Liver Disease Of Unknown Etiology Research Articles

Mycophenolate Mofetil for the Treatment of Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Despite advances in understanding the pathophysiology underlying this disorder, no effective medical therapy has been identified for halting disease progression. The aim of this investigation was to determine the safety and estimated efficacy of mycophenolate mofetil (MMF) for the treatment of PSC. Thirty patients with PSC received MMF 1 g daily to a maximum of 3 g daily for 1 yr. Liver tests were determined at 3-month intervals with the Mayo risk score calculated at baseline and at the end of therapy. Twenty-three (77%) patients completed 1 yr of therapy. Significant but clinically marginal improvement in serum alkaline phosphatase level after 1 yr of therapy was observed (1135 +/- 581 U/L vs 912 +/- 463 U/L, p= 0.02). No other significant changes in liver biochemistries or Mayo risk score was observed. Seven patients (23%) discontinued MMF due to adverse events possibly related to therapy. Adverse reactions resolved spontaneously or with dose reduction in 10 (33%) patients. One patient developed pancreatitis, bacterial cholangitis, and sepsis during the eighth month of MMF therapy. No patient developed cytopenia on therapy. In conclusion, MMF does not appear to have clinically important benefits for PSC despite being tolerated by most patients. The results of this pilot study do not support further study of MMF as a single agent in the treatment of PSC.

Primary sclerosing cholangitis as a cause of false positive bile duct brushing cytology: Report of two cases.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology characterized by ongoing inflammation, destruction, and fibrosis of intrahepatic and extrahepatic bile ducts. Irregular narrowing and dilation of the biliary duct system produces the characteristic beaded pattern seen on cholangiogram. Malignant degeneration resulting in cholangiocarcinoma is a well-recognized sequela of PSC. Bile duct brushing cytology is the primary screening technique for cholangiocarcinoma. It is associated with a relatively low sensitivity but high specificity. Few false positive bile duct brushings have been reported in the literature, with the majority of these having occurred in a background of PSC. We report two patients with PSC in whom bile duct brush cytologies were falsely positive for carcinoma.

Immunopathogenesis of Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology;however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease--especially ulcerative colitis--and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (HLA)- and non-HLA-associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and, therefore, evoking an abnormal immune response.

Oxidant stress in type I autoimmune hepatitis: the link between necroinflammation and fibrogenesis?

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology characterized by circulating autoantibodies, hyperglobulinaemia and interface hepatitis. The mechanisms of progression from initial autoimmune attack to fibrosis and cirrhosis are unclear but oxidant stress may be involved. Markers of lipid peroxidation, antioxidant status, hepatic fibrogenesis and liver function were measured in blood and urine in 35 controls and in 33 patients with type-1 AIH; histology was assessed in 18 patients. In AIH, markers of lipid peroxidation were significantly elevated (8-isoprostane in both plasma and urine P < 0.001; plasma malondialdehyde P = 0.017). Total antioxidant capacity in protein-free serum and total glutathione in both whole blood and plasma were significantly reduced (P = 0.007, P = 0.037, P < 0.001, respectively). The antioxidants selenium, vitamin A and vitamin E were significantly decreased (P = 0.007, P < 0.001, P = 0.025, respectively); vitamin C was unchanged. Urinary 8-isoprostane correlated positively with interface hepatitis and necroinflammatory score and with hepatic fibrogenesis (type III procollagen peptide). Interface hepatitis correlated negatively with vitamin A and whole blood total glutathione. Oxidant stress, as reflected in blood and urine by a wide range of pro- and antioxidant markers, is a significant feature of AIH and provides a probable mechanism linking hepatic necroinflammation to fibrogenesis and disease progression.

Autoimmunity and environmental factors in the pathogenesis of primary biliary cirrhosis

It is generally believed that autoimmune processes are initiated when tolerance to self‐proteins is broken. Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology. Autoimmune attack in PBC is predominantly organ‐specific, despite the presence of mitochondrial autoantigens, the major targets of autoimmunity in PBC, in all nucleated cells. Although the events that provoke initial activation remain unknown, the hypothesis of molecular mimicry implies that foreign pathogens with homology to self‐protein or modified self‐protein can break tolerance. Several reports have suggested the association of autoimmune diseases with drugs, chemicals, and other environmental factors. Specifically, many xenobiotics are metabolized in the liver. Liver autoantigens exposed to these chemicals could be modified and become immunogenic. We propose that exposure to the environmental xenobiotics is one of the initiating factors that leads to the loss of tolerance to self‐proteins in genetically susceptible hosts, resulting in development of PBC.

Primary biliary liver cirrhosis and overlap syndrome. Diagnosis and therapy

Primary biliary cirrhosis represents a chronic cholestatic liver disease of unknown etiology. It primarily affects females, is associated with extrahepatic immune-mediated syndromes, shows an immunogenetic association with HLA DR8, and displays serum autoantibodies, which makes an autoimmune etiology likely. The diagnosis is reached in patients with elevated alkaline phosphatase, gamma glutamyl transferase and bilirubin levels who exhibit normal bile ducts upon ultrasound examination, and in whom specific antimitochondrial autoantibodies are detectable. Half of all PBC patients additionally show specific antinuclear autoantibodies. Immunosuppressive therapy is ineffective; steroids, transplant immunosuppressants, colchicine, d-penicillamine and methotrexate are of limited clinical benefit. Ursodeoxycholic acid has few side effects and leads to a biochemical response and a delay of disease progression in most cases. When ursodeoxycholic acid therapy is ineffective an overlap syndrome with autoimmune hepatitis can be present, which can respond to steroid treatment. The only curative option is liver transplantation which should be considered when bilirubin levels exceed 100 microM/l.

Transvenous Liver Biopsy via the Femoral Vein

AIM: To study the safety, effectiveness and diagnostic value of transvenous forceps biopsy of the liver in 54 patients with coagulopathy, gross ascites or morbid obesity and suspected liver disease in whom percutaneous liver biopsy was contraindicated. MATERIAL AND METHODS: Forceps biopsy of the liver via the femoral vein was attempted in 54 adult patients with advanced liver disease of unknown aetiology who had coagulation disorders (41 cases), gross ascites (11 cases) or morbid obesity (two cases). In each patient two to six biopsies (average four) were taken using a radial jaw forceps inserted via the right or left femoral vein. RESULTS: The procedure was successful in 53 cases. Hepatic vein catheterization failed in one patient. Adequate liver tissue for diagnosis was obtained in 84% of cases. One patient developed delayed haemorrhage at 12 h from a capsular leak that was undetected during the biopsy procedure. This patient required blood transfusions and laparotomy to control bleeding. There were no deaths in the 53 patients studied. Transient minor chest and shoulder pain was encountered during sheath insertion into a hepatic vein in 23 patients. Three patients developed a femoral vein haematoma, which resolved with conservative treatment. CONCLUSION: Transvenous liver biopsy via the femoral vein is another safe, effective, simple alternative technique of biopsy when the percutaneous route is contraindicated.

Peculiar HLA polymorphisms in Italian patients with primary biliary cirrhosis

Background/Aims: Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease of unknown etiology with a highly variable progression rate and prevalence among different geographical areas. Data concerning human leukocyte antigen (HLA) polymorphisms in PBC come from a limited number of geographical areas, from which the association with the HLA-DRB1*08 allele has been consistently reported. Methods: To investigate whether HLA polymorphisms contribute toward disease susceptibility, we compared 186 well-defined Italian PBC patients with 558 healthy subjects matched by age, gender and geographical area (Northern, Central and Southern Italy). Patients and controls were HLA typed at low resolution by PCR-sequence specific oligonucleotides for the loci A and B; HLA-DRB1 alleles were typed by reverse line blot assay of PCR-amplified DNA. Results: HLA-DRB1*11 was associated with a markedly reduced risk of developing PBC (OR: 0.3; 95% CI: 0.2–0.5). No association was found with HLA-DRB1*08. The B*15 (2.5; 1.3–4.6), B*41 (12.0; 2.7–72.1), B*55 (2.9; 1.1–7.5) and B*58 alleles (6.8; 1.1–46.3) were more frequent in PBC. The frequency of HLA polymorphisms was similar in PBC patients with progressive or non-progressive disease, and in those with or without anti-mitochondrial antibodies. Conclusions: Our data on a large series of Italian patients suggest that PBC may have a peculiar genetic background in the Mediterranean area.

Genomic mutations with amino acid substitutions of circulating hepatitis B virus found in non-B, non-C patients with hepatocellular carcinoma.

Most hepatocellular carcinoma (HCC) in Japan is caused by chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). HBV DNA has been detected in the serum and liver tissue of some proportion of those patients who are HBs antigen-negative and HCV antibody-negative; i.e., non-B, non-C (NBNC) patients with HCC. We sought to detect HBV DNA in the serum from NBNC HCC cases and to investigate genomic mutations of HBV in seronegative cases. The sera from 26 NBNC HCC patients were examined by polymerase chain reaction (PCR) followed by southern blotting for existence of HBV DNA. The precore/core and polymerase regions of the HBV genome in the sera from five seronegative cases were analyzed by direct sequence. HBV DNA was detected in 17 of 26 patients (65.4%). Demographic factors such as age, gender, anti-HBs positivity, anti-HBc positivity, complication with cirrhosis, and excessive alcohol intake did not affect circulating HBV positivity. Genomic mutations with amino acid substitutions were detected in the polymerase and the precore regions from one of the five cases, and in the core region from four of the five cases. PCR-based HBV screening is necessary in patients suffering from liver diseases of unknown etiology, although its etiological importance and benefit of viral elimination have not been established. Genomic mutations in the precore/core and the polymerase region detected in this study might be involved in the lack of HBsAg in NBNC HCC cases.

High Prevalence of Transfusion-Transmitted Virus Infection in Patients with Chronic Liver Diseases in an Endemic Area of Hepatitis B and C Virus

Objective: To determine the prevalence and clinical impact of transfusion-transmitted virus (TTV) DNA in patients with chronic liver diseases in the Southeast Anatolia region of Turkey where hepatitis B and C viral infections are endemic. Subjects and Methods: Patients diagnosed with chronic liver disease by clinical, biochemical and histologic means were enrolled in the study. Serum samples of 60 patients (19 males, 41 females) with chronic liver diseases, and of 45 healthy volunteer blood donors as a control group were collected. The chronic liver disease group consisted of 11 patients with hepatitis B, 44 with hepatitis C and 5 with chronic liver disease of unknown etiology. Presence of TTV DNA was investigated by the polymerase chain reaction. Using a scoring system histological grading of inflammation and staging of fibrosis were performed only in the chronic hepatitis C group. Results: TTV DNA was detected in 47 (78%) patients with chronic liver disease and 5 (11%) volunteers in the control group. The difference was statistically significant (p < 0.001). Ten of the 11 (91%) patients with hepatitis B, 32 of 44 (73%) of those with hepatitis C-related chronic liver disease, and 5 of 5 (100%) of the patients with cryptogenic liver disease were positive for TTV DNA. Conclusion: TTV is highly prevalent in patients with chronic liver diseases in Southeast Anatolia, Turkey but no pathogenic effect attributable to TTV infection was detected.

Primary sclerosing cholangitis diagnosis and management

Primary sclerosing cholangitis is a progressive cholestatic liver disease of unknown etiology. The disease is characterized by inflammation and progressive fibrosis of the biliary tree with subsequent development of cirrhosis with risk of portal hypertension, liver failure and cancer. There is currently no treatment that has been shown to reverse or stabilize disease progression. Endoscopic retrograde cholangiopancreatography is important in making the diagnosis as well as palliating the effects of biliary obstruction. This article discusses the epidemiology, pathogenesis, clinical presentation, diagnosis, and management of primary sclerosing cholangitis with an emphasis on endoscopic principles and techniques.

21 OC TT virus infection in patients with chronic liver disease of unknown etiology

21 OC TT virus infection in patients with chronic liver disease of unknown etiology

Regulation of organic anion transporters in a new rat model of acute and chronic cholangitis resembling human primary sclerosing cholangitis

Background/Aims: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology. Although the primary defect affects cholangiocytes, cholestatic injury of hepatocytes may promote further liver damage. Since down-regulation of hepatocellular organic anion transporters is implicated in the molecular pathogenesis of cholestasis, expression of these transporters was determined in a novel rat model, which closely resembles human PSC. Methods: Hepatic protein and mRNA expression of basolateral (Ntcp, Oatp1, 2 and 4) and canalicular (Mrp2, Bsep) organic anion transporters were analyzed 1, 4 and 12 weeks after induction of experimental PSC by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Results: Specific down-regulation of basolateral and canalicular transport systems except Oatp4 and Bsep proteins occurred during the acute phase of inflammation. In chronic cholangitis 12 weeks after TNBS Mrp2 protein and mRNA remained down-regulated by 40–50% of controls ( P<0.05). In addition Oatp1 protein was also reduced by 40±13% ( P<0.05), whereas all other transporters returned to control values. Conclusions: In chronic cholangitis only canalicular Mrp2 expression remained down-regulated. This might represent the first injury to hepatocytes in chronic cholangitis as an extension of liver injury from the level of cholangiocytes to hepatocytes in PSC.

Granulomatous Liver Diseases of Unknown Etiology with an Emphasis of Primary Biliary Cirrhosis

Granulomatous Liver Diseases of Unknown Etiology with an Emphasis of Primary Biliary Cirrhosis

Identification and characterization of autoantibodies against catalase and alpha-enolase in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Recent studies have shown that genetic factors and both cellular and humoral immunological abnormalities are important in the pathogenesis of PSC. The most prominent autoantibodies in PSC are anti-neutrophil cytoplasmic antibodies (ANCA). The autoepitopes of ANCA in PSC are not well defined. The aim of this study was to identify corresponding ANCA autoantigens in patients with PSC. A biochemical approach with enrichment and partial purification of soluble neutrophil proteins, detection of autoantibodies by Western blot and partial amino acid sequencing were used. Two new autoantigen/autoantibody systems in patients with PSC were detected: catalase and alpha-enolase. The presence of catalase autoantibodies in 9/15 (60%) and alpha-enolase autoantibodies in 4/15 (27%) was confirmed by ELISA and Western blot. Furthermore, we showed immunoreactions of PSC sera with human biliary epithelial cells, showed the reduction of fluorescence in anti-catalase absorption experiments and observed partial co-localization of anti-catalase antibodies and PSC sera in double-staining experiments on biliary epithelial cells. The anti-catalase antibody-positive PSC patients had a more severe course of disease with a significantly higher alkaline phosphatase compared with the anti-catalase-negative PSC patients (P < 0.06). All ulcerative colitis control sera were anti-catalase antibody-negative. The identified antigens catalase and alpha-enolase can partly explain the ANCA fluorescence on ethanol-fixed and formaldehyde-fixed granulocytes in patients with PSC. Catalase is an important anti-oxidant enzyme and prevents cell damage from highly reactive oxygen-derived free radicals. Catalase autoantibodies might play a pathogenic role in patients with PSC. Our findings support the hypothesis that oxidative stress is one of the pathogenic mechanisms in patients with PSC.

Role of silent hepatitis B virus in chronic hepatitis B surface antigen(−) liver disease

Despite a number of studies documenting hepatitis B virus (HBV) infection in the absence of hepatitis B surface antigen (HBsAg) a causal relationship between silent HBV infection and liver disease remain difficult to establish. In particular, both the prevalence and clinical significance of this observation are poorly understood. Why is HBV replication apparently so low in these patients? A number of studies have tried to elucidate the mechanism of HBsAg negative infections, and considerable data documenting HBV infectivity or reinfection in the absence of detectable HBsAg support the hypothesis that in some of these cases, HBV is undergoing low-level replication in the liver and this, in several situations including: (1) chronic liver disease, alcoholic liver disease, hepatocellular carcinoma; (2) viral reactivation following cancer chemotherapy or immunosuppression and (3) transmission via transfusion or from human serum to chimpanzees. In a recent study including 50 patients with chronic liver disease of unknown etiology we could detect serum HBV DNA by nested polymerase chain reaction (PCR) in 15/50 patients (50% at the cirrhosis stage) in the absence of HBsAg; in the liver of the 15 patients both HBcAg and/or HBsAg can be detected at very low-level. Viral host factors allowing HBV persistence in the absence of HBsAg can depend on several mechanisms. Coinfections with HCV can explain only a proportion of HBsAg(−) HBV infections. Secondly, HBV mutations in the core promotor region leading to a minimal viral replication, or mutations in the HBsAg-encoding region might explain the absence of serological recognition. Finally, it is possible that in some cases host immune mechanisms can maintain HBV infection in a latent state until transmission to another individual who subsequently develops a more active infection especially when immunosuppressive therapy is employed. Existence of HBsAg(−) HBV infections should be taken into account by the use of sensitive PCR tests for prevention of viral transmission in the settings of blood donations and organ transplants.

Association of the tumour necrosis factor α −308 but not the interleukin 10 −627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis

BACKGROUND AND AIMSPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease....

Sclerosing cholangitis

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology. Immunogenetic factors are considered important in its pathogenesis. The genetic susceptibility to primary sclerosing cholangitis is associated, in part, with the HLA HLA-DRB1, DQA1, DQB1 haplotype. Liver histology in primary sclerosing cholangitis is characterized by a portal inflammatory infiltrate mostly composed of memory T cells. Many patients eventually will develop cholangiocarcinoma, and inactivation of the p16 tumor-suppressor gene might be involved in neoplastic transformation. Alcohol consumption might be a risk factor for cholangiocarcinoma, and, in some patients, elevation of serum CA19-9 marks the neoplastic transformation. To date, no medical treatment has been proven effective. Endoscopic therapy might be useful in some patients, but controlled studies are lacking. Liver transplantation remains the only effective treatment. Posttransplant survival and quality of life are continuously improving despite the fact that the disease may recur in some patients after transplantation. Nevertheless, patient selection and timing of indication for liver transplantation remain uncertain.

Detection of TT virus sequences in children with liver disease of unknown etiology

Detection of TT virus sequences in children with liver disease of unknown etiology

Liver transplantation for primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology that is progressive in most symptomatic patients, advancing toward cirrhosis and liver failure. Liver transplantation is the only therapeutic option for patients with end stage liver disease resulting from this disorder. The results of transplantation for PSC are excellent with one-year survival rates of 90-97% and five-year survival rates of 80-85%, but are closely related to pre-transplant Child-Pugh stage. Recurrence of PSC after liver transplantation is common, occurring in up to 20% of patients, but it appears to have little effect on patient survival, as survival of patients with recurrent PSC is similar to that of those without evidence of recurrence. Cholangiocarcinoma is a catastrophic complication of PSC and as yet no reliable screening method exists. The results of liver transplantation for patients with clinically apparent cholangiocarcinoma are extremely poor, however in patients in whom a microscopic tumour is detected in the explanted liver, survival is similar to those transplanted with PSC without cholangiocarcinoma. Activity of inflammatory bowel disease (IBD) appears to be more severe after transplantation, especially in units where steroid immunosuppression is withdrawn early. Colon cancer appears within the first few years after transplantation in approximately 7% of patients with IBD who are transplanted for PSC. Annual colonoscopy in this population seems prudent.