Liver/kidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis

Background—Liver/kidney microsomal antibody type 1 (LKM1) and liver cytosol antibody type 1 (LC1) are the serologicalmarkers of type 2 autoimmune hepatitis (AIH).
Aims—Since LKM1 and LC1 react against two distinctliver specific autoantigens (cytochrome P450IID6 (CYP2D6) and a 58 kDa cytosolic polypeptide respectively), the aim was to see whether LKM1and LC1 concentrations correlate with liver disease activity.
Patients—Twenty one patients with type 2 AIH were studied.
Methods—All sera were tested by indirectimmunofluorescence, counterimmunoelectrophoresis, and immunoblottingvisualised by enhanced chemiluminescence. To evaluate LKM1 and LC1levels, the 50 kDa microsomal reactivity (corresponding to CYP2D6) andthe 58 kDa cytosolic reactivity were quantified by densitometric analysis.
Results—Seven patients were positive for LKM1,nine for LC1, and five for both. Serial serum samples at onset andduring immunosuppressive treatment were analysed in 13 patients (fourpositive for LKM1, six positive for LC1 and three positive for both).During remission, LKM1 concentration remained essentially unchanged insix of seven patients, and decreased in only one. Conversely, in two ofnine patients, LC1 was completely lost, and, in the remaining seven, LC1 concentration was reduced by more than 50%. Afterimmunosuppression tapering or withdrawal, flare ups of liver necrosisensued with increasing LC1 concentration, but not LKM1.
Conclusions—LC1 concentration, at variance withthat of LKM1, parallels liver disease activity, and its participationin the pathogenic mechanisms of liver injury can be hypothesised.

     

Chronic hepatitis C associated with anti-liver/kidney microsome-1 antibody is not a subgroup of autoimmune hepatitis

To determine whether “autoimmune hepatitis type IIb” should be categorized as a subgroup of autoimmune hepatitis, we conducted a clinicopathological study of 25 adult Japanese patients who were positive for anti-liver/kidney microsome-1 (anti-LKM-1) antibody and infected with the hepatitis C virus (HCV). Anti-LKM-1 was determined by indirect immunofluo-rescence and by the double immunodiffusion assays we have developed. Twenty-two patients did not present any unusual symptoms or any associated diseases during the course of their chronic HCV infection. The spectrum of HCV genotypes of these patients did not significantly differ from that of anti-LKM-1-negative Japanese patients with chronic hepatitis C. Histological examination of liver biopsy specimens showed the usual characteristics of chronic hepatitis C and lack of characteristics of autoimmune hepatitis type I. No disease-specific HLA haplotypes were noted, and HLA-DR4, which is detectable in 88.7% of Japanese patients with autoimmune hepatitis type I, was detected in only 50.0% of our group, the same rate as the background frequency. Prednisolone was effective in none of the six patients treated, but interferon was effective in six of ten treated patients (60%). From these results, we conclude that “autoimmune hepatitis type IIb” should not be categorized as autoimmune hepatitis, and that this subgroup is essentially chronic hepatitis C in which an autoantibody has been produced during the course of chronic HCV infection.     

Long-term outcome of Japanese patients with type 1 autoimmune hepatitis

The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment. CONCLUSION: Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse.     

Features and consequences of untreated type 1 autoimmune hepatitis

Background/Aim: The existence of a mild form of autoimmune hepatitis that does not require treatment remains controversial. The aim of this study was to determine the existence, characteristics and outcome of this form. Methods: Untreated patients with type 1 autoimmune hepatitis who did not satisfy pre‐established criteria for severe disease were identified retrospectively and compared with treated patients. Results: Twenty‐one of 282 patients (7%) who were evaluated during a 32‐year period did not receive corticosteroid treatment. These asymptomatic patients constituted 15% of 137 patients who satisfied similar criteria for mild disease. Untreated patients with mild disease were indistinguishable from 116 treated patients with mild disease, and they differed from 145 treated patients with severe disease only by the pre‐established features that defined disease severity. The eight untreated patients with follow‐up assessments satisfied remission criteria less commonly than treated patients with mild or severe disease during 77±31 months of observation (12 vs 63%, P=0.006), and they had a lower 10‐year survival (67 vs 98%, P=0.01). Four patients did improve spontaneously albeit short of remission criteria and remained well for 28±15 months (range, 5–73 months). Four patients worsened during 125±51 months of observation (range, 32–239 months), including two of three patients with cirrhosis who died of liver failure. Conclusions: Mild type 1 autoimmune hepatitis does exist, and it may be as frequent as severe disease. Untreated patients with mild disease can improve spontaneously, but there are no confident indices by which to identify this subgroup and justify withholding treatment.     

Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2

A new autoantibody was detected by immunoprecipitation in the serum of 21 patients with chronic active hepatitis. The antibody reacted against a soluble cytosolic antigen in liver. The antibody was organ specific but not species specific and was therefore called anti-liver cytosol antibody Type 1 (anti-LC1). In seven of 21 cases, no other autoantibody was found; the remaining 14 cases had anti-liver/kidney microsome antibody Type 1 (anti-LKM1). With indirect immunofluorescence, a distinctive staining pattern was observed with the seven sera with anti-LC1 and without anti-LKM1. The antibody stained the cytoplasm of hepatocytes from four different animal species and spared the cellular layer around the central veins of mouse and rat liver that we have called juxtavenous hepatocytes. The immunofluorescence pattern disappeared after absorption of sera by a liver cytosol fraction. The 14 sera with both antibodies displayed anti-LC1 immunofluorescent pattern after absorption of anti-LKM1 by the liver microsomal fraction. The anti-LC1 was found in the serum only in patients with chronic active hepatitis of unknown cause. Anti-LC1 antibody was not found in sera from 100 patients with chronic active hepatitis associated with anti-actin antibody classic chronic active hepatitis Type 1, 100 patients with primary biliary cirrhosis, 157 patients with drug-induced hepatitis and a large number of patients with liver and nonliver diseases. This new antibody was considered a second marker of chronic active hepatitis associated with anti-LKM1 (anti-LKM1 chronic active hepatitis) or autoimmune chronic active hepatitis Type 2.     

Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis.

BACKGROUND & AIMS: Polymorphisms that control cytokine production can affect immunoregulation. The frequency and consequences of these polymorphisms in type 1 autoimmune hepatitis were determined. METHODS: DNA samples from 155 patients and 102 ethnically similar normal individuals were assessed by polymerase chain reaction for polymorphisms of 4 different cytokine-producing genes. RESULTS: Only genotypes associated with the guanine to adenine substitution at position -308 of the tumor necrosis factor gene occurred more commonly in patients than in normal subjects (56% vs. 26%; P < 0.001). Patients with this polymorphism had the HLA DRB1*0301 allele (81% vs. 10%; P < 0.000001) and A1-B8-DRB1*0301 (66% vs. 0%; P < 0.000001) phenotype more frequently and HLA DRB1*04 alleles less often (24% vs. 67%; P < 0.000001). They also entered remission less commonly (56% vs. 78%; P = 0.01), had treatment failure more often (20% vs. 7%; P = 0.03), and developed cirrhosis more frequently (40% vs. 19%; P = 0.05). These latter differences, however, were not statistically significant by adjusted P value. CONCLUSIONS: A polymorphism of the tumor necrosis factor gene occurs more commonly in patients with type 1 autoimmune hepatitis than in normal subjects; it is associated with a poorer response to corticosteroids. The polymorphism may be inherited as part of the extended A1-B8-DRB1*0301 haplotype and may affect both disease expression and behavior.     

Chronic active hepatitis associated with liver-kidney microsomal antibody of an autoimmune type

We report the findings in two sisters with active cirrhosis and an anti-liver-kidney microsomal antibody (anti-LKM) of the autoimmune type. This unusual disease is characterized by the presence of high levels of antibodies that react with the smooth and rough endoplasmic reticulum of the liver and other tissues. Our patients had the usual features of chronic hepatitis associated with presence of antibodies: they were young girls, they had anti-LKM antibodies of autoimmune type persisting at a high titer during the whole course of the disease, but with no smooth muscle antibodies; one had a low level of IgA. The occurrence of two cases in the same family has not yet been reported and is probably not coincidental because of the rare occurrence of this disease.     

丙型肝炎抗体阳性的自身免疫性肝炎1例报告

正1病例资料患者女性,50岁,因"反复右胁部隐痛不适伴乏力1年余,加重1个月"入院。患者1年前无明显诱因下出现右胁部隐痛,伴乏力、腹胀、呃逆,呈进行性加重,自行服用中草药"鱼腥草",症状未见好转,后出现身目黄染,小便洗肉水样,至当地人民医院就诊,期间查"ALT900 U/L",诊断为"慢性丙型肝炎"。服用"多烯磷脂酰胆碱、复方甘草酸苷、双环醇、葡醛内酯、复合维生素B",病情控制欠佳。1年内反复5次转氨酶升     

Antimitochondrial antibody -M2 positive autoimmune hepatitis during standard of care for chronic hepatitis C

The current standard of care (SoC) for chronic hepatitis C, i.e. the combination of a pegylated-interferon (PEG-IFN) with ribavirin (RBV), may activate underlying autoimmune conditions. Particularly, interferon (IFN) has been known to induce or exacerbate autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) in hepatitis C virus patients. We describe a severe, acute-onset antimitochondrial antibody (AMA)-M2 positive AIH appearing during the last weeks of SoC in a woman with chronic hepatitis C and no previous history of autoimmunity, and resolving on protracted steroids. In this context, the relevance of the characterization of the immunoglobulin isotype of portal plasma cells for a more appropriate diagnosis of autoimmune liver diseases can be emphasized.     

Clinical characteristics of patients with autoimmune hepatitis seropositive for anticentromere antibody

Aim: Recent studies have revealed that primary biliary cirrhosis patients with anticentromere antibody (ACA) commonly develop portal hypertension. However, the clinical characteristics of autoimmune hepatitis (AIH) remain uncertain. We investigated the clinical features of patients with AIH seropositive for ACA (ACA‐AIH), comparing them with those of patients with AIH seropositive for other immunofluorescent patterns of antinuclear antibodies (ANA) (other‐AIH). Methods: AIH was diagnosed on the basis of the scoring system proposed by the International Autoimmune Hepatitis Group. Seropositivity for ACA was determined by a discrete speckled pattern on HEp‐2 cells by an immunofluorescent technique. The severity of histological grading and staging was evaluated by the histological activity index (HAI) score. Results: Eight (17%) of 47 patients with AIH had ACA. No significant differences in age, sex, onset pattern of the disease, progression to hepatic failure and relapse rate were present between the ACA‐AIH and other‐AIH groups. The frequency of concurrent autoimmune diseases in ACA‐AIH was significantly higher than that in other‐AIH (75% vs 36%, P = 0.0406). Biochemical analysis revealed a significantly lower mean immunoglobulin G (IgG) level than that in other‐AIH (2176 ± 641 vs 3013 ± 923 mg/dL, P = 0.0150). However, there were no differences in serum alanine aminotransferase levels, titers of ANA, HAI scores or the positive rate of human leukocyte antigen (HLA)‐DR4 between the groups. Conclusion: These results suggest that the emergence of ACA is not a distinct entity of AIH, despite its clinical characteristics of a significantly higher frequency of concurrent autoimmune diseases and lower serum IgG levels.     

Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of "autoimmune" hepatitis

Sixty-five patients with histologically proven chronic active hepatitis of unknown cause but associated with the antiliver/kidney microsome antibody type 1, confirmed by immunofluorescence and immunoprecipitation, were selected as forming a special entity. This disease was found to be rare with a prevalence of 5/1,000,000. The female to male ratio was 8:1. The condition occurred at all ages but was most common between the ages of 2 and 14 years. In 22 of the 65 cases, the hepatitis was associated with an autoimmune disease, most commonly insulin-dependent diabetes, autoimmune thyroid disease and vitiligo. The same autoimmune diseases were present in first-degree relatives from seven families. In 36 cases, the onset of disease resembled acute viral hepatitis. Serum biochemical tests showed marked elevation in aminotransaminases and hypergammaglobulinemia. Paradoxically, serum and salivary IgA levels were often normal or low. Histologic findings were multifocal hepatic necrosis with bridging in the acute stage, and aggressive hepatitis with mononuclear cell infiltration or macronodular cirrhosis in the late stages. Serologically, apart from the presence of antiliver/kidney microsome antibody type 1, the disease was characterized by the absence of antiactin, antimitochondria and antinucleus antibodies; however, organ-specific autoantibodies were often present. The clinical course was usually severe: six patients in the acute stage presented with fulminant hepatitis, and all, except two, other patients progressed to cirrhosis. Prolonged treatment with corticosteroids and immunosuppressants was usually effective in rendering the cirrhosis inactive. The cumulative survival rate was 51% at 14 years. We propose to call this entity "anti-LKM1 chronic active hepatitis" or "autoimmune hepatitis type II" to differentiate it from classical "lupoid hepatitis" or autoimmune hepatitis type I.     

Association of antipituitary antibody and type 2 iodothyronine deiodinase antibody in patients with autoimmune thyroid disease

Antipituitary antibody (APA) has been reported to be detected in patients with autoimmune thyroid disease. Type 2 iodothyronine deiodinase (D2) is expressed in both pituitary gland and thyroid gland. We studied the association of APA and D2 peptide antibody in patients with autoimmune thyroid disease. Rat pituitary gland homogenate and D2 peptide were used as antigens in the present study. APA and D2 peptide antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in sera obtained from 42 patients with Hashimoto's disease, 26 patients with Graves' disease and 70 healthy control subjects. Moreover, D2 activity precipitation assay was performed in some patients with Hashimoto's disease. APA and D2 peptide antibody were elevated in patients with Hashimoto's disease and patients with Graves' disease, compared with control subjects. APA was positive in 32.4% (22/68), D2 peptide antibody was positive in 26.5% (18/68) of patients with autoimmune thyroid disease. APA was positive in 31.0% (13/42) of patients with Hashimoto's disease and 34.6% (9/26) of patients with Graves' disease. D2 peptide antibody was positive in 26.2% (11/42) of patients with Hashimoto's disease and 26.9% (7/26) of patients with Graves' disease. D2 peptide antibody was correlated with APA in patients with autoimmune thyroid disease. Moreover, precipitation of D2 activity was increased in some patients with Hashimoto's disease including a patient who also had idiopathic diabetes insipidus, and was correlated with D2 peptide antibody. These results suggest that D2 antibody may be associated with APA in patients with autoimmune thyroid disease.     

Heterogeneity of liver/kidney microsomal antibody type 1 in autoimmune hepatitis and hepatitis C virus related liver disease.

Liver/kidney microsomal antibody type 1 (LKM-1), the serological marker of a subset of autoimmune hepatitis, is also present in a proportion of patients with hepatitis C virus (HCV) related chronic liver disease. To characterise further this autoreactivity and to evaluate whether an autoantibody giving an identical immunofluorescence staining, and detected in two different clinical conditions, involves the same antigenic target(s), sera from autoimmune and HCV infected patients were tested with native, recombinant, and synthetic antigens. Sixty five sera were selected on the basis of the typical immunofluorescence pattern: 50 patients had serological markers of HCV infection, the remaining 15 suffered from autoimmune hepatitis. The reactivity of each serum with rat and human microsomal fractions, full length human recombinant CYP2D6, and two synthetic peptides spanning the amino acid regions 257-269 and 373-398 of CYP2D6 was systematically investigated by immunoblotting. Fourteen (93%) sera from autoimmune hepatitis patients and 39 (78%) from HCV infected patients reacted with rat and/or human microsomal polypeptides of 39 kD, 50 kD, 58 kD, and 66 kD in different associations, the 50 kD band being the most frequently observed. Reactivity to CYP2D6 and its amino acid sequence 257-269 was significantly more common in autoimmune hepatitis than in HCV infected patients (p < 0.001 and p < 0.0003, respectively). LKM-1 reactivity is directed against heterogeneous and not entirely defined autoantigens. The main target in autoimmune sera is CYP2D6 and its 257-269 amino acid region, while sera from patients with HCV infection are more likely to recognise other microsomal targets, the molecular identity of which is currently unknown.