the diagnosis. A retrospective analysis of 129 unenhanced CT scans of 68 patients with acute hepatitis, consisting of 23 with autoimmune acute liver failure (ALF) (group 1), 25 with early admission-viral ALF (group 2) and 20 with late admission-viral ALF (group 3), was performed. Autoimmune acute liver failure showed heterogeneous hypoattenuating areas and viral ALF diffuse ones (P < 0.001). The diffuse hypoattenuating areas were present in none of group 1, 15 (60%) of group 2, and 7 (30%) of group 3. The heterogeneous hypoattenuating areas were present in 15 (65%) of group 1, none of group 2 and 1 (5%) of group 3. Heterogeneous hypoattenuation on unenhanced CT was a characteristic CT imaging feature of autoimmune acute liver failure compared with viral ALF. This finding could be one of the tools for diagnosing autoimmune acute liver failure in combination with clinicopathological features.

Efficacy of Intravenous Glycyrrhizin in the Early Stage of Acute Onset Autoimmune Hepatitis

Acute onset autoimmune hepatitis (AIH) shows acute presentation like acute hepatitis and does not have typical clinicopathological features of AIH. There is no gold standard for making the diagnosis. Therefore, losing the timing of starting immunosuppressive therapy, some of the cases develop into severe or fulminant form and have poor prognosis. Our aim was to elucidate the efficacy of intravenous glycyrrhizin in decreasing alanine aminotransferase (ALT) level in the early stage of acute onset AIH. Thirty-one patients were defined as acute onset AIH based on our uniform criteria, and were enrolled in this study. We prospectively treated 17 patients with sufficient doses (100 ml/day) of intravenous glycyrrhizin (SNMC) at an early stage (SNMC group), and treated 14 patients of severe disease with intravenous glycyrrhizin and corticosteroids (CS) (SNMC + CS group). We examined their clinical and biochemical features and treatment responses. The ALT level could be controlled at an early stage using SNMC with no significant difference compared with SNMC + CS, and responsiveness to the therapy was determined by the disease severity at the time of starting therapy rather than the time duration from onset to therapy. Recovery rate was higher in the SNMC group than in the SNMC + CS group (P = 0.035). The early introduction of sufficient doses of SNMC might prevent disease progression in patients with acute onset AIH. SNMC can be used safely and be useful for patients with difficult-to-diagnose acute liver disease as an 'initial' treatment tool to improve liver inflammation before starting disease-specific treatments.

Autoimmune fulminant liver failure in adults: Experience in a Japanese center

After the establishment of the international criteria of autoimmune hepatitis (AIH) in 1999 and the recognition of acute onset AIH, the diagnosis of patients with fulminant type of AIH came to be made. We diagnosed autoimmune fulminant liver failure based on the criteria, and discussed the etiology of fulminant hepatitis (FH) and late onset hepatic failure (LOHF), and the characteristics of autoimmune fulminant liver failure. We investigated the etiology of 95 consecutive adult patients with FH or LOHF admitted to our liver unit between 1990 and 2009. Clinical and biochemical features, therapies and outcomes were examined in patients with AIH after 2000. Of 95 patients, 85 were FH and 10 LOHF. The etiology was due to viral infections in 51.6% (hepatitis A virus in 7.4%, hepatitis B virus in 43.2% and hepatitis E virus in 1.1%), AIH in 15.8%, drug allergy-induced in 12.6%, and unknown causes in 20.0%. The rate of patients with AIH increased significantly between 2000 and 2009 compared to the rate between 1990 and 1999 (P = 0.002). In recovered patients with AIH without transplantation after 2000, coma grade was lower, alanine aminotransferase level, prothrombin time activity and alfa-fetoprotein level were higher than in the others with statistical significance. AIH is not a rare cause of FH and LOHF, and the number of patients with unknown causes would surely decrease in concert with the precise diagnosis of AIH.

Dual Onset of Autoimmune hepatitis (AIH) and Graveʼs Disease in Hepatitis C (HCV) during Peg-interferon Alpha 2a Plus Ribavirin Therapy

Dual Onset of Autoimmune hepatitis (AIH) and Graveʼs Disease in Hepatitis C (HCV) during Peg-interferon Alpha 2a Plus Ribavirin Therapy

Clinicopathological features of severe and fulminant forms of autoimmune hepatitis

Diagnosis of the acute presentation of autoimmune hepatitis (AIH) is difficult because patients do not always show typical clinicopathological features of AIH. Although some of them progress to fulminant hepatitis, the survival rate of which is <20% without liver transplantation, their clinicopathological features have remained uncertain. We examined them for a better understanding and improvement of the prognosis of "life-threatening" severe and fulminant AIH. Clinical, biochemical and pathological features of 28 patients with severe or fulminant AIH and treatment responses were examined retrospectively. At the time of admission, mean immunoglobulin G was 2479 ± 1170 mg/dl, with 7 (25%) patients showing normal levels. Anti-nuclear antibody was ≤ 1:40 in 8 (29%). Liver histology showed severe activity in 95% and acute hepatitis in 86% of the patients. Centrilobular necrosis including submassive and massive necrosis was characteristic. Of the 25 patients treated with corticosteroids, 17 responded and 8 did not. Responders to corticosteroids showed younger age and higher prothrombin time (PT) activity than non-responders at the time of corticosteroid administration. The improvement of PT activity during 2 weeks and 4 weeks and total bilirubin level during 4 weeks was statistically significant in responders, but not in non-responders. We should diagnose and treat acute onset AIH patients before they develop into severe and fulminant disease. Performing liver biopsy at the early stage of acute onset AIH, evaluating the biopsy specimens precisely and initiating corticosteroid therapy may be essential for improving the prognosis without liver transplantation.

Influence of genes, sex, age and environment on the onset of autoimmune hepatitis

The pathogenesis of autoimmune hepatitis (AIH) is complex. However, it is believed that a susceptible individual, owing to his genetic background, sex and age, can develop the disease following exposure to an environmental trigger. Autoimmune hepatitis does not follow a Mendelian pattern of inheritance; hence no single causative genetic locus has been identified. However, several genes, inside and outside the HLA locus, have been linked to an increased susceptibility to AIH. Epidemiological evidence also suggests that the sex and age of the patient plays a role in AIH pathogenesis as the disease onset occurs mainly in the two first decades of life and a higher disease incidence is observed in females. No environmental trigger has been identified, but several have been proposed, mainly viruses and xenobiotics. This article aims at reviewing the current knowledge on susceptibility factors leading to AIH and putative triggers, emphasizing fundamental mechanisms responsible for the break of liver immunological tolerance.

Pathology of autoimmune liver diseases in children

Liver disorders are more diverse in children than in adults, and autoimmune liver diseases also develop in childhood, although rarely. The autoimmune diseases in children comprise autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). The pathology of AIH and PSC is described. Although AIH in children is rare, it occurs in early childhood, and some elementary school students have been reported to develop cirrhosis. The histology of AIH in children is essentially the same as that in adults. We analyzed eight patients with childhood AIH. Four of these patients had a high AIH score, with typical histological features of AIH, that is, interface hepatitis with infiltration of lymphocytes and plasma cells, a severe necroinflammatory reaction and rosette formation of hepatocytes. Multinucleated hepatocytes were observed in three patients. This finding seems characteristic of childhood AIH, although rarely observed in adult AIH. Clinically, the distinction between AIH and PSC is often difficult in childhood, and the overlapping of both has also been reported. PSC-like histological features may be observed in some pediatric patients with AIH. In patients with acute onset of AIH, they show a pronounced necroinflammatory reaction in zone 3 (central area). Because an autoimmune phenomenon may occur in the early stage of childhood PSC, it is difficult to differentiate it from AIH in some patients. Some patients are diagnosed with AIH in the early stage, but with PSC during long-term follow up. The histopathological findings of childhood PSC are the same as those of adult PSC, and are characterized by biliary-type portal fibrosis and onion-like periductal fibrosis in medium-sized portal tracts.

Clinicopathologic Features of the Severe Form of Acute Type 1 Autoimmune Hepatitis

Acute onset autoimmune hepatitis (acute AIH) is difficult to diagnose by using serologic data. In addition, some patients with the severe form of acute AIH do not respond to immunosuppressive therapy and have a poor outcome. In this study, we analyzed the clinicopathologic features of patients who were diagnosed as having acute AIH. Retrospective review of patients with presumed acute AIH at Ehime University Graduate School of Medicine was performed. In liver tissue, infiltrates in the portal area and plasma cell infiltration are more common in acute AIH compared with acute hepatitis caused by other causes. Patients with acute AIH who did not have severe jaundice at the time of diagnosis exhibited a very good response to corticosteroid therapy, despite lower titers of antinuclear antibody (ANA). Most patients with acute AIH with higher levels of bilirubin and titers of ANA in sera respond poorly to corticosteroid therapy. Histologic findings might be useful for the early diagnosis of acute AIH. Acute AIH patients with high levels of bilirubin and high titers of ANA in sera often do not respond to corticosteroid therapy.

A case of acute hepatitis with positive autoantibodies who actually had hepatitis E virus infection

Hepatitis E virus (HEV) is one of the major causative agents of acute hepatitis in many developing countries. On the other hand, recent intensive investigation has revealed the existence of non-imported cases in industrialized countries. We encountered a sporadic patient with hepatitis E in 1999, who had had no recent travel abroad. He was a 67-year-old Japanese, and his laboratory data were negative for serum markers of hepatitis A, B and C virus infection and positive anti-nuclear antibody, anti-smooth muscle antibody and high level of serum immunoglobulin G. He scored as probable autoimmune hepatitis (AIH) with the scoring system by the international AIH group. He was given a diagnosis of acute cryptogenic hepatitis including acute onset AIH in those days, but the recent retrospective examination with frozen stocked serum revealed his exact diagnosis. In conclusion, we must take HEV infection into consideration for the diagnosis of cryptogenic acute hepatitis even in the developed countries, and some patients with hepatitis E could demonstrate positive for autoantibodies similar to clinical features of AIH. This case demonstrated the needs for further studies about clinical feature of acute hepatitis E virus infection.

A case of rapid onset autoimmune hepatitis resembling drug-induced liver disease in a Japanese young woman

A case of rapid onset autoimmune hepatitis resembling drug-induced liver disease in a Japanese young woman

Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: a study of 68 patients.

Autoimmune hepatitis (AIH) is a chronic liver disorder of unknown etiology. Disease presentation ranges from asymptomatic to symptomatic onset, fulminant, acute, or chronic. To evaluate the prognosis of patients with asymptomatic versus symptomatic AIH and to determine the role of early treatment and prognostic factors in this subgroup of patients. Sixty-eight patients with AIH were retrospectively evaluated for clinical presentation, liver function tests, autoantibody profile, liver biopsy, treatment, and long-term prognosis. Twenty-three patients were classified as having asymptomatic AIH. They were compared with the 45 AIH patients with symptomatic onset. Patients with symptomatic and asymptomatic presentations were indistinguishable by age, but there was a relative male predominance in the asymptomatic group. Aminotransferase and immunoglobulin levels were lower in the asymptomatic group. In contrast, the histopathologic picture was indistinguishable between the two groups. Lobular hepatitis of a moderate to severe degree, portal fibrosis, and bridging fibrosis were detected in similar frequencies in both groups. Asymptomatic onset led to a delay in diagnosis and, consequently, in the initiation of treatment and was associated with use of relatively lower doses of corticosteroids. Response to treatment and long-term prognosis of asymptomatic patients was better than that observed in the symptomatic group. Asymptomatic onset of AIH is relatively common. The clinical presentation appears in correlation with liver functions tests but not with liver histology. This subgroup of AIH carries a better response to treatment and a favorable prognosis.

Autoimmune hepatitis in the elderly

OBJECTIVES: Autoimmune hepatitis (AIH) is widely believed to be a disease of young women and menopause. Little is known about the frequency and clinical characteristics in patients aged ≥65 yr. METHODS: We reviewed charts of 120 consecutive outpatients with known AIH to identify patients who were diagnosed at the age of 65 or older. These 20 patients (median age, 69 yr) were compared to the same number of younger patients (median age, 24 yr) with well-documented AIH from the same cohort. RESULTS: Seventeen percent (20/120) of our patients were ≥65 yr at the time of diagnosis. In the older patients median time to diagnosis was significantly longer than in the younger patients (8.5 >vs 3.5 months). Patients most commonly presented with an acute icteric hepatitis. Complete remission was achieved to a similar extent (18/20 and 17/20 patients). Fewer older patients expressed human leukocyte antigen A1-B8 ( p = 0.005). CONCLUSIONS: Diagnosis of AIH often seems to be delayed in the elderly, presumably because AIH is erroneously considered to be a disease of young age. Presentation with acute icteric hepatitis is similar to that of younger patients, supporting the assumption that beneficial effects of hormonal changes associated with menopause are not as pronounced in AIH as in other autoimmune diseases. Human leukocyte antigen type seems to have an influence on the age of onset of AIH. Prognosis is excellent, and AIH should be considered in the older patient to avoid delayed initiation of immunosuppressive therapy.

Autoimmune hepatitis in the elderly.

Autoimmune hepatitis (AIH) is widely believed to be a disease of young women and menopause. Little is known about the frequency and clinical characteristics in patients aged > or =65 yr. We reviewed charts of 120 consecutive outpatients with known AIH to identify patients who were diagnosed at the age of 65 or older. These 20 patients (median age, 69 yr) were compared to the same number of younger patients (median age, 24 yr) with well-documented AIH from the same cohort. Seventeen percent (20/120) of our patients were > or =65 yr at the time of diagnosis. In the older patients median time to diagnosis was significantly longer than in the younger patients (8.5 vs 3.5 months). Patients most commonly presented with an acute icteric hepatitis. Complete remission was achieved to a similar extent (18/20 and 17/20 patients). Fewer older patients expressed human leukocyte antigen A1-B8 (p = 0.005). Diagnosis of AIH often seems to be delayed in the elderly, presumably because AIH is erroneously considered to be a disease of young age. Presentation with acute icteric hepatitis is similar to that of younger patients, supporting the assumption that beneficial effects of hormonal changes associated with menopause are not as pronounced in AIH as in other autoimmune diseases. Human leukocyte antigen type seems to have an influence on the age of onset of AIH. Prognosis is excellent, and AIH should be considered in the older patient to avoid delayed initiation of immunosuppressive therapy.

AUTOIMMUNE HEPATITIS IN CHILDREN WITH PREEXISTING LIVER DISEASE

88 Autoimmune hepatitis (AIH) is characterized histologically by a dense mononuclear infiltrate in the portal tracts and sinusoids and serologically by the presence of non-liver specific antibodies and increased levels of immunoglobulin G (IgG) in the absence of a known etiology (Semin Liver Dis 1998; 18(3): 271-279 ). We present three cases of new onset AIH in children with preexisting liver disease. All patients had negative serology for hepatitis A, B, C, cytomegalovirus and Ebstein-Barr virus. Patient 1 is a 17 year old female with Alagille's who at age 15 years developed fever, abdominal pain and progressive jaundice with total/direct bilirubin of 7.8/6.0 mg/dl, ALT 524 IU/L, AST 357IU/L, alkaline phosphatase (AP) of 385 IU/L. Erythrocyte sedimentation rate (ESR) was 70 mm/hr and anti-nuclear antibody (ANA) titer was 1:640, antimitochondrial antibody (AMA) and anti-smooth muscle antibody (ASMA) titers were negative. Liver biopsy showed ductopenia and chronic active hepatitis with lymphoplasmacytic infiltration. Treatment with azathioprine and prednisone achieved remission. Patient 2 is a 19 year old female with cystic fibrosis liver disease, who at 17 years developed an ALT 359 IU/L, AST 409 IU/L, AP 391 IU/L and total bilirubin 2.6 mg/dl; serum IgG was 1950 mg/dl. Liver biopsy showed moderate panlobular hepatitis with numerous plasma cells and portal fibrosis. ASMA titer was 1:40, ANA 1:640, anti-DNA 1:640; AMA and anti-liver kidney microsomal antibody (anti-LKM) were negative. Prednisone and azathioprine treatment resulted in remission followed by relapse with reduction of prednisone. Patient 3 is a 25 year old female with sickle cell disease and neurological impairment who at 24 years was noted to have hepatomegaly, elevated transaminases, direct bilirubin, chronic cholecystitis and elevated IgG. She underwent open cholecystectomy and concurrent liver biopsy showed sinusoidal hemophagocytosis of sickled red blood cells, portal fibrosis and increased lobular T-lymphocytes. ESR was >130 mm/hr, ASMA titer 1:320, ANA 1:320; anti-LKM and AMA were negative. The patient expired from sepsis complicating a jejunostomy procedure and therapy for AIH was never initiated.

A case of the aged man with acute onset autoimmune hepatitis

A case of the aged man with acute onset autoimmune hepatitis