Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis

Background/Aims: Autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis are chronic liver diseases with probable autoimmune background. Overlapping features have been described for primary biliary cirrhosis and autoimmune hepatitis. In contrast, there have been only a few case reports on an overlap of autoimmune hepatitis and primary sclerosing cholangitis.Methods: We describe three male patients with clinical and histological overlapping features of primary sclerosing cholangitis and autoimmune hepatitis.Results: All initially asymptomatic patients had elevated levels of aminotransferases, alkaline phosphatase, γ-glutamyltranspeptidase and IgG. Anti-nuclear antibodies and/or smooth muscle antibodies were positive and anti-neutrophil cytoplasmic antibodies were detected in all patients. Retrograde endoscopic cholangiography showed bile-duct strictures characteristic for primary sclerosing cholangitis. Histopathology showed necro-inflammatory activity of portal tracts with bridging necrosis in all patients at the time of first diagnosis. Aminotransferase levels and the necro-inflammatory activity responded well to immuno-suppressive treatment. Predominant periductular fibrosis as a typical histopathological feature of primary sclerosing cirrhosis was seen to develop in all patients. Cholestatic serum parameters remained elevated and periductular fibrosis as endoscopic bile duct changes progressed despite immunosuppression.Conclusions: We suggest that these patients present an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis as they fulfill the diagnostic criteria for both conditions.     

Liver transplantation in autoimmune liver diseases

Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.     

Shared Genetic Risk Factors in Autoimmune Liver Disease

To determine if shared genetic risk factors for autoimmune liver disease affect clinical manifestations, we evaluated 271 patients and 92 normal subjects by DNA-based techniques. Genetic risk factors were intermixed in all conditions, and frequency varied according to disease type. DR4 distinguished autoimmune hepatitis (P = 0.0002) and primary biliary cirrhosis (P = 0.004) from primary sclerosing cholangitis. DR52 distinguished primary sclerosing cholangitis from autoimmune hepatitis (P = 0.0007) and primary biliary cirrhosis (P = 0.00007) and DR3 distinguished autoimmune hepatitis (P = 0.002) and primary sclerosing cholangitis (P = 0.0005) from primary biliary cirrhosis. Only the occurrence of DR4 in primary sclerosing cholangitis was lower than in normal subjects (P = 0.02). Patients with mixed genetic risk factors did not have distinctive features or manifestations of hybrid conditions. We conclude that patients with shared genetic risk factors do not have characteristic features nor do they have overlap syndromes. DR4 may be protective against primary sclerosing cholangitis.     

Antineutrophil cytoplasmic autoantibodies in autoimmune liver and inflammatory bowel diseases

Abstract: Perinuclear antineutrophil cytoplasmic autoantibodies have been described in inflammatory bowel diseases and in primary sclerosing cholangitis. Because the data concerning their occurrence are conflicting, we have used indirect immunofluorescence on ethanol-fixed neutrophils to test the sera from a large population of 382 patients with various liver and digestive diseases: in particular, from 27 patients with primary sclerosing cholangitis, 105 patients with autoimmune chronic active hepatitis, 30 patients with primary biliary cirrhosis and 124 patients with inflammatory bowel disease. The prevalence of the perinuclear antineutrophil cytoplasmic autoantibodies was 37% in ulcerative colitis and 15% in Crohn's disease. They would not be helpful in the differential diagnosis between these two inflammatory bowel diseases. Within the group of autoimmune liver diseases, perinuclear antineutrophil cytoplasmic autoantibodies were detected in 44% of sera from patients with primary sclerosing cholangitis and in 36% of sera from patients with type I autoimmune active hepatitis, but not in primary biliary cirrhosis. When primary sclerosing cholangitis was associated with an inflammatory bowel disease, the prevalence of these autoantibodies was 60%. They were 88% specific for primary sclerosing cholangitis and 86% specific for type I autoimmune active hepatitis. Despite their moderate sensitivity and specificity in primary sclerosing cholangitis, they remain the only serologic marker of this autoimmune liver disease. Moreover, they turned out to be a more sensitive marker for inflammatory bowel disease with associated primary sclerosing cholangitis     

Co-existence of primary biliary cirrhosis and primary sclerosing cholangitis: a rare overlap syndrome put in perspective

Overlap syndromes between autoimmune hepatitis and both primary biliary cirrhosis and primary sclerosing cholangitis are well described, but overlap between primary biliary cirrhosis and primary sclerosing cholangitis is not recognized. We present two cases of an unusual autoimmune liver disease, both of which included an overlap between primary biliary cirrhosis and primary sclerosing cholangitis, while one had features of all three conditions. The diagnoses were based on clinical, biochemical, serological, histological and cholangiographic findings. The two cases were identified from a consecutive cohort of 261 patients with autoimmune liver disease followed prospectively in secondary care over a 20-year period, which gives perspective to this uncommon overlap syndrome.     

Polymorphisms in tumour necrosis factor alpha, interleukin-10 and transforming growth factor beta1 genes and end-stage liver disease

OBJECTIVE: To determine any relationship between polymorphisms in the genes encoding tumour necrosis factor alpha (TNFalpha), interleukin-10 (IL-10) and transforming growth factor beta1 (TGFbeta1) and end-stage liver disease. METHODS: Whole-blood samples were taken from patients attending the Scottish Liver Transplant Unit with end-stage liver disease (primary biliary cirrhosis, n = 61; alcoholic liver disease, n = 25; primary sclerosing cholangitis, n = 17; viral disease, n = 8; type 1 auto-immune hepatitis, n = 8; acute liver failure, n = 20). DNA was extracted and the polymorphisms at positions TNF -308, IL-10 -1082 and TGFbeta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Samples were also analysed from normal healthy controls. RESULTS: There was a significant difference between patients with primary sclerosing cholangitis and healthy controls, with 65% of patients (11/17) possessing at least one TNF2 allele (A at position -308) compared with 38% of controls (P = 0.02). Four of the eight patients with auto-immune hepatitis were homozygous for TNF2 while the other four were heterozygous (P = 0.001). No significant difference between controls and patients was seen in polymorphisms for IL-10 or TGFbeta1. No association between genotype and Child's class was found in primary biliary cirrhosis. CONCLUSION: Patients with primary sclerosing cholangitis and auto-immune hepatitis are more likely to possess TNF2 than normal controls. This allele has been associated with an increased production of TNFalpha in vitro and may indicate a predisposition to these inflammatory conditions.     

Clinical significance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver diseases

BACKGROUND/AIMS: The clinical relevance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver disease is unclear. Defining the antigenic specificities of ANCA in these diseases may improve their clinical significance. METHODS: We studied the target antigens of ANCA in 88 patients with autoimmune hepatitis, 53 patients with primary biliary cirrhosis, and 55 patients with primary sclerosing cholangitis by indirect immunofluorescence, antigen-specific enzyme-linked immunosorbent assays, and immunodetection on Western blot, using an extract of whole neutrophils as a substrate. We related the data to clinical symptoms of autoimmune liver disease. RESULTS: By indirect immunofluorescence, ANCA were present in 74% of patients with autoimmune hepatitis, 26% of patients with primary biliary cirrhosis, and 60% of patients with primary sclerosing cholangitis. Major antigens were catalase, alpha-enolase, and lactoferrin. The presence of ANCA as detected by indirect immunofluorescence was associated with the occurrence of relapses in autoimmune hepatitis, with decreased liver synthesis function in primary biliary cirrhosis and in primary sclerosing cholangitis, and with increased cholestasis in primary sclerosing cholangitis. ANCA of defined specificities had only limited clinical relevance. CONCLUSIONS: ANCA as detected by indirect immunofluorescence seem associated with a more severe course of autoimmune liver disease. The target antigens for ANCA in these diseases include catalase, alpha-enolase, and lactoferrin. Assessment of the antigenic specificities of ANCA in autoimmune liver disease does not significantly contribute to their clinical significance.     

High prevalence of small duct primary sclerosing cholangitis among patients with overlapping autoimmune hepatitis and primary sclerosing cholangitis

BackgroundOverlap syndrome is a term used for overlapping features of autoimmune hepatitis and primary sclerosing cholangitis or primary biliary cirrhosis and for autoimmune cholangitis. We describe a high prevalence of small duct primary sclerosing cholangitis among patients with overlapping autoimmune hepatitis and primary sclerosing cholangitis.MethodsWe sought to retrieve all patients with overlap syndrome between primary sclerosing cholangitis and autoimmune hepatitis in six university hospitals in Sweden. The revised autoimmune hepatitis scoring system proposed by the International Autoimmune Hepatitis Group was used to establish the diagnosis autoimmune hepatitis. Endoscopic retrograde cholangiography and/or magnetic resonance cholangiography were used to separate the primary sclerosing cholangitis cases diagnosed through liver biopsy into small and large primary sclerosing cholangitis. A histologocial diagnosis compatible with both autoimmune hepatitis and primary sclerosing cholangitis was required for inclusion.Results26 patients fulfilled our criteria for histological overlap of autoimmune hepatitis and primary sclerosing cholangitis, 7 (27%) of which had small duct primary sclerosing cholangitis. The reliability of the diagnosis small duct primary sclerosing cholangitis was supported by a very close similarity between small and large duct primary sclerosing cholangitis patients in clinical and laboratory data, and by a poor response to immunosuppressive therapy in the small duct primary sclerosing cholangitis patients. Patients with large duct overlap syndrome had a good response to immunosuppressive therapy. In both groups, our limited experience from ursodeoxycholic acid was largely poor.ConclusionsSmall duct primary sclerosing cholangitis is prevalent in the overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis.     

临床病理学在自身免疫性肝病诊治中的重要性

肝脏组织学在自身免疫性肝病的诊断中起着重要作用,尤其是临床表现非特异、自身抗体阴性的患者。介绍了几种自身免疫性肝病在组织学上的特征性表现。自身免疫性肝炎(AIH)的特征性表现包括界面性肝炎伴淋巴-浆细胞浸润、玫瑰花环及穿入现象,而慢性非化脓性胆管炎、上皮样肉芽肿常提示原发性胆汁性肝硬化(PBC)。胆管周围洋葱皮样纤维化是原发性硬化性胆管炎(PSC)特征性表现,席纹状纤维化伴IgG4阳性浆细胞浸润常须考虑为IgG4相关硬化性胆管炎。最后指出,在日常工作中,临床医生和病理医生加强沟通有利于提高自身免疫性肝病的诊治。     

The Overlap Syndromes of Autoimmune Hepatitis

Autoimmune hepatitis has two major variant phenotypes in which the features of classical disease are co-mingled with those of primary biliary cirrhosis or primary sclerosing cholangitis. These overlap syndromes lack codified diagnostic criteria, established pathogenic mechanisms, and confident management strategies. Their clinical importance relates mainly to the identification of patients who respond poorly to conventional corticosteroid treatment. Scoring systems that lack discriminative power have been used in their definition, and a clinical phenotype based on pre-defined laboratory and histological findings has not been promulgated. The frequency of overlap with primary biliary cirrhosis is 7–13 %, and the frequency of overlap with primary sclerosing cholangitis is 8–17 %. Patients with autoimmune hepatitis and features of cholestatic disease must be distinguished from patients with cholestatic disease and features of autoimmune hepatitis. Variants of the overlap syndromes include patients with small duct primary sclerosing cholangitis, antimitochondrial antibody-negative primary biliary cirrhosis, autoimmune sclerosing cholangitis, and immunoglobulin G4-associated disease. Conventional corticosteroid therapy alone or in conjunction with ursodeoxycholic acid (13–15 mg/kg daily) has been variably effective, and cyclosporine, mycophenolate mofetil, and budesonide have been beneficial in selected patients. The key cholestatic features that influence the prognosis of autoimmune hepatitis must be defined and incorporated into the definition of the syndrome rather than rely on designations that imply the co-mingling of different diseases with manifestations of variable clinical relevance. The overlap syndromes in autoimmune hepatitis are imprecise, heterogeneous, and unfounded, but they constitute a clinical reality that must be accepted, diagnosed, refined, treated, and studied.     

Overlap Syndromes of Autoimmune Hepatitis: An Open Question

The headword “overlap syndromes” of liver diseases includes the coexistence of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. These syndromes often represent a diagnostic and therapeutic challenge for hepatologists; it remains unclear whether these overlap syndromes form distinct entities or they are only variants of the major autoimmune liver diseases. The most frequent reported association occurs between autoimmune hepatitis and primary biliary cirrhosis, whereas the overlap between autoimmune hepatitis and primary sclerosing cholangitis is less frequent, typically at young age and often attendant with an inflammatory bowel disease. The choice therapy is based on ursodeoxycholic acid and immunosuppressive drugs, used at the same time or consecutively, according to the course of disease. The diagnostic scores for autoimmune hepatitis can help for diagnosis, even though their definitive soundness is lacking.     

Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease

AIM:To assess the role of IgM and IgG immunohistochemistry(IHC) in the evaluation of autoimmune liver conditions-autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC),and primary sclerosing cholangitis(PSC).METHODS:Forty one biopsies from untreated patients diagnosed with autoimmune liver disease(AIH,n = 20;PBC,n = 13;PSC,n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected.IgM and IgG-positive plasma cells were counted in each sample.RESULTS:A predominance of IgG-positive plas...     

Primary sclerosing cholangitis in children

Primary sclerosing cholangitis (PSC), a chronic inflammatory process affecting the extrahepatic and/or medium to large bile ducts, is not rare in children. It has features suggesting an autoimmune pathogenesis, although the mechanism of tissue damage remains unknown. The clinical presentation of childhood primary sclerosing cholangitis is highly variable and frequently without obvious features of cholestasis. Clinical similarity to autoimmune hepatitis is common. Association with chronic colitis is less common than in adults. Cholangiography is essential for the diagnosis and examination of the medium to large intrahepatic ducts is mandatory, as 40% of children lack extrahepatic duct involvement. Histological findings may help to distinguish childhood PSC from autoimmune hepatitis. In children, sclerosing cholangitis may also develop secondary to other disease processes, notably Langerhans histiocytosis, congenital immunodeficiencies and cystic fibrosis. Neonatal sclerosing cholangitis is chronic inflammatory disease of bile ducts which presents initially with neonatal cholestasis; its pathogenesis remains uncertain and may not be the same as for primary sclerosing cholangitis. Effective treatment modalities for childhood PSC remain undetermined. Liver transplantation is required for children who progress to biliary cirrhosis and hepatic decompensation.     

Hepatic manifestations of autoimmune rheumatic diseases

Hepatic manifestations in autoimmune disease include chronic active hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and nodular regenerative hyperplasia. These diseases are rare and may occur concomitantly or serially. Clinicians must be aware of the possibility of liver disease so that it can be treated as soon as possible.     

Intrahepatic IgG/IgM plasma cells ratio helps in classifying autoimmune liver diseases

Background/AimPlasma cells infiltrate in the liver is a prototype lesion of autoimmune liver diseases. The possible role of plasma cells isotyping (IgM and IgG) in the liver in the diagnostic definition of autoimmune liver disease, and particularly in variant syndromes such as autoimmune cholangitis and the primary biliary cirrhosis/autoimmune hepatitis overlap syndrome, is less defined.MethodsWe analysed the clinical, serological and histological features of 83 patients with autoimmune liver disease (40 primary biliary cirrhosis, 20 autoimmune hepatitis, 13 primary sclerosing cholangitis, 4 autoimmune cholangitis and 6 overlap syndrome) compared to 34 patients with chronic hepatitis C and evaluated the expression of IgM and IgG plasma cells in their liver by immunostaining.ResultsBy Spearman's correlation, the mean-counts of IgM plasma cells in portal tracts were significantly correlated with female gender, serum alkaline phosphatase, gamma-glutamyl transferase and IgM values, positivity for anti-mitochondrial antibody-M2 and, on liver biopsy, with bile duct changes, orcein-positive granules and granulomas. Whereas IgG plasma cells resulted more correlated with alanine aminotransferase levels. IgG/IgM ratio lower than 1 was found no only in primary biliary cirrhosis but also in all patients with autoimmune cholangitis. Conversely, all patients with overlap syndrome showed IgG/IgM ratio higher than 1.ConclusionImmunostaining for IgM and IgG plasma cells on liver tissue can be a valuable parameter for better diagnosis of autoimmune liver disease and also for variant or mixed syndromes.     

Immunohistochemical evidence for hepatic progenitor cells in liver diseases

BACKGROUND/AIM: Proliferative bile ductular reactions occur in a variety of liver diseases in humans. It is a matter of debate whether such reactions result from progenitor cell proliferation with biliary and hepatocytic differentiation, versus biliary metaplasia of damaged hepatocytes. We investigated bile ductular reactions in liver diseases, paying particular attention to the presence of cells with intermediate (hepatocytic/biliary) features (oval-like cells). METHODS: Five specimens each were selected of submassive hepatic necrosis and cirrhosis due to hepatitis B, hepatitis C, autoimmune hepatitis, alcohol injury, primary biliary cirrhosis and primary sclerosing cholangitis. Immunohistochemical stains were performed for biliary markers (cytokeratins [CKs] 7 and 19), as well as hepatocytic markers (HepParl and alpha-fetoprotein[AFP]) in sequential sections. The degree of staining of each cell type (biliary, hepatocytic, intermediate) was graded semiquantitatively. RESULTS: Hepatocytes always stained diffusely for HepParl, occasionally for CK7, and rarely for CK19. Biliary cells were always diffusely positive for CK7 and CK19, and rarely for HepParl. Intermediate cells were identified in all cases and showed widespread staining for both HepParl and CK7, and less commonly for CK19. AFP was not expressed in any cell type. The morphologic and immunohistochemical features of bile ductular reactions were similar in the different diseases. CONCLUSIONS: Proliferating hepatic parenchymal cells with intermediate (hepatocytic/biliary) morphologic features and combined immunophenotype can be identified in a variety of acute and chronic liver diseases. The similarity of bile ductular reactions among chronic hepatitic, alcoholic and biliary diseases suggests that they result from proliferation of oval-like progenitor cells.     

Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts

Fractalkine is a chemokine with both chemoattractant and cell-adhesive functions, and in the intestine it is involved with its receptor CX3CR1 in the chemoattraction and recruitment of intraepithelial lymphocytes. We examined the pathophysiological roles of fractalkine and CX3CR1 in normal and diseased bile ducts. Expression of fractalkine and CX3CR1 were examined in liver tissues from patients with primary biliary cirrhosis (17 cases) and controls (9 cases of primary sclerosing cholangitis, 10 cases of extrahepatic biliary obstruction, 20 cases of chronic viral hepatitis C, and 18 cases of histologically normal livers). Expression of fractalkine in biliary epithelial cells (BECs) in response to cytokine treatments was examined using a human cholangiocarcinoma cell line (HuCC-T1) and human intrahepatic BEC line. The chemotaxis of CX3CR1-expressing monocytes (THP-1) toward fractalkine was assayed using chemotaxis chambers. Fractalkine messenger RNA/protein were expressed on BECs of normal and diseased bile ducts, and their expression was upregulated in injured bile ducts of primary biliary cirrhosis. CX3CR1 was expressed on infiltrating mononuclear cells in portal tracts and on CD3(+), CD4(+), and CD8(+) intraepithelial lymphocytes of injured bile ducts in primary biliary cirrhosis. Fractalkine messenger RNA expression was upregulated in two cultured BECs on treatment with lipopolysaccharide and Th1-cytokines (interleukin 1beta, interferon gamma, and tumor necrosis factor alpha). THP-1 cells showed chemotaxis toward fractalkine secreted by cultured cells. In conclusion, Th1-cytokine predominance and lipopolysaccharide in the microenvironment of injured bile ducts resulting from primary biliary cirrhosis induce the upregulation of fractalkine expression in BECs, followed by the chemoattraction of CX3CR1-expressing mononuclear cells, including CD4(+) and CD8(+) T cells, and their adhesion to BECs and the accumulation of biliary intraepithelial lymphocytes.     

Histological and immunohistochemical study of the gall bladder lesion in primary sclerosing cholangitis.

The histological features and type of mononuclear cell infiltrate in gall bladders from six patients with primary sclerosing cholangitis were studied using routine staining techniques and immunohistochemistry. Control studies were performed using the gall bladders from six patients (age and sex matched) with chronic cholecystitis and four with primary biliary cirrhosis. A range of histological abnormalities was present in gall bladders from patients with primary sclerosing cholangitis including a mild to moderate degree of epithelial hyperplasia, pseudogland formation, and mononuclear cell infiltrate of the epithelium; moderate to severe chronic inflammatory cell infiltrate and fibrosis affecting the superficial and deep layers of the gall bladder wall; and minimal smooth muscle hypertrophy. These abnormalities were non-specific and were also present in gall bladders from patients with chronic cholecystitis and primary biliary cirrhosis. Vasculitis and granulomas were not present in the patients with primary sclerosing cholangitis. Immunohistochemistry showed that the superficial and deep mononuclear cell infiltrate in primary sclerosing cholangitis gall bladders was composed predominantly of lymphocytes, in contrast to chronic cholecystitis where macrophages were found in similar or greater numbers. Moreover, T lymphocytes (activated and resting) were present throughout the lymphocytic infiltrate and were apposed to the base and interdigitated between the biliary epithelial cells in significantly greater numbers than in chronic cholecystitis gall bladders. B lymphocytes were present only in lymphoid follicles. Comparative studies using liver biopsy specimens from three of the primary sclerosing cholangitis patients showed a similar T lymphocyte portal tract infiltrate. We conclude that a number of non-specific chronic inflammatory histological abnormalities were present in primary sclerosing cholangitis gall bladders. Immunohistochemistry found other features that were present in this disease - a predominantly lymphocytic mononuclear cell infiltrate of the superficial and deep layers of the gall bladder wall and the presence of T lymphocytes that infiltrated the biliary epithelial cells. These findings support the hypothesis that aberrant cell mediated immune mechanisms may play a role in the pathogenesis of both the intrahepatic and extrahepatic lesions in primary sclerosing cholangitis.     

The relationship between hepatic immunoglobulin production and CD154 expression in chronic liver diseases.

BACKGROUND: CD40-CD154 is a receptor-ligand pair that provides key communication signals between cells of the adaptive immune system in states of inflammation and autoimmunity. The CD40 receptor is expressed constitutively on B lymphocytes, for which it provides important signals regulating clonal expansion and antibody production. CD154 is a member of the tumor necrosis factor superfamily, which is primarily expressed by activated T cells. METHODS: Because many chronic liver diseases are characterized by lymphocytic infiltration of the liver and several have increased immunoglobulin (Ig) production, the role of CD40-CD154 in hepatic Ig production was investigated in patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis, autoimmune hepatitis (AIH), hepatitis C, hepatitis B, alcoholic and non-alcoholic steatohepatitis, as well as normal controls. RESULTS: Soluble CD154 levels in the serum were found to be no different in chronic liver diseases vs normal controls. Likewise, CD154 mRNA levels in peripheral blood mononuclear cells did not differ. However, mRNA for CD154 was significantly increased in the liver of individuals with PBC and AIH as compared with the other groups. The quantity of CD154 mRNA in the liver correlated positively with the quantity of mRNA for secretory Ig. CONCLUSION: These findings suggest that CD40-CD154 signals may be involved in Ig production within the liver of autoimmune liver diseases.     

A unique combination of celiac disease, mesenteric lymph node cavitation, splenic atrophy and necrotizing hepatitis

We report on a patient who was diagnosed six years before with celiac disease, with a current combined problem of asplenism, mesenteric cysts and elevated liver function tests. The implications of splenic atrophy mimic those of post-splenectomy patients. Mesenteric lymph node cavitation is a rare complication of celiac disease that is most often associated with splenic atrophy. The pathogenesis is unknown. The clinical implications of the cavitated mesenteric lymph nodes are unclear. The association of celiac disease with liver disease was reported many years ago, but only recently these associations have been more clearly defined. Liver involvement shows a clinical spectrum varying from nonspecific reactive hepatitis, chronic active hepatitis, steatohepatitis to frank cirrhosis. Associations with autoimmune hepatitis, autoimmune cholangitis, primary biliary cirrhosis and primary sclerosing cholangitis have been described. In our patient, we found no obvious cause for the necrotizing hepatitis and the negative auto-antibodies made it impossible to firmly establish the diagnosis of autoimmune hepatitis. The causal relationship with celiac disease, if any, remains unproven.