A novel mutation in the biliverdin reductase-A gene combined with liver cirrhosis results in hyperbiliverdinaemia (green jaundice).

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 C-->T 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.

Transitions between variant forms of primary biliary cirrhosis during long-term follow-up.

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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Small duct primary sclerosing cholangitis is prevalent in the overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis.

Budd-Chiari syndrome in Sweden: epidemiology, clinical characteristics and survival - an 18-year experience.

BACKGROUND: 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. AIMS: To investigate the epidemiology, clinical presentation and survival in patients with BCS. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Living-related liver transplantation in children--a single center evaluation of the outcome of donor candidates and recipients.

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.

Autoimmune hepatitis among fertile women: strategies during pregnancy and breastfeeding?

OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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 p<0.01). 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. CONCLUSIONS: 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.

Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis.

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 kappaB. 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-1beta, interleukin-8, interferon gamma, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and transforming growth factor beta. 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.

Abdominal tenderness in ascites patients indicates spontaneous bacterial peritonitis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP), which has been reported to be present in 10-30% of patients with cirrhotic ascites, may easily be overlooked. An important aim of our study was to determine whether there are any clinical signs which, in clinical practice, may predict or exclude SBP. METHODS: We studied 133 patients with cirrhotic ascites from medical units at nine Swedish university hospitals where there had been at least one diagnostic ascites tap with analysis of polymorphonuclear leukocytes in the ascites fluid. The patients had initially been questioned about background factors and physically examined according to a standardized case record form. Samples of blood, urine, and ascites were then drawn for analysis according to a structured schedule. RESULTS: SBP could be excluded in 80% of all the cases and was confirmed in 8% of the 133 patients in the final analysis. Abdominal pain and abdominal tenderness were more common in patients with SBP (p<0.01), but no other physical sign or laboratory test could separate SBP cases from the others. CONCLUSIONS: SBP was present in about one-tenth of the hospitalized patients with cirrhotic ascites in this cohort. Performing repeated physical examinations and paying particular attention to abdominal tenderness may be the best way to become aware of the possible development of this complication.

Celiac disease and risk of liver disease: a general population-based study.

BACKGROUND & AIMS: Celiac disease (CD) is an important cause of hypertransaminasemia. CD might also be associated with severe forms of liver disease. We investigated the risk of liver disease in 13,818 patients with CD (1964-2003) and 66,584 age- and sex-matched reference individuals from a general population cohort. METHODS: We used Cox regression to estimate hazard ratios (HRs) for later liver disease and conditional logistic regression to estimate the risk of CD in individuals with liver disease before study entry. RESULTS: CD was associated with an increased risk of acute hepatitis (HR, 5.21; 95% confidence interval [CI], 1.88-14.40; P = .001), chronic hepatitis (HR, 5.84; 95% CI, 2.89-11.79; P < .001), primary sclerosing cholangitis (HR, 4.46; 95% CI, 2.50-7.98; P < .001), fatty liver (HR, 6.06; 95% CI, 1.35-27.16; P = .018), liver failure (HR, 3.30; 95% CI, 2.22-4.88; P < .001), liver cirrhosis or liver fibrosis (HR, 2.23; 95% CI, 1.34-3.72; P < .001), and primary biliary cirrhosis (HR, 10.16; 95% CI, 2.61-39.49; P < .001). There was no increased risk of liver transplantation (HR, 1.07; 95% CI, 0.12-9.62; P = .954). Adjustment for socioeconomic index or diabetes mellitus had no notable effect on the risk estimates. Prior liver disease was associated with a statistically significant 4-fold to 6-fold increased risk of later CD. CONCLUSION: This study suggests that individuals with CD are at increased risk of both prior and subsequent liver disease.

Genetic polymorphisms associated with inflammatory bowel disease do not confer risk for primary sclerosing cholangitis.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Changes over a 20-year period in the clinical presentation of primary sclerosing cholangitis in Sweden.

OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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 (p<0.05). CONCLUSIONS: 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.

Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis.

We report the case of a middle-age patient presenting with severe progressive protoporphyric cholestasis. To halt further progression of liver disease, medical treatment was given aimed at different mechanisms possibly causing cholestasis in erythropoietic protoporphyria. Within eighty days, liver biochemistry completely normalized and liver histology markedly improved. Bone marrow transplantation was performed to prevent relapse of cholestatic liver disease by correcting the main site of protoporphyrin overproduction. Thirty-three months after cholestatic presentation and ten months after bone marrow transplantation, liver and porphyrin biochemistry remains normal. The patient is in excellent condition and photosensitivity is absent. The theoretical role of each treatment used to successfully reverse cholestasis and the role of bone marrow transplantation in erythropoietic protoporphyria are discussed. Medical treatment can resolve hepatic abnormalities in protoporphyric cholestasis. Bone marrow transplantation achieves phenotypic reversal and may offer protection from future protoporphyric liver disease.

Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation.

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.

Perinatal events and the risk of developing primary sclerosing cholangitis.

AIM: To investigate whether perinatal events, intrauterine or postpartum, are associated with the development of primary sclerosing cholangitis (PSC) later in life. METHODS: Birth records from 97 patients with adult PSC in Sweden were reviewed. Information on perinatal events including medications and complications during pregnancy, gestation length, birth weight and length were collected. Two control children of the same sex were selected for each subject. Conditional multiple logistic regression was used to assess associations of the perinatal measures with development of PSC. RESULTS: No significant associations were found between gestational age, birth length, breastfeeding, and the majority of medical complications including infections or medication during pregnancy for the mothers or postpartum for the children. Vaginal bleeding and peripheral oedema showed associations with PSC, with matched odds ratios of 5.70 (95% CI, 1.13-28.83) and 2.28 (95% CI, 1.04-5.03), respectively. CONCLUSION: The associations of vaginal bleeding and oedema with subsequent PSC cannot readily be explained, so our findings do not strongly support the hypothesis of a significant role of perinatal events as a risk for the development of PSC later in life.

Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis.

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; RR(rs1054190) = 3.1, 95% CI: 1.4-7.1; and RR(rs3814058) = 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.

Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis.

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.

A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no additional treatment in liver transplantation for hepatocellular carcinoma.

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/m(2) weekly, starting from acceptance onto the waiting list for LT. One intraoperative dose of 15 mg/m(2) was given, and postoperatively doxorubicin was given weekly at a dose of 10 mg/m(2), depending on the clinical course, up to a cumulative dose of 400 mg/m(2). 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.

Primary sclerosing cholangitis can present with acute liver failure: Report of two cases.

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.