Autoimmune Chronic Active Hepatitis Research Articles

Autoimmune Hepatitis Markers in Association with Chronic Viral Hepatitis Type B and C

Circulating auto-antibodies have gained great significance for the diagnosis of autoimmune hepatitis (AIH) and various autoantibodies have been reported in patients infected by chronic viral hepatitis. Enzyme linked immunosorbent assay (ELISA) was used to assess these autoantibodies in the sera of 116 seropositive hepatitis B & C virus patients admitted to Baghdad Teaching Hospital from March 2009 to the end of December 2009. The presence of autoantibodies against cell nuclei (ANA), smooth muscle (SMA), liver- cytosol type-1 (anti LC1) and liver kidney microsome type1 (anti LKM-1) for all the affected patients' sera was measured. Antinuclear antibodies (ANA) results showed that 18 (16%) of cases revealed seropositive results, while anti- smooth muscle antibodies (SMA) results showed only two (2%) seropositive results both of which are of HCV patients. Results of anti LC-1 autoantibodies and anti LKM1 autoantibodies showed seropositivity in 6 (5%) and 8 (7%) cases, respectively, all of which are of HCV type. The current study suggest that chronic HCV infection can mimic autoimmune chronic active hepatitis; and special care must be held in patients who are unresponsive to immunosuppressive treatment, as HCV may be the role here.

Approach to the patient with acute severe autoimmune hepatitis.

SummaryAutoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.

2402 A Rare Case of IPEX Syndrome With Hepatic Complications

INTRODUCTION: Immunodysregulation, polyendocrinopathy and enteropathy X-linked (IPEX) Syndrome is a rare autoimmune illness affecting only males starting in the early few months of life. It can be associated with autoimmune hepatitis among other systemic ailments and ultimate treatment is immunosuppression or bone marrow transplant. We present a case of undiagnosed IPEX Syndrome leading to liver failure requiring eventual liver transplantation. CASE DESCRIPTION/METHODS: A 19 year-old male patient had undergone a liver transplant at age 2 for suspected autoimmune hepatitis resulting in acute liver failure. No specific cause was identified at time of diagnosis. He remained on chronic immunosuppression thereafter, eventually progressing to chronic active autoimmune hepatitis in the transplanted liver. He was diagnosed with IPEX Syndrome at age 16, for which he underwent a bone marrow transplant. He presented to the hospital with neutropenia, and hepatology was consulted for liver transplant rejection in light of mild transaminitis. On admission, vital signs were normal and pertinent labs include: AST/ALT 50/74 units/L, Alkaline Phosphatase 811 IU/L, Albumin 3.4 g/dL, WBC 0.6 × 109 cells/L. He reportedly had multiple episodes of acute rejection in the past which were treated with steroids. Chronically, he was on mycophenolate mofetil, tacrolimus, and prednisone. His liver biopsy did not show evidence of acute rejection, but suggested chronic rejection and liver fibrosis. A prior liver biopsy had suggested autoimmune hepatitis, but no evidence of a flare on current biopsy. He was continued on his current immunosuppression regimen, and he was subsequently discharged home. DISCUSSION: Due to its rarity, incidence of IPEX syndrome is not entirely known, but is estimated to be 1 in 1,609,490. Generally, it is diagnosed in infancy and is often fatal. Our case is unique as the diagnosis was missed for more than a decade during which period the patient had even received a liver transplant for autoimmune hepatitis. Autoimmune hepatitis reportedly occurs in 20% of patients with IPEX Syndrome. There are currently no reports of liver failure requiring liver transplant in such scenarios. The fact that our patient developed recurrent autoimmune hepatitis in the transplanted liver highlights the underlying defect in his genetic disorder. This case should serve as a reminder to clinicians to consider IPEX syndrome in the differential for early onset autoimmune hepatitis, as early diagnosis could reduce significant morbidity.

Psoriasis and Hashimoto's thyroiditis in a child with down syndrome

Down syndrome (DS), or trisomy 21, is the most common chromosomal disorder. DS has been associated with autoimmune diseases including autoimmune thyroiditis, Type 1 diabetes mellitus, celiac disease, autoimmune chronic active hepatitis, alopecia, vitiligo, hypoparathyroidism, psoriasis, and psoriatic arthritis. To our knowledge, we herein report the first concurrence of psoriasis and Hashimoto's thyroiditis in an individual with DS, emphasizing the predisposition of DS individuals to autoimmune diseases.

Comparison of the serological tests ICT and ELISA for the diagnosis of alveolar echinococcosis in France.

Serological diagnosis of alveolar echinococcosis (AE) is a key element for efficient patient treatment management. A rapid immunochromatography test kit (ICT) using the recombinant Em18 antigen (rEm18) was recently developed. The aim of our study was to assess this test on a panel of sera from French patients with alveolar echinococcosis and control patients. In a blind test, a total of 112 serum samples were tested including samples of AE (n = 30), cystic echinococcosis [CE] (n = 15), and polycystic echinococcosis [PE] (n = 1). For the comparison, 66 sera from patients with hepatocarcinoma, fascioliasis, toxocariasis, Caroli’s disease, or autoimmune chronic active hepatitis were used. The diagnostic test sets we used were the rEm18-ICT and two validated ELISAs with rEm18 and Em2-Em18 antigens, respectively. For the ICT, 27/30 sera from AE patients, 4/15 sera from CE patients and the PE patient serum were positive. One serum from the control panel (toxocariasis) was positive for the ICT. The rEm18-ICT sensitivity (90.0%) and specificity (92.7%) for detection of Em18-specific antibodies confirmed it as a relevant tool for AE diagnosis. The rEm18-ELISA had a sensitivity of 86.7% and specificity of 91.5%, and the Em2-Em18-ELISA had a sensitivity of 96.7% and specificity of 87.8%. However, when AE patient sera are recorded as weak in intensity with the ICT, we recommend a double reading and use of a reference sample if the ICT is used for patient follow-up.

Letter: treatment of autoimmune acute liver failure - beyond consensus guidelines; author's reply

AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Sirs, Dr Fujiwara and colleagues emphasise three key concepts in the diagnosis and management of acute severe (fulminant) autoimmune hepatitis.1 First, its occurrence is underestimated in most experiences. The abrupt onset of the disease may not allow the classical phenotype to emerge, and patients may lack hypergammaglobulinemia, high titres of autoantibodies and classical histological patterns.2 Furthermore, the concept that an archetypal form of chronic hepatitis can present de novo as acute liver failure may not be uniformly entrenched in clinical practice. Second, the diagnosis can be difficult. Classical features may be absent or altered; diagnostic scores by the comprehensive international scoring system may be low; and liver tissue examination may be avoided.3 Doctor Fujiwara and colleagues have already emphasised the importance of liver tissue assessment in the evaluation of these patients,4 and they have indicated that the presence of heterogeneous hypoattenuated areas within the liver by unenhanced computerised tomography is another means of supporting the diagnosis.5 Third, corticosteroid therapy can be life-saving, but it cannot be indefinite. Septic complications can occur and jeopardise the opportunity for successful liver transplantation.6 Patients with multilobular necrosis at presentation who fail to improve at least one liver test within 2 weeks of treatment7 and icteric patients who do not improve mathematical models of end-stage liver disease by at least 2 points within 7 days of therapy have dismal outcomes,8 and they must be considered for liver transplantation. Worsening of any feature during treatment also compels this intervention. A decision regarding the appropriate strategy must be made within 7–14 days.9 The Japanese experience has taught us much about the nature and behaviour of autoimmune hepatitis, and we are indebted to Dr Fujiwara and colleagues for their insights. Acknowledgement The author's declarations of personal and financial interests are unchanged from those in the original article.10 References 1Fujiwara K, Yasui S, Yokosuka O. Letter: treatment of autoimmune acute liver failure – beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38: 1143– 4. 2Yasui S, Fujiwara K, Yonemitsu Y, Oda S, Nakano M, Yokosuka O. Clinicopathological features of severe and fulminant forms of autoimmune hepatitis. J Gastroenterol 2011; 46: 378– 90. 3Abe M, Hiasa Y, Masumoto T, et al. Clinical characteristics of autoimmune hepatitis with histological features of acute hepatitis. Hepatol Res 2001; 21: 213– 9. 4Fujiwara K, Fukuda Y, Yokosuka O. Precise histological evaluation of liver biopsy specimen is indispensable for diagnosis and treatment of acute-onset autoimmune hepatitis. J Gastroenterol 2008; 43: 951– 8. 5Yasui S, Fujiwara K, Okitsu K, Yonemitsu Y, Ito H, Yokosuka O. Importance of computed tomography imaging features for the diagnosis of autoimmune acute liver failure. Hepatol Res 2012; 42: 42– 50. 6Ichai P, Duclos-Vallee JC, Guettier C, et al. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl 2007; 13: 996– 1003. 7Czaja AJ, Rakela J, Ludwig J. Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis. Gastroenterology 1988; 95: 448– 53. 8Yeoman AD, Westbrook RH, Zen Y, et al. Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis. Hepatology 2011; 53: 926– 34. 9Czaja AJ. Corticosteroids or not in severe acute or fulminant autoimmune hepatitis: therapeutic brinksmanship and the point beyond salvation. Liver Transpl 2007; 13: 953– 5. 10Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38: 343– 64. Volume38, Issue9November 2013Pages 1144-1144 ReferencesRelatedInformation

Fréquence et facteurs prédictifs de récidive de l’hépatite auto-immune

In a restrospective study of 84 patients with chronic viral hepatitis (64 HCV and 20 HBV), we report 7 cases of auto-immune chronic active hepatitis « type Iassociated with HCV. The frequency of clinic or biologic patterns of auto-immunity is greater in HCV chronic hepatitis than in HBV, the more often in women older aged and presenting cirrhosis or severe active hepatitis. The question of the treatment remains: 6 patients were steroid-resistant, one received α interferon without any improvement.

Slipped upper femoral epiphysis in Hashimoto’s thyroiditis in a 29-year-old man

Slipped upper femoral epiphysis (SUFE) with an open physis is rare in an adult and the condition may present without prior diagnosis of an underlying medical condition. We have treated a 29-year-old man with bilateral SUFE associated with autoimmune hypothyroidism. The management was delayed and complicated by co-existing autoimmune chronic active hepatitis. He underwent thyroxine therapy and bilateral pinning in situ with a single ASNIS screw. Closure of the physis occurred after five months on the right side. The left side required a further corrective intertrochanteric osteotomy, and it was only after 13 months that complete fusion of this physis was seen. The case highlights the need to consider endocrine and metabolic conditions in atypical presentation of SUFE.

Early onset of type I diabetes mellitus, Hashimoto’s thyroiditis and celiac disease in a 7-yr-old boy with Down’s syndrome

Patients with Down's syndrome are at higher risk for developing autoimmune diseases than those of the general population. Autoimmune diseases like Hashimoto's thyroiditis, Graves' disease, diabetes mellitus type I, celiac disease, autoimmune chronic active hepatitis, alopecia, vitiligo and hypoparathyroidism are recognized associations with Down's syndrome. We describe the case of a very young boy with Down's syndrome who was diagnosed with diabetes mellitus type I, Hashimoto's thyroiditis and celiac disease before 8 yr of age. Unspecific symptoms like weight loss, unstable blood sugar with high amplitudes, behavioural problems and dry skin were suspicious for other endocrine disorders or celiac disease in our case. The boy was showing the typical human leukocyte antigen profile for these autoimmune diseases. The prevalence of these autoimmune diseases is higher in Down's syndrome than in general population. Therefore, we advice to follow children with Down's syndrome who develop more than two autoimmune diseases very carefully.

High serum levels of CD8 antigen in primary biliary cirrhosis: a possible cause of suppressor cell dysfunction?

Reduced suppressor cell number and function have been described in a number of autoimmune diseases and this may contribute to pathogenesis. Suppressor cell function depends upon the interaction of the CD8 antigen expressed on suppressor cells with other limbs of the immune system. Recently, soluble membrane antigens including CD8 have been identified in serum and it is possible that the loss of such antigens from viable cells could result in functional deficit. In order to examine whether the decreased suppressor cell function reported in autoimmune type of chronic liver disease is associated with soluble serum CD8 levels, sera from 23 patients with primary biliary cirrhosis (PBC), 12 with autoimmune chronic active hepatitis (AI-CAH) and 21 healthy controls were tested using a commercially available enzyme immunoassay. The proportion of cells expressing the CD8 antigen and the intensity of its display were also determined using an immunofluorescent technique and an ELISA, respectively, for 12 PBC and 10 healthy controls. The soluble serum CD8 levels were significantly higher in PBC (mean U/ml +/- s.d., 777 +/- 331), and AI-CAH (575 +/- 291) than controls (322 +/- 115) (P less than 0.001 and P = 0.004, respectively). While the intensity of CD8 antigen expression on suppressor/cytotoxic populations was not significantly different in PBC (347 +/- 125 per 10(4) cells) compared with controls (441 +/- 206), the mean proportion of CD8 positive cells was significantly less in PBC (14.1 +/- 6.8%) than controls (20 +/- 4.7%) (P less than 0.05). These data suggest that the apparent reduction in suppressor cell number found for patients with PBC and AI-CAH may be a consequence of the shedding or secretion of CD8 antigen from cell membrane of CD8 positive lymphocyte. It is also possible that the loss of this antigen is responsible for the reduced suppressor cell function seen in these conditions.

Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease.

To study the possible role of T cells bearing the gamma delta T cell receptor (TCR) heterodimer in the pathogenesis of autoimmune chronic active hepatitis (AI-CAH) and primary sclerosing cholangitis (PSC) in children, we measured levels of gamma delta+ T cells in the peripheral blood, assessed the proportion of cells bearing the disulphide-linked (BB3+) and non-disulphide-linked (A13+) subtypes of the receptor, and studied the co-expression of TCR-gamma delta and the activation markers HLA-DR and IL-2 receptor (IL-2R), and the memory cell marker CD45RO. Percentage levels and absolute numbers of gamma delta +T cells were higher in both groups of patients than in controls (P less than 0.01), mainly as a result of an increase in both percentage levels and absolute numbers of the A13+ subtype (P less than 0.001). Co-expression of IL-2R and TCR-gamma delta was not found in controls but was present in some patients with AI-CAH (four out of 17) and PSC (six out of 12) at low levels (median 2.3%, range 1.7-5.0%). Expression of HLA-DR on gamma delta+ T cells was similar in both groups of patients and controls. The majority of gamma delta+ T cells in children with AI-CAH and PSC also expressed CD45RO (74.7 +/- 18.4% and 79.8 +/- 24.3%, respectively) at levels significantly higher than in controls (53.3 +/- 17.2%, P less than 0.01). These results suggest that autoimmune liver diseases in children are associated with an expansion and activation of gamma delta+ T cells in the peripheral blood, which may be important in the pathogenesis of these disorders.

Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis

Autoantibodies against microsomal antigen of liver and kidney (LKM-1) are diagnostic markers for a subgroup of autoimmune chronic active hepatitis (AI-CAH). Cytochrome P450dbl, now classified as cytochrome P450 IID6, is the major antigen of LKM-1 antibodies. Immunohistological studies suggest that hepatic injury in AI-CAH is mediated by liver-infiltrating T cells. In the present study the specificity and function of liver-infiltrating T cells was analysed at the clonal level. Phenotypical characterization of 189 T cell clones isolated from four liver biopsies of LKM-1 antibody-positive patients showed an enrichment of CD4+ CD8- T cell clones proliferated specifically in the presence of recombinant human LKM-1 antigen (rLKM). This reaction was restricted to autologous antigen-presenting cells and to HLA class II molecules. In order to see whether rLKM was also recognized by peripheral blood T lymphocytes (PBL) we tested the proliferative response of PBL from several individuals. PBL from three of the four patients with LKM-1 antibody-positive AI-CAH proliferated to rLKM, whereas no response was seen with PBL from patients with LKM-1 antibody-negative chronic liver diseases and from healthy blood donors. These data demonstrate that the LKM-1 antigen is recognized by liver-infiltrating T cells in LKM-1 antibody-positive AI-CAH. For further functional characterization, liver-derived T cell clones were tested for their cytotoxic activity. In the presence of phytohaemagglutinin 24 out of 26 CD4- CD8+ but also 20 out of 63 CD4+ CD8- T cell clones lysed autologous as well as allogenic EBV-transformed B cell lines or K562 cells. Five CD4- CD8+ T cell clones lysed autologous but not allogenic B cell lines spontaneously in a HLA class I-restricted manner. Although the antigen specificity of these clones is still unknown the data show the presence of autoreactive T cells at the site of inflammation that could contribute in the pathogenesis of AI-CAH.

Liver-infiltrating T helper cells in autoimmune chronic active hepatitis stimulate the production of autoantibodies against the human asialoglycoprotein receptor in vitro.

Autoantibodies against the human asialoglycoprotein receptor (ASGPR) occur in the sera of patients with autoimmune liver disorders. Liver-infiltrating T cell clones that specifically recognize the ASGPR have been described in patients with autoimmune chronic active hepatitis (AI-CAH) and primary biliary cirrhosis (PBC). Recently, we have shown that peripheral blood mononuclear cells (PBMC) from patients with AI-CAH or PBC but not chronic viral hepatitis secreted anti-ASGPR antibodies in vitro. In this study we characterized the influence of liver-infiltrating T cells on the secretion of ASGPR-specific autoantibodies by autologous B cells in cell culture supernatants. T cell clones from liver biopsies of three patients with chronic autoimmune liver disorders (one with AI-CAH, two with PBC) were isolated and investigated for their proliferative response to soluble ASGPR and their helper function provided to autoantibody-secreting B lymphocytes. PBMC from these patients secreted autoantibodies spontaneously in their cell culture supernatants and showed a proliferative response to ASGPR. T cell-depleted PBMC, however, lacked spontaneous antibody secretion. Four CD4+CD8- liver-infiltrating T cell clones showed a proliferative response to ASGPR and also induced spontaneous anti-ASGPR antibody production in cell culture supernatants when added to autologous T cell depleted PBMC. Activated supernatants of these T cell clones failed to induce antibody production. None of seven CD4+CD8- and two CD4-CD8+ T cell clones non-responding to ASGPR provided this help for antibody secretion. Anti-ASGPR secretion in vitro could not be inhibited by the addition of MoAbs raised against monomorphic determinants on HLA class II molecules. The addition of purified ASGPR or polyclonal-activating pokeweed mitogen showed no influence on the production of autoantibodies in these cultures. These data show that B lymphocytes require T cell help for the production of ASGPR-specific antibodies. This help can be provided by ASGPR-responsive T helper cells via cellular interactions.

Antibodies against sulphatide in sera from patients with autoimmune rheumatic diseases.

We tested sera of patients with various autoimmune rheumatic diseases for the presence of antibodies against sulphatide (an acidic glycosphingolipid), identified as a target antigen for antibodies against the liver cell membrane. Thirty-five percent (7/20) of patients with lupus in the active stage possessed anti-sulphatide antibodies, whereas 10% (2/20) of those in the inactive stage and 20% (4/20) of those in the stationary stage possessed such antibodies. Moreover, 10% (3/29) of patients with other autoimmune rheumatic diseases also possessed anti-sulphatide antibodies. The level of anti-sulphatide antibodies was significantly correlated with the levels of anti-double-stranded (ds) DNA antibodies (r = 0.634, P less than 0.001) and dextran sulphate-binding IgG (r = 0.407, P less than 0.001). The serum levels of antibodies against sulphatide were correlated with a history of seizures or psychosis in patients with autoimmune rheumatic diseases. Gels coupled with polyanionic dextran sulphate, monoanionic sulphanilic acid and DNA were shown effectively to adsorb anti-sulphatide antibodies in the sera of patients with active systemic lupus erythematosus (SLE) and autoimmune chronic active hepatitis (AI-CAH). These results suggest that the observed reactivity with sulphatide is due to the presence of antibodies capable of reacting with various anionic molecules in the sera of patients with autoimmune rheumatic diseases as well as those with AI-CAH.

Anti-LKM-1 antibodies determined by use of recombinant P450 2D6 in ELISA and western blot and their association with anti-HCV and HCV-RNA.

Several subtypes of anti-liver-kidney microsome antibodies (LKM) are known. LKM-1 antibodies associated with autoimmune chronic active hepatitis recognize P450 2D6, a cytochrome P450 mono-oxygenase. The frequent association of anti-LKM-1 antibodies and hepatitis C virus (HCV) infections and the probable existence of an infectious and autoimmune form of anti-LKM-1-associated hepatitis, requiring different therapeutical strategies, necessitates the exact determination of anti-LKM-1 specificities. Therefore, we compared various antibody tests (immunofluorescence, ELISA with recombinant P450 2D6, and Western blot with recombinant and natural antigens and agargel double diffusion) with sera of 27 anti-LKM-1-positive chronic active hepatitis (CAH) patients, with 61 sera harbouring anti-mitochondrial antibodies, 100 sera each from HCV-RNA-positive and HCV-RNA-negative patients, and 50 sera of healthy persons. Western blot techniques using recombinant MS2-polymerase P450 2D6 fusion protein were found to be the most sensitive and specific method for anti-LKM-1 antibody determination in routine laboratory. The recently recognized association of anti-LKM-1 antibody and HCV infection was confirmed by the results of this study. In anti-HCV and HCV-RNA-positive patients with anti-LKM-1 antibodies there was a preponderance of males with higher mean age and lower antibody titres. The results support the hypothesis of the existence of an autoimmune as well as an infectious (HCV triggered) subgroup of anti-LKM-1-positive hepatitis.

Immunoserologic differentiation of chronic cholestatic hepatitis. Significance of antimitochondrial antibodies and hepatic membrane antibodies

In 22 of 45 patients with chronic cholestatic liver inflammation and humoral immune phenomena, followed over 15 years with at least one liver biopsy, there was the histological picture of primary biliary cirrhosis (PBC), stages I to IV, with constantly demonstrable antimitochondrial antibodies (AMA) of M2-type. In 12 patients there were signs of PBC and chronic active hepatitis (CAH) in the liver histology, and they were M2-positive. Six of them also had M4-antibodies and were thus classified as 'mixed form'. The other six were seropositive for liver-membrane antibodies (LMA) and (or) antinuclear antibodies (ANA) and thus demonstrated an overlap between PBC and autoimmune or lupoid CAH. In five patients there was autoimmune CAH of lupoid type, in four of them with LMA or ANA without M2- or M4-antibodies. The remaining six patients had pericholangitis with persisting ANA and increased serum concentrations of immunoglobulin M without M2- and M4-antibodies, as well as LMA. Clinically a nondestructive polyarthritis predominated without definite signs of collagenosis. The listed immunoserological parameters make it largely possible to differentiate classical PBC, mixed forms or overlap of PBC and CAH, autoimmune CAH and nonpurulent cholangitis of pericholangitic type.

Relapse following treatment withdrawal in patients with autoimmune chronic active hepatitis.

A prospective study was performed to evaluate the outcome of treatment withdrawal in 30 patients with "autoimmune" chronic active hepatitis in remission for periods of 1.5 to 9 years on maintenance corticosteroid and azathioprine therapy. Reactivation of disease, with marked rises in serum aminotransferase level (mean 668 +/- S.D. 458 IU per liter) and accompanied by severe symptoms, occurred in 25 (87%) patients within 52 weeks (median 9 weeks; range 5 to 52) and was associated with the histological features of piecemeal necrosis and lobular hepatitis in all 20 liver biopsies examined. Age, sex, duration of disease and remission, presence of cirrhosis, autoantibody status, or immunoglobulin levels did not differentiate patients who relapsed from those who remained in remission. The response to reinstitution of treatment with prednisolone was satisfactory in 25 patients and clinical and biochemical abnormalities resolved within 10 weeks (median 6; range 3 to 10), death occurred in one patient within 48 hr of readmission to hospital.

An 8-year-old boy with autoimmune hepatitis and Candida onychosis as the first symptoms of autoimmune polyglandular syndrome (APS1): identification of a new homozygous mutation in the autoimmune regulator gene (aire)

An 8-year-old boy presented in 1995 with a 2-year history of hypertransaminasemia and hypergammaglobulinemia. Afterwards the patient displayed onychosis with a positive culture test for Candida albicans (CA). Because of the persistence of hypertransaminasemia, a percutaneous liver biopsy was performed showing 'low grade chronic active autoimmune hepatitis' (AIH), positive for liver-kidney microsomal autoantibodies and antibodies to the hepatic autoantigen cytochrome P450-1A2. Immunosuppressive treatment was initiated. In 2003 he developed Addison's disease resulting in the diagnosis of autoimmune polyendocrinopathy candidiasis-ectodermal dysplasia (APECED) syndrome, also known as autoimmune polyendocrine syndrome type 1 (APS1). Anti-17OH hydroxylase antibodies tested negative, anti-21-OH hydroxylase autoantibodies were positive. Among the other relevant organ- and non organ- specific autoantibodies, aromatic L-amino acid decarboxylase (ADDC) autoantibodies and anti-tryptophan hydroxylase autoantibodies were positive. The patient also presented polyuria and polydypsia with diabetes insipidus. Because of the presence of two diagnostic criteria of APS1, mutations in the autoimmune regulator gene (AIRE) were performed, which revealed the presence of a novel mutation (c1314- 1326 del 13/insGT) in exon 11. In conclusion, the diagnosis of APECED should be suspected in any child with minimal hypertransaminasemia, anti-microsomal autoantibodies and Candida albicans onychosis.

Hepatocyte membrane-bound IgG and circulating liver-specific autoantibodies in chronic liver disease: relation to hepatitis B virus serum markers and liver histology.

Hepatocytes isolated from 101 biopsies were examined for membrane-bound IgG. The sera of the patients were tested for anti-liver-specific lipoprotein by radioimmunoassay and for liver membrane autoantibody (by indirect immunofluorescence on isolated rabbit hepatocytes. The seven patients with normal liver or minor nonspecific alterations were negative for membrane IgG and serum antibodies. Membrane IgG with granular distribution was found in 41 patients [21 hepatitis B virus-related chronic active hepatitis (CAH), 3 cryptogenic CAH, 3 chronic persistent hepatitis, 6 prolonged viral hepatitis, 1 alcoholic cirrhosis, and 6 primary biliary cirrhosis]. Membrane IgG with linear fluorescence pattern was detected in 12 cases (4 autoimmune CAH, 3 HBsAg-positive CAH, 2 alcoholic cirrhosis, 1 anti-HBc positive CAH, 1 cryptogenic CAH, and 1 prolonged viral hepatitis). A strong association between granular IgG and serum HBsAg was found. Nuclear localization of IgG was found in 34 patients and correlated with the positivity of granular membrane IgG. The highest prevalence of anti-liver-specific lipoprotein was found in primary biliary cirrhosis and autoimmune CAH cases which were also positive for liver membrane autoantibody. No relationship was found between the presence of membrane IgG and circulating liver-specific autoantibodies. Membrane IgG and anti-liver-specific lipoprotein correlated with the presence of moderate and severe portal inflammatory infiltration but not with piecemeal necrosis or transaminase levels. Eleven of the twelve patients with linear membrane IgG presented chronic active liver disease with moderate to severe signs of liver damage. Therefore, it is suggested that, while granular membrane IgGs are related to hepatitis B virus, antigenic expression on the hepatocyte surface and/or the presence of immune complexes, linear membrane IgG could play a role in the immunopathogenesis of liver cell damage particularly in "autoimmune" cases which present high percentages of positive cells liver-specific autoantibodies.

Haematogenous metastasis to ascending colon in a patient with hepatocellular carcinoma and autoimmune hepatitis

The association of hepatocellular carcinoma with chronic active autoimmune hepatitis and haematogenous metastasis to ascending colon has not been reported previously in the literature. The patient was asymptomatic for colonic disease and the finding of colonic involvement was incidental on scans subsequently confirmed by colonoscopy. Usually hepatocellular tumour mass would involve the colon by direct contiguity. Owing to haematogenous metastasis, which is extremely rare, the colonic mass was discontiguous from hepatic tumour lesions. The unique presentation of this case and the differential diagnosis of hepatic tumours coexisting with colonic tumours are highlighted in this case report.