Search

BACKGROUND: Conditions exhibiting features of two different autoimmune liver diseases are designated overlap syndromes. Variant forms display some, but not all, characteristics of a distinct autoimmune liver disease. We describe transitions over time between variant forms of PBC, i.e. AMA-negative PBC, autoimmune hepatitis (AIH)-PBC overlap and autoimmune cholangitis (AIC) in a large cohort of PBC patients in Sweden. METHODS: We retrieved all patients with variant forms of PBC in six university hospitals in Sweden, covering 60% of the Swedish population. The diagnosis of PBC and its variants was based on laboratory findings and compatible histological features. The revised autoimmune hepatitis scoring system proposed by the International Autoimmune Hepatitis Group was used to establish the diagnosis of AIH. RESULTS: In a population of 800 patients with PBC, we identified 35 (5%) variant forms; 25 patients with AIH-PBC overlap, 8 with AIC and 2 with AMA-negative PBC at the time of our study. The initial diagnoses were PBC (3 patients), AIH (3), AIH-PBC overlap (16), AIC (8) and AMA-negative PBC with (1) or without (4) concomitant AIH. The median follow-up was 125 (41-360) months. Immunosuppression and ursodeoxycholic acid induced a complete or good regression of increased aminotransferases in about half of the patients who were given one or both of these treatments. CONCLUSIONS: Variant forms of PBC are seen in approximately 5% of PBC patients in Sweden. Transition between different forms may occur, emphasizing the value of repeat biopsies, but established overlapping AIH-PBC seems to be stable over time.

The aim was to study the outcome of donor candidate investigations for living-related donor liver transplantation from adult to child. The charts of 25 donor candidates were reviewed. All 22 recipients, of whom 18 had BA, were already listed for DD organ transplantation. Eleven donor candidates were accepted. Seven of them successfully donated the left lateral liver segment. At follow-up, all donors and recipients were well from the surgery. However, one donor developed Crohn's disease. In the four remaining cases the recipient deteriorated before transplantation was possible or other surgical approaches were utilized. For three candidates the investigations were never finalized, due to either clinical deterioration of the recipient or the availability of a DD organ. Eleven donor candidates were rejected. Four of them (three being parents of BA patients) had liver abnormalities. Another three were rejected for cardiopulmonary disorders and the remaining four for other reasons. We conclude that only seven out of 25 (28%) candidates donated a liver segment. The fact that parents of BA patients have potential liver pathology may be of importance for the understanding of the etiology of the disease and have possible implications for the choice of donors.

Background & Aims: Primary sclerosing cholangitis (PSC) is an autoimmune liver disease with destruction of hepatic bile ducts. A high frequency of biliary epithelial cell antibodies (BEC-Ab) is present in PSC. Here, we studied the mechanisms and signaling pathways used by these Ab in causing BEC dysfunction. Methods: Immunoassays were performed using freshly isolated BECs to study the signaling capacity of purified immunoglobulin (Ig) G and F(ab)′2 fractions from 33 patients with PSC with anti–BEC-Ab. Results: We provide evidence that stimulation of BECs with PSC IgG, but not control IgG, induced expression of Toll-like receptor (TLR) 4 and TLR9 and specific phosphorylation of extracellular signal–regulated kinase (ERK) 1/2 as well as the transcription factors ELK-1 and nuclear factor κB. A specific inhibitor of ERK1/2 abrogated phosphorylation of ELK-1 and protein expression of TLR4 but not TLR9 on BECs. TLR-expressing BECs, when further stimulated with lipopolysaccharide and CpG DNA, produced high levels of interleukin-1β, interleukin-8, interferon γ, tumor necrosis factor α, granulocyte-macrophage colony–stimulating factor, and transforming growth factor β. Bile ducts stained positively for TLR4 and TLR9 in 58% of liver specimens taken from patients with PSC with BEC-Ab, as compared with 14% in those without BEC-Ab and also less frequently in diseased control livers. Conclusions: Our data show that binding of PSC BEC-Ab initiates ERK1/2 signaling and up-regulation of TLR, which upon ligation induces BECs to produce cytokines/chemokines, leading to the possible recruitment of inflammatory cells. Thus, in PSC, BECs are not only targets of the immune attack but may also be active participants and mediators of their own destruction. BEC-Ab may be critical regulators of cholangitis in PSC.

Background: The liver may have a role in peripheral tolerance, by serving as a site for trapping, apoptosis and phagocytosis of activated T cells. It is not known which hepatic cells are involved in these processes. It was hypothesised that liver sinusoidal endothelial cells (LSEC) which are strategically placed for participation in the regulation of sinusoidal blood flow, and express markers involved in recognition, sequestration and apoptosis, may contribute to peripheral tolerance by inducing apoptosis of activated T cells. Methods: By using immunoassays and western blot analysis, the fate of activated T cells when incubated with human LSEC isolated from normal healthy livers was investigated. Results: Evidence that activated (approximately 30%) but not non-activated T cells undergo apoptosis on incubation with human LSEC in mixed cell cultures is provided. No difference in the results was observed when unstimulated and cytokine-stimulated LSEC were used. T cell–LSEC contact is required for induction of apoptosis. Apoptosis induced by LSEC was associated with caspase 8 and 3 activity and strong expression of the proapoptotic molecule Bak. Transforming growth factor β (TGFβ) produced constitutively by LSEC is partly responsible for the caspase-induced apoptosis, as neutralising antibodies to TGFβ markedly attenuated apoptosis, up regulated the antiapoptotic molecule Bcl-2 and partially blocked caspase-3 activity. Conclusion: These findings broaden the potential role of LSEC in immune tolerance and homeostasis of the immune system. This study may provide insight for exploring the mechanisms of immune tolerance by liver allografts, immune escape by some liver pathogens including hepatitis C and pathogenesis of liver diseases.

The use of magnetic resonance cholangiopancreaticography (MRCP) as a non-invasive diagnostic tool for primary sclerosing cholangitis (PSC), together with increased clinical awareness of the disease, has led to earlier diagnosis. The aim of this study was to investigate the clinical presentation of PSC including its association with inflammatory bowel disease (IBD) and the development of cholangiocarcinoma at one centre over an observation period of 20 years.All patients with well-defined PSC, diagnosed after 16 years of age and treated at Huddinge University Hospital between 1984 and 2004, were included in the study (n=246). PSC and IBD characteristics were retrieved from the patients' medical records. The patients were subdivided according to the date of diagnosis: 185 PSC patients diagnosed before 30 October 1998 were compared with 61 patients diagnosed after that date.Patients diagnosed after 1998 were significantly older at diagnosis (mean age 41 versus 37 years) and presented fewer symptoms (47% versus 63%) as well as a lower frequency of coexisting IBD (69% versus 82%). In the whole group, women had significantly more symptoms than men, particularly pruritus (p0.05).The clinical spectrum of PSC in Sweden has changed over the past 20 years; today, PSC patients are older at diagnosis and associated IBD is less frequent.

Five to 15% of patients with primary sclerosing cholangitis (PSC) develop cholangiocarcinoma (CC) with a median survival of 5 to 7 months, an outcome not significantly improved by liver transplantation. However, if CC is found incidentally during the procedure or in the explanted liver, 5-year survival rates of 35% are reported. A noninvasive method to detect CC small enough to allow for intended curative surgery is needed. Unfortunately, computed tomography (CT) and ultrasonography (US) have poor sensitivity for detection of CC in PSC; however, positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) differentiates well between CC and nonmalignant tissue. We examined whether PET findings are valid using a blinded study design comparing pretransplantation FDG-PET results with histology of explanted livers. Dynamic FDG-PET was performed in 24 consecutive patients with PSC within 2 weeks after listing for liver transplantation and with no evidence of malignancy on CT, magnetic resonance imaging, or ultrasonography. The PET Center staff was blinded to clinical findings, and surgeons and pathologists were blinded to the PET results. Three patients had CC that was correctly identified by PET. PET was negative in 1 patient with high-grade hilar duct dysplasia. In 20 patients without malignancies, PET was false positive in 1 patient with epitheloid granulomas in the liver. In conclusion, dynamic FDG-PET appears superior to conventional imaging techniques for both detection and exclusion of CC in advanced PSC. FDG-PET may be useful for screening for CC in the pretransplant evaluation of patients with PSC.

Background/Aims Mucosal addressin cellular adhesion molecule-1 ( MAdCAM-1 ) has been implicated in the aberrant homing of intestinal lymphocytes to the liver in primary sclerosing cholangitis (PSC). Intercellular adhesion molecule-1 ( ICAM-1 ) has also been implicated in the pathogenesis of PSC and the E/E genotype of the K469E polymorphism has been reported to be associated with PSC susceptibility. The aims of this study were to determine if MAdCAM-1 polymorphisms or the K469E polymorphism of ICAM-1 are associated with PSC in Scandinavia. Methods Seven single nucleotide polymorphisms (SNPs) in MAdCAM-1 and the G421R and K469E ICAM-1 SNPs were genotyped in 365 PSC patients from Norway and Sweden. 327 Norwegian ulcerative colitis (UC) patients and 368 Norwegian bone marrow donors served as controls. Results No significant association with PSC was found for any of the MAdCAM-1 or ICAM-1 SNPs. Allele frequencies for these polymorphisms were not significantly different between PSC patients with UC, UC patients and healthy controls. Conclusions Polymorphisms in MAdCAM-1 are not likely to significantly affect PSC susceptibility. In addition, the E/E genotype of the K469E in ICAM-1 does not influence PSC susceptibility in Scandinavia.

CCR5 is a chemokine receptor expressed on T-cells and macrophages. A 32-base pair deletion in the chemokine receptor 5 gene (CCR5-Delta32) leads to a non-functional receptor. Conflicting evidence exists whether this deletion is associated with primary sclerosing cholangitis (PSC). We genotyped the CCR5-Delta32 variant in 363 PSC patients and 366 controls. No significant increase in the Delta32 allele frequency was detected in the PSC patients compared to controls (12.7% vs 10.7% OR = 1.22, 95% CI [0.88, 1.68], P = 0.23). Survival analysis did not reveal any significant effects from CCR5-Delta32 genotypes on disease progression. Thus, in this study (power > 90%, given OR = 2, alpha = 0.05), we were unable to replicate previous findings and our results do not support an involvement of CCR5-Delta32 in either PSC susceptibility or progression.

Background/Aims The aim of the present study was to determine whether PSC can present with acute liver failure (ALF) and to determine its frequency. Methods Medical records from all patients with a well-defined PSC ( n =246), treated at Karolinska University Hospital, Huddinge between 1984 and 2004 were scrutinized. Information on PSC and inflammatory bowel disease (IBD) characteristics including mode of presentation of PSC was evaluated. A group of patients with ALF of indeterminate cause at our hospital diagnosed (1993–2003) was identified as a reference group ( n =46). Results Two patients with PSC presented with ALF (1%) and are described in detail. Both of them had an underlying IBD. Nobody in the reference group had IBD. Conclusions In conclusion, PSC patients can present with ALF in approximately 1% of all patients. PSC should be considered as a differential diagnosis in patients with ALF of indeterminate cause, especially in patients with IBD.

The prevalence of inflammatory bowel disease (IBD) in patients with PSC differs in various part of the world. Ulcerative colitis (UC) is most common, but 1 to 14% of all primary sclerosing cholangitis (PSC) patients have Crohn disease with colonic involvement. Many PSC patients without clinical symptoms of IBD have colonoscopic and histological findings compatible with IBD, and the subclinical phase may last several years before onset of symptoms of active colitis. The characteristics of UC in patients with PSC are different from those in UC patients without PSC. The colitis is usually substantial, the clinical course of the colitis is quiescent, and rectal sparing is common. Moreover, PSC patients with UC have a higher risk of developing colorectal dysplasia/carcinoma than UC patients without PSC. In patients having an ileal pelvic pouch with ileal anal anastomosis, PSC is a risk factor for development of pouchitis. It is important that all PSC patients with UC are included in colonoscopic surveillance programs.

During acute liver allograft rejection, most of the tissue damage to bile duct epithelium is thought to occur as a consequence of direct immunologic injury by T-cell-mediated immune effector mechanisms. However, the role of antibodies to biliary epithelial cells (BECs) in liver transplant rejection is not known. We therefore investigated cross-match sera obtained immediately before liver transplantation from 95 patients for the presence of BEC-reactive antibodies to determine their association with acute rejection. BECs were isolated from one normal healthy liver. Antibody binding was detected by using flow cytometric analysis. Donor lymphocyte-specific cross-matches using complement-dependent cytotoxicity (CDC) and flow cytometric assays also were performed. The 2-year patient survival rate in this study was 86.3%. Eleven patients were positive for either CDC or flow cytometric cross-matches. BEC antibodies were detected in 41 serum samples (43.2%). Patients with BEC antibodies experienced acute rejection more frequently (65.9%) compared with 42.5% without antibodies (P

Primary sclerosing cholangitis (PSC) is a common indication for liver transplantation, but evaluation of patients and timing of liver transplantation remain as major problems. Data from PSC and control patients listed for liver transplantation from 1990 through 2000 in the Nordic countries were recorded prospectively. Outcomes from the waiting list and after transplantation have been recorded for both groups. For PSC patients, regression analyses have been performed to analyze predictors of outcome. A total of 255 PSC and 610 control patients were accepted on the liver transplantation waiting list from 1990 to 2000. In the PSC group, 223 patients (87%) received a first liver allograft, and 32 patients (13%) died without transplantation. The corresponding figures for the control group were 89% and 10%. For PSC patients, the 5- and 10-year survival from the time of acceptance was 68% and 58%, respectively. A higher Model for End-Stage Liver Disease score and a shorter duration of PSC predicted death on the waiting list for PSC patients. PSC is a frequent indication for liver transplantation. In our material, serum bilirubin or Model for End-Stage Liver Disease score and PSC duration are predictors of outcome including survival of the waiting list.

Patients with ulcerative colitis and primary sclerosing cholangitis have an increased risk of developing carcinoma both in the bile ducts and in the colon.To investigate whether this patient group also has an increased risk of developing atrophy and neoplasia in the ileal pouch mucosa after construction of a pelvic pouch with an ileoanal anastomosis or a continent Kock ileostomy.Flexible video endoscopic examinations of the ileal pouch were performed in 16 patients with ulcerative colitis and primary sclerosing cholangitis and in 16 matched patients with ulcerative colitis without sclerosing cholangitis. Biopsies were sampled from different locations in the pouch for histologic assessment of mucosal atrophy and dysplasia and for flow cytometric DNA analysis assessing chromosomal aberrations.The patients with sclerosing cholangitis developed moderate or severe atrophy in the pouch significantly more often (P0.01). Persistent severe mucosal atrophy was revealed in eight patients with sclerosing cholangitis and only in two controls. One patient with sclerosing cholangitis had high-grade dysplasia in multiple locations. Low-grade dysplasia was assessed in three patients with sclerosing cholangitis and in two of the controls. DNA aneuploidy was displayed in three patients, all with sclerosing cholangitis and dysplasia. All patients with neoplastic transformation had a pouch with ileoanal anastomosis and a long pouch duration (8 years).Patients with ulcerative colitis and primary sclerosing cholangitis with an ileal reservoir are more prone to developing mucosal atrophy in the pouch and seem to have a higher risk of neoplastic transformation in the pouch mucosa than patients with ulcerative colitis without sclerosing cholangitis.

Aim: Sera of patients with autoimmune liver diseases were investigated for the presence of autoantibodies binding to human biliary epithelial cells (BECs). Furthermore, their functional capacity was investigated by testing their capacity to fix complement as well as induce expression of various adhesion molecules and production of cytokines. Methods: Sera from patients with various stages of primary sclerosing cholangitis (PSC; n=30), primary biliary cirrhosis (PBC; n=29), autoimmune hepatitis (AIH; n=25), and normal controls (n=12) were investigated for the presence of antibodies that reacted with unstimulated and cytokine stimulated BECs isolated from a normal healthy liver. To demonstrate organ specificity, lung epithelial cells (LECs) were used as control cells. Antibodies were tested for their functional capacity. Results: Compared with controls (8%), significantly higher numbers of PSC patients (63%, p=0.001), but not PBC (37%, NS) or AIH (16%, NS) patients, had anti-BEC antibodies. In 90% of PSC patients, the autoantibodies reacted only with cytokine stimulated target cells. Lower numbers of PSC (6%), PBC (10%), and AIH (0%) patients had LEC antibodies. Other significant findings were that anti-BEC antibodies were found in (i) PSC patients with either the HLA-DRB1*0301 or DR2 allele compared with those without (p=0.007); and (ii) in PBC patients with end stage disease compared with those without (p=0.018). Furthermore, anti-BEC antibodies from PSC and PBC but not AIH patients induced BECs to produce high levels of the cytokine interleukin 6. IgM and IgG fractions isolated from PSC but not PBC and AIH sera induced significantly increased expression of the cell adhesion molecule CD44. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western blot analysis of BEC membranes demonstrated a specific band of 40 kDa with PSC sera and 45, 42, 30, and 33 kDa bands with PBC sera, which were absent in control groups. Conclusion: Thus for the first time we have demonstrated the presence of functionally important autoantibodies to cell surface expressed antigens on the relevant target cells of destruction, namely BECs, in PSC and PBC. These finding have important implications for the pathogenesis of bile duct destruction in these patients.

More precise prognostic models are needed for prediction of survival in patients with primary sclerosing cholangitis (PSC), particularly for the selection of candidates for liver transplantation. The aim of this study was to develop a time-dependent prognostic model for the calculation of updated short-term survival probability in PSC. Consecutive clinical and laboratory follow-up data from the time of diagnosis were collected from the files of 330 PSC patients from 5 European centers, followed for a median of 8.4 years since diagnosis. Time-fixed and time-dependent Cox regression analyses, as well as the additive regression model, were applied. The reliability of the models was tested by a cross-validation procedure. Bilirubin (on a logarithmic scale), albumin, and age at diagnosis of PSC were identified as independent prognostic factors in multivariate analysis of both the time-fixed and the time-dependent Cox regression models. The importance of bilirubin was more pronounced in the time-dependent model (hazard ratio [HR], 2.84) than in the time-fixed analysis (hazard ratio, 1.51). The additive regression model indicated that once the patients survive beyond the first 5 years, the impact on prognosis of albumin at diagnosis ceases. The time-dependent prognostic model was superior to the time-fixed variant in assigning low 1-year survival probabilities to patients that actually survived less than 1 year. In conclusion, a time-dependent Cox regression model has the potential to estimate a more precise short-term prognosis in PSC compared with the traditional time-fixed models.

The major cholesterol oxidation products in the human circulation are 27-hydroxycholesterol, 24-hydroxycholesterol, and 7α-hydroxycholesterol. These oxysterols are formed from cholesterol by specific cytochrome P450 enzymes, CYP27, CYP46, and CYP7A, respectively. An additional oxysterol present in concentrations comparable with 7α- and 24-hydroxycholesterol is 4β-hydroxycholesterol. We now report that patients treated with the antiepileptic drugs phenobarbital, carbamazepine, or phenytoin have highly elevated levels of plasma 4β-hydroxycholesterol. When patients with uncomplicated cholesterol gallstone disease were treated with ursodeoxycholic acid, plasma 4β-hydroxycholesterol increased by 45%. Ursodeoxycholic acid, as well as the antiepileptic drugs, are known to induce cytochrome P450 3A. Recombinant CYP3A4 was shown to convert cholesterol to 4β-hydroxycholesterol, whereas no conversion was observed with CYP1A2, CYP2C9, or CYP2B6. The concentration of 4α-hydroxycholesterol in plasma was lower than the concentration of 4β-hydroxycholesterol and not affected by treatment with the antiepileptic drugs or ursodeoxycholic acid. Together, these data suggest that 4β-hydroxycholesterol in human circulation is formed by a cytochrome P450 enzyme.

No prospective study has analyzed simultaneously chronic viral hepatitis and alcoholism as risk factors for liver carcinogenesis, while taking into consideration the role of cirrhosis. Nor has the risk for hepatocellular carcinoma among patients with chronic viral hepatitis been prospectively evaluated in a low-risk Western population. Last, the relationship between hepatocellular carcinoma risk factors and bile duct cancer remains to be clarified. We analyzed prospectively the risk for primary liver and extrahepatic biliary tract cancer among 186,395 patients hospitalized with either chronic viral hepatitis, alcoholism, cirrhosis, or any combination of these conditions through linkages between national Swedish registers. Compared with the general population, the relative risk of hepatocellular carcinoma was 34.4 for chronic viral hepatitis alone, 2.4 for alcoholism alone, and 40.7 for cirrhosis alone. Among patients with combinations of these risk conditions, the relative risk of hepatocellular carcinoma was 27.3 for chronic viral hepatitis and alcoholism, 118.5 for chronic viral hepatitis and cirrhosis, 22.4 for alcoholism and cirrhosis, and 171.4 for all 3 conditions. We found limited evidence for an excess risk of intrahepatic, but not for extrahepatic, biliary duct cancer. Cirrhosis amplifies the risk of hepatocellular carcinoma among patients with chronic viral hepatitis, but it is not a prerequisite for liver carcinogenesis. In contrast, cirrhosis may be a necessary intermediate for the development of hepatocellular carcinoma among alcoholics.

The increased risk for cholangiocarcinoma in primary sclerosing cholangitis (PSC) is well established, but the factors responsible for the malignant development in the bile ducts in this disease are not known. The pathogenesis of cholangiocarcinoma in PSC including the role of chronic inflammation and oncogenic mutations will be discussed. Cholangiocarcinoma is a leading cause of death in PSC and the prognosis even after liver transplantation is poor, with a median survival after cancer diagnosis of 5 months. Therefore, it is of great importance to identify PSC patients who are at risk of developing cholangiocarcinoma in order to transplant them before cancer has developed.

BACKGROUND—Primary sclerosing cholangitis (PSC) is considered to be a chronic autoimmune disease where infiltrating T lymphocytes have been implicated in the destruction of bile ducts. Altered function of these T cells may reflect abnormalities in the immune response leading to tissue damage. AIM—We investigated the proliferative and functional capacity of freshly isolated liver derived T lymphocytes (LDLs) and natural killer (NK) cells from PSC patients. METHODS—The proliferative responses to common mitogens such as phytohaemagglutinin (PHA), concanavalin A (Con A), and lipopolysaccharide (LPS) were studied, and the cytotoxic function of T lymphocytes was measured using allogeneic target cells. NK (CD56+/16+) cytotoxic function was measured using the two cell lines K562 (NK sensitive) and Raji lymphoma cells (NK resistant). RESULTS—Compared with patients with primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and normal controls (without liver disease), in PSC: (1) LDLs contained a low percentage of T cells; (2) there was significantly decreased expression of interleukin (IL)-2 receptor (p

The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P

Patients with primary sclerosing cholangitis (PSC) have an increased risk of developing cholangiocarcinoma (CC), which is notoriously difficult to diagnose since these patients may have increased levels of bilirubin due to benign strictures. To evaluate the validity of different tumor markers as an aid to diagnosing CC, we have carried out serial serum tumor marker analyses in patients with PSC who have been followed for several years.Seventy-five patients with PSC, without any clinical signs of CC were included in the study. They were investigated every 6th months for 3 years, with extensive liver function tests and four tumor serum markers CEA, CA 19-9, CA 50 and CA 242. The patients were then followed for 5 years to exclude the possibility that CC remained unrecognized.Of the 75 patients, two (3%) developed CC during the 3-year period. One of these had normal levels, and one had significantly increased levels of the tumor markers. In the follow-up part of the study two further patients died from CC and one from hepatocellular carcinoma, 3 and 4 years after the 3-year study, respectively. Twenty-one patients had an increase of one of the markers on at least one occasion. Five patients had a transient increase of more than double the upper normal limit of the tumor markers on more than one occasion. There was a good correlation between CA 19-9, CA 50 and CA 242, but not with CEA. Fourteen of the 75 patients had periods of increased bilirubin levels, but none of these showed increased tumor markers.The serum tumor markers CEA, CA 19-9, CA 50 and CA 242 are of limited value for the detection of CC in patients with PSC because of low specificity. However, we found no falsely increased values in patients with hyperbilirubinemia.

BackgroundThe role of the recently discovered GB virus C (GBV-C)/hepatitis G virus in fulminant hepatic failure (FHF) has been debated. Although GBV-C RNA has been detected in many cases of FHF, recent data suggest that the relation between GBV-C and FHF may be accidental.AimsTo retrospectively investigate the possible relation between the presence of GBV-C markers (RNA or antibodies to the GBV-C envelope 2 (E2) glycoprotein) and FHF.MethodsThe presence of GBV-C RNA was determined in serum samples from 58 patients diagnosed with FHF using a reverse transcriptase polymerase chain reaction. Amplified genetic fragments were directly sequenced by the dideoxy chain termination method. Antibodies to GBV-C in serum samples were detected by enzyme immunoassay based on a recombinant GBV-C E2 protein.ResultsNine (16%) patients with FHF had GBV-C RNA and 14 (24%) had GBV-C E2 antibodies, which are higher frequencies than in healthy subjects (pConclusionsThe frequencies of both GBV-C RNA and antibodies are higher in patients with FHF than in healthy subjects. However, these increased frequencies may in many cases be explained by the use of contaminated blood and/or blood products given as therapy.

Bacterial infections, especially cholangitis, are still common complications after liver transplantation (LTx). During recent years, multiresistant enterococci have become a nosocomial problem in transplant units. The present prospective study on 26 patients, including 24 patients with chronic liver disease, demonstrated that enterococci were the predominant micro-organism involved in post-LTx bacterial infections. They were cultured in the feces and in other sites of 10 out of 13 (77%) patients who underwent extensive examinations. Ampicillin-resistant Enterococcus faecium strains were isolated in urine or feces of 2 of the 13 patients prior to LTx. Similarly, resistance to ampicillin and gentamicin, the empirically used antibiotics for patients with fever of unknown origin, was found in E. faecium strains in 3 and 2 patients, respectively. Moreover, multiresistant E. faecium and E. faecalis strains were demonstrated in 46% of the patients in the postoperative period (3 months). However, no vancomycin-resistant enterococci were isolated. The use of antibiotics within 4 months prior to LTx significantly increased the risk of developing ampicillin-resistant bacteria at the time of LTx and of infections with bacteria of enteric origin after LTx (P = 0.03 and 0.01, respectively). We conclude that stool and urine cultures performed prior to LTX may be useful for selecting prophylactic antibiotic regimens.

Background: The reported prevalence of antineutrophil cytoplasmic antibodies (ANCA) in primary sclerosing cholangitis (PSC) varies considerably (26-85%). Part of this may reflect methodological differences but part may reflect the differences in the patient groups analysed. To resolve this issue we compared the sensitivity and specificity of the immunoalkaline phosphatase (IALP) and immunofluorescence (IF) techniques in four different populations. Method: Sera from four centres were tested blind on alcohol-fixed neutrophils using both techniques. Patients: USA: 14 PSC, 14 primary biliary cirrhosis (PBC); Sweden: 32 PSC, 3 autoimmune hepatitis (AIH), 14 PBC, 11 chronic liver disease; Norway: 32 PSC, 14 AIH, 13 PBC, 1 hepatitis C. Italy: 8 PSC, 14 PBC, 8 viral hepatitis. Thirty-six normal healthy volunteers from Oxford, together with positive and negative controls, were also tested. Results: The healthy controls were all ANCA negative. The diagnostic sensitivity and specificity, respectively, of ANCA for PSC using the IALP technique for the different test sera were: USA 71% and 93%, Sweden 66% and 96%, Norway 69% and 46%, Italy 50% and 95%. The diagnostic sensitivity and specificity, respectively, of the IF technique on the same sera were: USA 50% and 86%, Sweden 56% and 86%, Norway 47% and 61%, Italy 50% and 91%. Overall, combining all four groups, detection of ANCA using the IALP technique gave a diagnostic sensitivity of 66% with a specificity of 74% for PSC. In contrast, the IF technique gave an overall diagnostic sensitivity of only 51% (P=0.044, compared with IALP) with a specificity of 73%. Although overall the IALP technique was more sensitive than IF, the differences in sensitivity and specificity between the two techniques did not reach statistical significance for any individual group. Furthermore, the small differences in sensitivity between the four groups using either technique were not significant. However, the IALP technique had greater specificity in the US, Swedish and Italian groups compared with the Norwegian group (P

PURPOSE: A small group of patients with ulcerative colitis (UC) also suffer from primary sclerosing cholangitis (PSC). Genetic and immunologic differences exist between UC patients with and without concomitant PSC. Furthermore, UC patients with PSC are more prone to developing colonic dysplasia/aneuploidy compared with patients with UC only. Because colonic disease activity and treatment with sulfasalazine have been found to be of independent importance for development of colonic carcinoma in UC, this study aims to determine if differences exist concerning colonic disease activity in UC patients with and without PSC. METHODS: Twenty-nine PSC patients with total colitis were matched to two UC patients with total colitis but without liver disease. Case records and questionnaires were used to gain information on pharmacologic treatment and disease activity. RESULTS: Observation time was 20 (PSC group) and 23 years (UC only). Number of patients taking prophylactic treatment did not differ between groups. Patients with UC only had received treatment with systemic and local corticosteroids significantly more often than UC patients with PSC (P< 0.05 andP< 0.02). Patients with UC only were hospitalized because of colonic activity significantly more often (P< 0.02). Number of patients undergoing colectomy because of disease activity or number of patients with chronic continuous symptoms did not differ between the two groups. CONCLUSION: UC in patients with PSC runs a milder course than UC in patients without this complication, although the number of patients taking prophylactic treatment was the same. If lower disease activity reflects differences in pathogenesis of UC in patients with PSC or if it can explain increased risk to develop colonic malignancy in patients with both PSC and UC needs further elucidation.

Primary sclerosing cholangitis (PSC) is a biliary destructive disease mostly affecting patients with ulcerative colitis (UC). PSC has been suggested to be an independent risk factor for the development of colorectal malignancy in UC. Patients with PSC also have an increased risk of developing cholangiocarcinoma. This study aimed at assessing the cumulative risk of colorectal neoplasia in PSC and UC, and also to determine risk factors for the development of cholangiocarcinoma. Fifty-eight PSC patients were included. Forty PSC patients having extensive UC were each matched to two control patients of the same age, with extensive colitis and a comparable duration of the colitis, but without PSC. All UC patients had been under colonoscopic surveillance with multiple biopsies. Among the 40 PSC patients with UC, 16 developed colonic dysplasia or carcinoma, versus 10 in the control group (P < .001). The absolute cumulative risk of developing colorectal dysplasia/carcinoma in the PSC/UC groups was 9%, 31%, and 50% after 10, 20, and 25 years of disease duration. In the group with UC only, the corresponding risk was 2%, 5%, and 10%, respectively (P < .001). Ten patients with PSC developed cholangiocarcinoma, all but one having UC. In the control group, no cholangiocarcinoma occurred. Patients with PSC and UC with colorectal neoplasia developed cholangiocarcinoma significantly more often compared with patients with UC and PSC without colonic dysplasia/carcinoma (P < .02). This study demonstrates not only that patients with PSC and UC have a significantly higher risk of developing colorectal neoplasia compared with patients having UC only, but also that patients with PSC and UC having colorectal neoplasia are more prone to develop cholangiocarcinoma.

Primary sclerosing cholangitis (PSC) is a biliary destructive disease mostly affecting patients with ulcerative colitis (UC). PSC has been suggested to be an independent risk factor for the development of colorectal malignancy in UC. Patients with PSC also have an increased risk of developing cholangiocarcinoma. This study aimed at assessing the cumulative risk of colorectal neoplasia in PSC and UC, and also to determine risk factors for the development of cholangiocarcinoma. Fifty-eight PSC patients were included. Forty PSC patients having extensive UC were each matched to two control patients of the same age, with extensive colitis and a comparable duration of the colitis, but without PSC. All UC patients had been under colonoscopic surveillance with multiple biopsies. Among the 40 PSC patients with UC, 16 developed colonic dysplasia or carcinoma, versus 10 in the control group (P < .001). The absolute cumulative risk of developing colorectal dysplasia/carcinoma in the PSC/UC groups was 9%, 31%, and 50% after 10, 20, and 25 years of disease duration. In the group with UC only, the corresponding risk was 2%, 5%, and 10%, respectively (P < .001). Ten patients with PSC developed cholangiocarcinoma, all but one having UC. In the control group, no cholangiocarcinoma occurred. Patients with PSC and UC with colorectal neoplasia developed cholangiocarcinoma significantly more often compared with patients with UC and PSC without colonic dysplasia/carcinoma (P < .02). This study demonstrates not only that patients with PSC and UC have a significantly higher risk of developing colorectal neoplasia compared with patients having UC only, but also that patients with PSC and UC having colorectal neoplasia are more prone to develop cholangiocarcinoma.

The mechanisms underlying iron-induced liver fibrogenesis in patients with genetic hemochromatosis are poorly understood. We studied signs of Kupffer cell activation and inflammatory responses in liver biopsy specimens obtained from 15 patients with untreated and six patients with treated hemochromatosis. Immunohistochemistry was performed on 11 of the untreated and all treated patients. Three of the untreated patients (20%) had cirrhosis and eight (53%) had fibrosis. None had chronic active hepatitis (CAH). Immunohistochemistry indicated that 55% of the untreated patients had sparse intercellular adhesion molecule-1 (ICAM-1) expression by hepatocytes, and all of these had Kupffer cell iron overload. No ICAM-1 expression was seen by hepatocytes in treated patients or healthy controls. ICAM-1 was strongly expressed by hepatocytes from control patients with inflammatory liver disease. HLA-DR reactivity was seen on sinusoidal cells in all groups, but not on hepatocytes except for two of the control patients with CAH. Twenty-seven percent of the untreated hemochromatosis patients displayed moderate infiltration by CD3-positive lymphocytes. Electron microscopy of samples from untreated hemochromatosis patients showed hypertrophic Kupffer cells containing iron-rich remnants of phagocytosed hepatocytes. Fat-storing cells close to iron-laden hepatocytes contained multiple lipid droplets and adjacent collagen fibril bundles. Thus, in patients with untreated genetic hemochromatosis and Kupffer cell iron overload, hepatocytes occasionally express ICAM-1. In regions with heavy iron overload, Kupffer cell hypertrophy and transition of fat-storing cells are seen. Our findings indicate that release of factors from iron-loaded, activated Kupffer cells is of importance for the transformation of fat-storing cells and increased collagen deposition seen in genetic hemochromatosis.

Background/Aims: The association between primary sclerosing cholangitis (PSC) and the HLA haplotype A1, B8, DR3, DQ2 is well established. During the last few years, several additional HLA associations have been suggested in PSC. Furthermore, two different HLA-DR specificities have been reported to be markers for rapid disease progression. Our aim was to critically evaluate all of the current and as yet mostly unconfirmed HLA class II issues in PSC. Methods: Seventy-five Swedish patients with PSC were HLA-DR and HLA-DQ genotyped. Results: Of the recently described HLA associations in PSC, the association with the DRB1∗1301, DQA1∗ 0103, DQB1∗0603 haplotype was decisively confirmed, whereas the DRB1∗04 specificity was only slightly under-represented and the frequency of DR2 was neutral. The association with codon 38 of DRB genes was secondary to the DRB3∗0101 association. HLA-DR and HLA-DQ alleles were not found to be markers for disease progression. Conclusions: The HLA-associated genetic susceptibility to PSC cannot be attributed to specific amino acid positions of the DRβ chains. The highly discrepant results obtained in two previously reported studies and the present investigation indicate that HLA class II alleles are not markers for a more aggressive clinical course in PSC.

In an epidemiological study of the incidence of ulcerative colitis (UC) in the county of Stockholm between 1955 and 1979, 1274 patients with UC were discovered. Almost all these patients had regularly been investigated with liver function tests; 142 (11%) of them showed signs of hepatobiliary disease. A follow up study on all 142 patients with abnormal liver function and UC was made between 1989 and 1991 to evaluate the cause of the liver abnormality and to find out if the liver disease had affected the survival rates. At follow up, eight patients were reclassified as having Crohn's disease, 60 had developed normal liver function as judged from test results, while the remaining 74 still had signs of hepatobiliary disease. The most common explanation for a transient abnormality in liver function was active colitis. The temporary signs of liver injury were not associated with changes in survival rates for these patients. Infections, especially those because of hepatitis B and C virus transmitted by blood transfusions accounted for the abnormalities in liver function in 21 patients, nine of which had a chronic, but non-fatal course. Twenty nine (2.3%) of the patients developed primary sclerosing cholangitis (PSC), and 12 of them died during the study period four because of cholangiocarcinoma and eight because of hepatic failure; one patient had a transplant. The estimated median time of survival from the first presentation of evidence of a liver function, compatible with the diagnosis of PSC, to death or liver transplantation was 21 years. A comparison of survival rates in patients with UC and patients with UC and concurrent PSC showed, a significant reduction in survival in the PSC group (p

Recently three large studies have been presented in which the prognostic significance of clinical, laboratory and histological parameters measured early in the course of the disease was determined in primary sclerosing cholangitis patients. A different prognostic index was presented in each study. The aim of the present study was to evaluate these prognostic indices in a group of 37 patients with primary sclerosing cholangitis, assessed for liver transplantation. The results are compared to the outcome in the patients. At first referral, 12 patients were considered too healthy for transplantation and 17 were accepted for transplantation, six of whom died during the waiting time. Ten patients had cholangiocarcinoma or hepatocellular cancer. Albumin and bilirubin differed significantly between the patients accepted for transplantation and those considered too healthy. Only one prognostic index, presented by Dickson et al., could discriminate between "too healthy" and "in need of transplantation". However, the overlap between the groups was large, suggesting that this index may be of little or no help in the clinical situation with individual patients. Moreover, neither the prognostic index, nor any of the laboratory values could identify the patients with cancer. It is concluded that prognostic indicators have been found that may help to characterise primary sclerosing cholangitis patients. However, primary sclerosing cholangitis patients with an accompanying cholangiocarcinoma still cannot be identified.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by immunoregulatory disturbances and fibrosis. Several cytokines may be of importance for the inflammatory response and the development of fibrosis. In the present study the capacity to produce tumor necrosis factor (TNF) and interleukin-1 (IL-1) was determined in 11 patients with PSC, 10 patients with PBC, and 20 healthy control subjects. As compared with the controls, in vitro cultured mononuclear cells from PBC patients showed a lower spontaneous TNF production (median, 16,499 cpm; range, 7181-41,907; p less than 0.02), whereas the TNF production of PSC patients was similar to that of the controls. Lipopolysaccharide (LPS)-stimulated TNF production was also lower in the PBC group (median, 40,564 cpm; range, 23,493-69,452) than in PSC patients (median, 58,898 cpm; range, 37,997-91,485; p less than 0.03). The spontaneous and LPS-stimulated IL-1 production did not differ in patients and healthy controls. The cytokine production in patients with PBC and PSC did not correlate to histologic activity, associated diseases such as ulcerative colitis and bilirubin, or to Child-Pugh classification. Thus, in contrast to hepatocellular diseases, in which cytokine production is reported to be increased, PBC and PSC are accompanied by low or normal TNF and IL-1 production.

Background: Hyperbiliverdinaemia is a poorly defined clinical sign that has been infrequently reported in cases of liver cirrhosis or liver carcinoma, usually indicating a poor long-term prognosis. Aims: To clarify the pathogenesis of hyperbiliverdinaemia in an extended case report. Methods: A 64-year-old man with alcoholic cirrhosis was admitted to hospital with severe bleeding from oesophageal varices. Ultrasonography showed ascites, but no dilatation of the biliary tree. The skin, sclerae, plasma, urine and ascites of the patient showed a greenish appearance. Bilirubin levels were normal, and there were no signs of haemolysis. Biliverdin was analysed in plasma and urine with liquid chromatography coupled to mass spectrometry. The seven exonic regions of the biliverdin reductase-A (BVR-A) gene was amplified by polymerase chain reaction and sequenced. Results: Biliverdin was present in plasma and urine. In nucleotide 52 of exon I of the DNA isolated from the hyperbiliverdinaemic patient, we discovered a novel heterozygous CT nonsense mutation converting an arginine (CGA) in position 18 into a stop codon (TGA) (R18Stop) predicted to truncate the protein N-terminally to the active site Tyr97. Two children of the proband were heterozygous for the identical mutation in the BVR-A gene, but had no clinical signs of liver disease and had normal levels of biliverdin. The BVR-A gene mutation was not found in 200 healthy volunteers or nine patients with end-stage liver cirrhosis. Conclusion: Hyperbiliverdinaemia (green jaundice) with green plasma and urine may be caused by a genetic defect in the BVR-A gene in conjunction with decompensated liver cirrhosis.

The exact incidence and prevalence of Budd-Chiari syndrome (BCS) is unknown in the general population. Published reports differ in terms of the clinical characteristics, effects of therapy and survival. To investigate the epidemiology, clinical presentation and survival in patients with BCS. Retrospective multicentre study in Sweden reviewing the medical records of all patients with BCS 1986-2003, identified from the computerised diagnosis database of 11 hospitals, including all university hospitals and liver transplantation centres. Forty-three patients with BCS were identified, of whom nine (21%) had concomitant portal vein thrombosis. The mean age-standardised incidence and prevalence rates in 1990-2001 were calculated to be 0.8 per million per year and 1.4 per million inhabitants respectively. Myeloproliferative disorders (38%), thrombophilic factors (31%) and oral contraceptives (30%) were common aetiological factors. Two or more risk factors were present in 44%. In 23%, no risk factor was evident. The median follow-up time was 2.7 years. Seventy-two percent were on anticoagulant therapy during follow-up. Transjugular intrahepatic portosystemic shunting, surgical shunting procedures and liver transplantation were performed in 4, 6 and 18 patients respectively. Nineteen patients died. The overall transplantation-free survival at 1, 5 and 10 years was 47, 28 and 17% respectively. Budd-Chiari syndrome is a rare disorder; the mean age-standardised incidence and prevalence rates in Sweden in 1990-2001 were calculated to be 0.8 per million per year and 1.4 per million inhabitants respectively. The presence of a myeloproliferative disorder was a common aetiological factor in our cohort and about half of the patients had a multifactorial aetiology. The transplantation-free survival was poor. (Less)

Hepatobiliary disorders are well known complications in patients with ulcerative colitis but it is not possible to predict those patients with ulcerative colitis who will eventually develop liver disease. In this study, liver biopsies from 74 patients with ulcerative colitis have been reevaluated. None of the patients showed clinical or biochemical signs of liver disease at the time of biopsy. Thirty seven (50%) had a completely normal liver biopsy. The others showed minimal portal inflammation or fatty infiltration. The biopsies of three patients displayed concentric, periductular fibrosis, or so called 'onion skin' lesions. None showed other signs of fibrosis or cirrhosis. The histological findings were unrelated to either activity or extent of colitis, except for the onion skin lesions which were seen exclusively in biopsies of patients with involvement of the total colon. Sixty eight of the 74 patients were reviewed after a mean interval of 18 years. The majority had no symptoms of hepatobiliary disorders and only two had developed liver disease; one suffered from cryptogenic cirrhosis, possibly due to non-A, non-B hepatitis and the other of an autoimmune liver disease and later developed a bile duct carcinoma. Both were women with total colonic involvement. At the time of the first liver biopsy one showed no histological abnormalities and the other only minor fatty infiltration. Thus, minor abnormalities in liver tissue are common in patients with ulcerative colitis without biochemical evidence of liver disease. The morphological changes are of little help in predicting the future risk of a patient with ulcerative colitis developing a clinically relevant hepatobiliary complication. The absence of biochemical parameters for liver disease during the early years of ulcerative colitis predict a favourable longterm diagnosis as regards hepatobiliary complications.

This study describes the distribution of the major histocompatibility class II antigens HLA-DR, HLA-DP, and HLA-DQ in liver tissue from eight patients with primary sclerosing cholangitis, by means of the immunoperoxidase technique on cut cryostat sections. HLA-DR was expressed on the bile duct epithelium and vascular endothelium from all patients. HLA-DP showed an expression much like HLA-DR on the bile duct epithelium, but the vascular endothelium mostly did not stain for HLA-DP. HLA-DQ was generally more weakly expressed, and only three of the patients expressed HLA-DQ on the bile ducts. None of the hepatocytes expressed any of the MHC class II antigens.

Overlap 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.We 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 histological diagnosis compatible with both autoimmune hepatitis and primary sclerosing cholangitis was required for inclusion.26 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.Small duct primary sclerosing cholangitis is prevalent in the overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis.

In published studies there is a lack of data about the risks, management and how women with autoimmune hepatitis (AIH) decide on and are advised about pregnancy. The aim of this study was to investigate how women with AIH consider pregnancies, are advised and pharmacologically treated, as well as the outcome.A questionnaire was mailed to 128 women with AIH diagnosed during their fertile period and data from the Swedish National Birth Register was also used for matched controls.There was an 83% response rate to the questionnaires. Sixty-three pregnancies were reported by 35 women. 48% did not consult their doctors before getting pregnant. More than half of the women reduced or stopped the immune suppression during pregnancy or breastfeeding. Some women were advised to abstain from pregnancy or even to have an abortion. Caesarean sections were performed more frequently in the AIH group (16% compared with 6.5% in the control group p0.01). There were no significant differences in the number of stillborn infants or infants with malformations. However, 30% of the patients experienced flare-up after delivery.In general, the outcome of pregnancy in women with AIH seems to be good. Current pharmacological treatment appears to be safe, including azathioprine during pregnancy and lactation. After delivery an active preparedness to increase pharmacotherapy should be considered.

Five to 15% of patients with primary sclerosing cholangitis (PSC) develop cholangiocarcinoma (CC) with a median survival of 5 to 7 months, an outcome not significantly improved by liver transplantation. However, if CC is found incidentally during the procedure or in the explanted liver, 5-year survival rates of 35% are reported. A noninvasive method to detect CC small enough to allow for intended curative surgery is needed. Unfortunately, computed tomography (CT) and ultrasonography (US) have poor sensitivity for detection of CC in PSC; however, positron emission tomography (PET) using 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) differentiates well between CC and nonmalignant tissue. We examined whether PET findings are valid using a blinded study design comparing pretransplantation FDG-PET results with histology of explanted livers. Dynamic FDG-PET was performed in 24 consecutive patients with PSC within 2 weeks after listing for liver transplantation and with no evidence of malignancy on CT, magnetic resonance imaging, or ultrasonography. The PET Center staff was blinded to clinical findings, and surgeons and pathologists were blinded to the PET results. Three patients had CC that was correctly identified by PET. PET was negative in I patient with high-grade hilar duct dysplasia. In 20 patients without malignancies, PET was false positive in I patient with epitheloid granulomas in the liver. In conclusion, dynamic FDG-PET appears superior to conventional imaging techniques for both detection and exclusion of CC in advanced PSC. FDG-PET may be useful for screening for CC in the pretransplant evaluation of patients with PSC.

Approximately 80% of patients with primary sclerosing cholangitis (PSC) of Northern European origin have concurrent inflammatory bowel disease (IBD). The majority have ulcerative colitis, but there is also an association with Crohn's colitis. The pathogenetic link between PSC and IBD is unknown. We aimed to assess whether genetic risk factors in PSC can be identified on the basis of known IBD susceptibility genes and the shared PSC-IBD phenotype.IBD-associated polymorphisms in the CARD15, TLR-4, CARD4, SLC22A4, SLC22A5, DLG5, and MDR1 genes were genotyped in a large cohort of 365 Scandinavian PSC patients and 368 healthy controls using TaqMan technology.No significant association between any of the investigated genetic IBD risk variants and overall susceptibility to PSC was observed. Apart from a tendency toward an increased carrier frequency of the mutant CARD15 alleles in PSC patients with concurrent Crohn's disease as compared with healthy controls (15.6%vs 9.0%, P = 0.22), no association with any of the polymorphisms investigated was evident even when considering only PSC patients with concurrent IBD.It seems unlikely that IBD-associated polymorphisms in the CARD15, TLR-4, CARD4, SLC22A4, SLC22A5, DLG5, and MDR1 genes confer susceptibility to PSC. The current knowledge of genetic risk factors in IBD may not contribute to our understanding of molecular mechanisms involved in the pathogenesis of PSC or the IBD phenotype in PSC.

Hepatitis C virus (HCV)-induced cirrhosis is the major indication for liver transplantation globally, and an increasing indication for liver transplantation in Sweden. We have retrospectively examined the 120 patients transplanted for HCV cirrhosis from 1987 through 2005, including 11 who received more than one graft. The 1-, 3-, and 5-year postoperative survivals for all patients transplanted for HCV with or without hepatocellular cancer (HCC) were 77%, 66%, and 53%, respectively. HCV patients without HCC had a 1-, 3-, and 5-year survivals of 78%, 73%, and 61%, compared with 84%, 79% and 74%, respectively, for patients transplanted with chronic liver diseases without cancer or HCV. The number of patients with HCV cirrhosis transplanted in our center is increasing. Compared with patients transplanted for other chronic liver diseases, we experienced inferior results among patients with HCV cirrhosis.

Summary The role of adjuvant systemic chemotherapy in liver transplantation (LT) for hepatocellular carcinoma (HCC) is controversial. Here, we report the results of a Nordic prospective, randomized, multi-centre trial of systemic low-dose doxorubicin in patients with HCC. Between February 1996 and April 2004, 46 patients were randomized to receive either neoadjuvant doxorubicin in combination with LT (chemo group; n = 19) or LT alone (control group; n = 27). In the chemo group, doxorubicin was administered intravenously, 10 mg/m2 weekly, starting from acceptance onto the waiting list for LT. One intraoperative dose of 15 mg/m2 was given, and postoperatively doxorubicin was given weekly at a dose of 10 mg/m2, depending on the clinical course, up to a cumulative dose of 400 mg/m2. Actuarial, 3-year overall survival (OS) and disease-free survival (DFS) in the control group were 70% and 50%, respectively. In the chemo group, both OS and DFS were 63%. Freedom from recurrence at 3 years was 55% in the control group and 74% in the chemo group. None of the differences was statistically significant. Neoadjuvant treatment with systemic low-dose doxorubicin seems not to improve either survival or freedom from recurrence in patients with HCC undergoing LT.

Background & Aims: The steroid and xenobiotic receptor (SXR) is a ligand-dependent transcription factor that mediates protection against bile acid-induced liver injury in cholestatic animal models. Ursodeoxycholic acid and rifampicin are known ligands. We investigated whether functional polymorphisms of the SXR gene influence disease susceptibility or disease progression in patients with primary sclerosing cholangitis (PSC). Methods: Polymorphisms at 8 loci across the SXR gene were genotyped in 327 Scandinavian PSC patients and 275 healthy controls. Kaplan–Meier survival analyses and Cox regressions were performed to estimate effects from genotypes on patient survival, defined as time from diagnostic cholangiography to death or liver transplantation. Results: Susceptibility to PSC was not associated with any of the SXR polymorphisms studied. Median survival was significantly reduced in patients homozygous for the minor allele as compared with patients carrying at least 1 major allele of the neighboring polymorphisms rs6785049 (10.8 vs 14.0 years, respectively, P = .01), rs1054190 (3.6 vs 13.6 years, respectively, P = .004), and rs3814058 (3.5 vs 13.3 years, respectively, P = .01). The increased risk of death or liver transplantation was confirmed in univariate Cox regressions (relative risk [RR]rs6785049 = 1.7, 95% CI: 1.1–2.6; RRrs1054190 = 3.1, 95% CI: 1.4–7.1; and RRrs3814058 = 2.2, 95% CI: 1.2–4.2 for the 3 polymorphisms, respectively). In multiple Cox regressions including age at PSC onset, rs1054190 remained an independent risk factor. Conclusions: Functional SXR gene variants appear to modify disease course in PSC. Further investigations of polymorphisms in the SXR gene may provide insight into the prognostic importance of SXR-regulated pathways in this disease, perhaps even in a therapeutic perspective.

Aim. Liver sinusoidal endothelial cells (LSECs) have been implicated to play a role in the induction of liver allograft rejections. Here, we studied the clinical consequences of preformed LSEC-reactive antibodies and their functional capacity in modulating T-cell responses. Methods. Pre- and posttransplant sera and T lymphocytes from 95 liver transplant patients were used in this study. LSECs were isolated from a normal healthy liver. Binding of antibodies to LSECs was detected using flow cytometric analysis. To study whether LSEC antibodies facilitated cell-mediated immunity, a mixed cell culture (MCC) assay was used. Cytokines in the supernatant of MCC were also measured by enzyme-linked immunosorbent assay. Immunohistochemical staining on liver biopsy sections was performed to detect deposition of immunoglobulins in LSEC during rejections. Results. Significantly higher numbers of patients with rejections had LSEC antibodies (35/50, 70%) compared with 8/45 (18%) without rejections (P

Human hepatic progenitor cells (HPCs) have been shown to co-express the hematopoietic stem cell (HSC) markers, CD117 and CD34. These cells differentiate not only into hepatocytes and cholangiocytes but also into pancreatic ductal and acinar cells under certain conditions. The fetal liver (FL) is rich in precursor/stem cells; however, little is known about (i) the markers expressed by liver cells during fetal development and (ii) whether an equivalent to the adult liver stem-like progenitors exists in the FL. Here, (i) FL tissue obtained from human 5-18-week-old fetuses were evaluated by means of flow cytometry, immunocyto-, and histochemistry for the emergence of cells expressing and co-expressing known hematopoietic, hepatic, and pancreatic cell markers, and (ii) isolated putative HPCs were phenotypically and molecularly characterized. We report that (i) red blood and endothelial cell precursors were most abundant in early gestation. Cells expressing HSC and pancreatic markers were found in the first trimester, while cells expressing hepatic markers appeared in the second trimester. Very few committed cells were present in FLs obtained early in the first trimester. In addition, cells expressing pancreatic markers co-expressed the HSC marker CD117. (ii) Isolated CD117+/CD34+/CD90- cells in vitro expressed both the genes and proteins for the hepatic markers such as albumin, alpha feto protein (AFP), alpha1-antitrypsin, and cytokeratin 19 (CK19). Our study suggests that hepatoblast and ductal plate/bile duct development mainly occurs during the second trimester. FLs in gestation weeks 5-9 had the highest numbers of precursor cells and the least committed cells. Cells that differentiate into Alb+ or CK19+ can be isolated from early FLs and may be appropriate progenitors for establishing novel systems to investigate basic mechanisms for cell therapy.

There is no medical treatment of proven benefit for primary sclerosing cholangitis. This study aimed at studying the effect of a higher dose of ursodeoxycholic acid than previously used on survival, symptoms, biochemistry, and quality of life in this disease.A randomized placebo-controlled study was performed in tertiary and secondary gastroenterology units. A total of 219 patients were randomized to 17 to 23 mg/kg body weight per day of ursodeoxycholic acid (n = 110) or placebo (n = 109) for 5 years. Follow-up data are available from 97 patients randomized to ursodeoxycholic acid and for 101 randomized to placebo. Quality of life was assessed by using the Medical Outcomes Study 36-item Short-Form Health Survey.The combined end point "death or liver transplantation" occurred in 7 of 97 (7.2%) patients in the ursodeoxycholic acid group vs 11 of 101 (10.9%) patients in the placebo group (P = .368; 95% confidence interval, -12.2% to 4.7%). The occurrence of liver transplantation as a single end point showed a similar positive trend for ursodeoxycholic acid treatment (5/97 [5.2%] vs 8/101 [7.9%]; 95% confidence interval, -10.4% to 4.6%). Three ursodeoxycholic acid and 4 placebo patients died from cholangiocarcinoma, and 1 placebo patient died from liver failure. Alkaline phosphatase and alanine aminotransferase tended to decrease during the first 6 months. There were no differences between the 2 groups in symptoms or quality of life. Analyses of serum ursodeoxycholic acid concentration gave no evidence that noncompliance may have influenced the results.This study found no statistically significant beneficial effect of a higher dose of ursodeoxycholic acid than previously used on survival or prevention of cholangiocarcinoma in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic, progressive, destructive, biliary disease of unknown causes, characterized by multiple, fibrosing, inflammatory strictures of the extrahepatic and intrahepatic bile ducts. The disease often progresses to cirrhosis and leads to premature death caused by liver failure or cholangiocarcinoma. PSC has become a major indication for liver transplantation. 110 The diagnosis of PSC has evolved in recent years from an initially very rigid set of criteria to a diagnosis is based on characteristic clinical, biochemical, histological and—most importantly—radiological features, with irregularity and beading of the intrahepatic or extrahepatic bile ducts. 24,114 Secondary causes of sclerosing cholangitis, such as previous biliary surgery, biliary stone disease, ischemic bile-duct damage caused by treatment with floxouridine, congenital biliary-tree abnormalities, cholangiopathy associated with acquired immunodeficiency syndromes, or bile duct neoplasms must be excluded. 23,61 Cholangiographic features simulating intrahepatic PSC can also be seen in patients with cirrhosis, hepatocellular carcinoma, polycystic liver disease, submassive hepatic necrosis, amyloidosis, intrahepatic portal thrombosis, liver metastases, leukemia and lymphoma, 100 pointing to the importance of combining clinical, histological and cholangiographic features when diagnosing PSC. Some patients with inflammatory bowel disease (IBD), cholestatic biochemical abnormalities and histology consistent with PSC have a normal cholangiogram. These patients are considered to have small bile duct sclerosing cholangitis which may be part of the spectrum of PSC. 59,109

Liver sinusoidal endothelial cells (LSECs) may be implicated in the induction of liver allograft rejections. We studied the clinical consequences of LSEC-reactive antibodies and their functional capacity in modulating T-cell responses during acute rejections. Pre- and posttransplant sera and T lymphocytes from 95 liver transplant patients were used in this study. LSECs were isolated from normal healthy liver. Binding of antibodies to LSECs was detected using flow cytometry. To study whether LSEC antibodies facilitated cell-mediated immunity, a mixed cell culture (MCC) assay was used. Cytokines in the supernatants of MCC were measured by enzyme-linked immunosorbent assay. Liver biopsy sections were stained to detect the deposition of immunoglobulins in LSECs during rejections. The 2-year patient survival was 86.3%. A significantly higher number of patients with rejections had LSEC antibodies (35/50; 70%) than those without rejections (8/45; 18%) (P < .0001). Purified fractions of LSEC antibodies induced the expression of the costimulatory molecule CD86 on LSECs. A significantly higher number of patients with LSEC antibodies and rejections had an increased proliferation of T cells and markedly decreased levels of transforming growth factor β (TGF-β) in the MCC than those without antibodies and rejections (P < .0001, P < .0001, respectively). Deposition of antibodies in LSECs during rejection episodes was observed in the biopsies of patients with LSEC antibodies but not in those without LSEC antibodies. In conclusion, antibodies to LSECs may facilitate acute liver allograft rejections by down-regulating the immune modulating cytokine TGF-β and thus up-regulating alloreactive T-cell proliferation. (HEPATOLOGY 2004;40:1211–1221.)