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Background: Liver cirrhosis is characterized by a silent phase until decompensation, which is defined by ascites, bleeding from esophageal varices or hepatic encephalopathy. Aim: We compare the clinical course, patterns of survival and causes of death by etiology during long-term follow-up in a large population-based cohort of patients with incident cirrhosis. Material and methods: We used population-based medical registries for a cohort study of patients with liver cirrhosis diagnosed January 2001 to December 2010, in the Scania region of Sweden. Medical records were reviewed. Patients were classified according to etiology and clinical parameters were registered. Patients were followed until December 2017. Results: The cohort comprised 1317 patients, 631 were decompensated at diagnosis and 387 decompensated during follow-up. The cumulative 10-year incidence of decompensation, with death and transplantation as competing risks, was 89% in alcoholic cirrhosis, 58% in hepatitis C and 75% in cryptogenic cirrhosis. The lowest 10-year transplantation-free survival rates were found in cryptogenic cirrhosis (11%), alcohol-related cirrhosis (18%) and alcohol combined with hepatitis C (12%). Autoimmune hepatitis cirrhosis showed the best 10-year survival (53%) and hepatitis C, non-alcoholic steatohepatitis, primary biliary cholangitis, and primary sclerosing cholangitis and other causes averaged 30%. Decompensation at diagnosis was an important predictor for death in all etiologies apart from alcoholic cirrhosis. 991 patients died and 91 were transplanted. Conclusion: Our results show that the clinical course and survival in cirrhosis differ considerably by both etiology and state at diagnosis. (Less)

Objectives: Liver cirrhosis is characterized by a silent phase until decompensation, which is defined by onset of ascites, variceal bleeding, or encephalopathy. Although it is presumed that the survival of decompensated patients is the same regardless of when decompensation occurs, data to support this are scarce. We aimed to study the impact of time of decompensation on the clinical course and survival of patients with cirrhosis in a large population-based cohort. Materials and methods: We used medical registries to define a 10-year cohort of 1317 patients with incident liver cirrhosis in the Scania region of Sweden. Medical records were reviewed. Patients were followed until December 2011, and for death or transplantation until December 2014. Results: In the cohort, 629 patients were decompensated at diagnosis, of which 505 had ascites and 44 variceal bleeding only. During follow-up, 228 patients developed ascites and 39 variceal bleeding as first complication. Patients with ascites as first complication showed worse survival than patients who had ascites at diagnosis. (5-year survival 33% vs. 15%, HR 1.60 (95% CI 1.34–1.90)). This difference persisted after adjustment for confounders, including hepatocellular cancer (HR 1.38 (95% CI 1.15–1.67)). Worse survival was also seen when bleeding from varices occurred during follow-up rather than at diagnosis. Conclusions: Our results provide evidence for an association between transplantation-free survival after decompensation and the time of decompensation in liver cirrhosis, with worse survival when decompensation occurs during follow-up, thus challenging the generally held, view that the survival after decompensation is independent of when decompensation occurs.

Summary Background In Sweden, the most common causes of liver cirrhosis are alcohol overconsumption and hepatitis C. However, recent data on the clinical characteristics of Swedish patients with cirrhosis are scarce. Aims To determine the incidence, clinical presentation, aetiological spectrum and survival rates of liver cirrhosis in Southern Sweden from 2001 to 2011. Methods We used population-based medical registries to conduct a cohort study of all patients with liver cirrhosis in the southernmost region of Sweden with a population of 1.17 million. Medical records and histopathology data were reviewed. Patients were classified according to aetiology, and clinical parameters were registered. Patients were followed until death or December 2014. Results A total of 1317 patients with cirrhosis were identified. The crude annual incidence of cirrhosis was estimated at 14.1/100 000. The most common aetiology was alcohol overconsumption with or without additional causes of cirrhosis (58%) followed by HCV alone (13%) and cryptogenic cirrhosis (12%). At diagnosis, ascites occurred in 43%, variceal bleeding in 6% and overt encephalopathy in 4%. The median follow-up was 4.3 years. The total 1-, 5- and 10-year survival rates were 79%, 47% and 27% respectively. Survival rates were better for women than for men. A 10-year cumulative incidence of transplantation was 7.3%. Mortality was worst for alcoholic cirrhosis with concomitant HCV when adjusted for age and gender. Conclusions Sweden continues to have a low incidence of cirrhosis compared with other European countries. Mortality varies with gender, aetiology and severity at diagnosis. Patients with alcoholic cirrhosis with concomitant HCV infection fare worst. (Less)

BACKGROUND & AIMS: Corticosteroids alone or in conjunction with azathioprine (AZA) is the standard treatment in autoimmune hepatitis (AiH). Individual variations in thiopurine (TP) metabolism may affect both drug efficacy and toxicity. Our aim was to investigate the utility of thiopurine methyltransferase (TPMT) as well as thioguanine nucleotide (TGN) and methylthioinosine monophosphate (meTIMP) metabolite measurements with regard to clinical outcome. METHODS: Two hundred thirty-eight patients with AiH were included in this cross-sectional study. TPMT status was assessed in all patients, while TGN and meTIMP were measured in patients with ongoing TP medication. Clinical outcome was evaluated by liver tests and the ability to withdraw steroids. RESULTS: TPMT genotyping (n=229) revealed 207 (90.4%) wild-type and 22 heterozygous patients. One hundred forty-three patients had ongoing TP therapy with AZA (n=134) or mercaptopurine (MP; n=9); response was judged as complete response (CR) in 113 patients and partial response (PR) in 30 patients. Both TP dose (1.64 vs 1.19mg/kg; p=0.012) and TPMT activity (14.3 vs 13.5; p=0.05) were higher in PR, resulting in similar TGN levels (PR: 121pmol/8x10(8) red blood cells [RBC]; CR: 113pmol/8x10(8) RBC; p=0.33) but higher meTIMP levels in PR (1350 vs 400pmol/8x10(8) RBC; p=0.004). Patients able to withdraw steroids or who were using 5mg prednisolone daily were treated with lower TP doses than patients on higher steroid doses (1.15 vs 1.18 vs 1.82mg/kg; p

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.

Serum γ-globulin levels have been determined by paper electrophoresis in 54 patients with cirrhosis of the liver before and after establishment of a portocaval shunt. As a control group 23 patients operated on for cancer of the lung were studied in the same way. A significant average increase from 18.6 to 23.0 g/1 in the cirrhotics was found, whereas no increase in the control group was observed. Serum immunoglobulins and antibodies to E. coli 0 group antigens were studied in 31 patients with cirrhosis and a portocaval shunt and 128 patients with cirrhosis without portocaval shunt. Significantly higher levels of IgG and E. coli antibodies were found in the patients with a portocaval shunt. It is proposed that these observations can be explained by the change in liver circulation brought about by the operation. If the cirrhotic liver has retained some of the ability of the normal liver to inhibit immunogens as previously proposed by us, the observed changes in immunoglobulins and E. coli antibodies should be expected.

Autoimmune Hepatitis (AIH) is a liver disease which may lead to liver cirrhosis. Cirrhosis is a well-known risk factor for hepatocellular cancer. Lymphoma is a disease, where immune modulating drugs as well as the autoimmune disease itself may contribute to the elevated risk. The aim was to investigate the risks of malignancies in a large cohort of AIH patients.Four hundred and seventy-three patients with AIH were matched to the Swedish national cancer register as well as to the death cause register.We found an overall higher risk of malignancies in the cohort of AIH patients from the date of diagnosis with a SIR of 1.51 (95% CI 1.10-2.03). SIR in the subpopulation of well defined catchment areas and complete case finding was 23.28 (95% CI 7.5-54.34) for HCC. Lymphomas were found a SIR of 13.09 (95% CI 4.22-30.56).There was an overall increased risk of malignancies in a cohort of AIH patients, which manly was caused by hepatobiliary cancers. However, the true risk of HCC in an AIH cirrhotic cohort has yet to be investigated. A significantly higher risk of lymphomas was also found, but no clear cut association to the use of immune modulators.

Longitudinal, population-based data on the occurrence, localization, and severity of bacterial infections over time in patients with alcoholic compared with nonalcoholic cirrhosis are limited.All patients with incident cirrhosis diagnosed in 2001-2010 (area of 600,000 inhabitants) were retrospectively identified. All bacterial infections resulting in or occurring during an inpatient hospital episode during this period were registered. The etiology of cirrhosis (alcoholic vs. nonalcoholic), infection localization, and outcome as well as bacterial resistance patterns were analyzed. Patients were followed until death, transplant, or the end of 2011.In all, 633 cirrhotics (363 alcoholic, 270 nonalcoholic) experienced a total of 398 infections (2276 patient-years). Among patients diagnosed with cirrhosis each year from 2001 to 2010, increasing trends were noted in the occurrence of infection (from 13 to 27%, P0.001) and infection-related in-hospital mortality (from 2 to 7%, P=0.05), the latter mainly in the alcoholic group. Although alcoholic etiology was related to the occurrence of more frequent infection (Kaplan-Meier, P0.001), this relationship was not significant after adjustment for confounders in Cox regression analysis (P=0.056). Resistance to piperacilin-tazobactam and carbapenems was more common in infections occurring in alcoholic versus nonalcoholic cirrhosis (13 vs. 5%, P=0.057 and 12 vs. 2%, P=0.009). Alcoholic etiology predicted pneumonia and infections caused by Gram-positive bacteria in multivariate analysis (P0.05 for both).In a population-based cirrhotic cohort, bacterial infections increased over time, which, in the case of alcoholic cirrhosis, was associated with pneumonia and bacterial resistance to antibiotics. However, alcoholic etiology was not related indepedently to the occurrence of bacterial infections.

Population-based data on the impact of bacterial infections on the course of compensated and decompensated cirrhosis as well as the occurrence, predictors of infection-related acute-on-chronic liver failure (ACLF) and its fatal outcome are limited.All patients with incident cirrhosis in the period 2001-2010, residing in an area of 600,000 inhabitants, were retrospectively identified. All serious bacterial infections (resulting in or occurring during an inpatient hospital episode) during this period were analyzed. Infection site and acquisition type, comorbid illness (Charlson comorbidity index) and infection severity features were analyzed. Patients were followed up until death, transplant, or the end of 2011.Overall, 398 serious bacterial infections occurred in 241/633 (38%) patients (106/332 diagnosed with compensated and 135/301 with decompensated disease; follow-up time was 2276 patient-years). ACLF occurred in 95/398 (24%) serious infections with an in-hospital mortality of 50%. In logistic regression analysis, the model for end-stage liver disease score, active alcohol misuse and healthcare-associated infections were predictors of infection-related ACLF (p0.05 for all). In-hospital mortality in infections with ACLF was related to albumin levels, Charlson comorbidity index1 and occurrence of one or more organ failures (p0.05 for all). In Cox regression analysis, infection-related ACLF was an independent negative predictor of transplant-free survival in decompensated patients (p = 0.049).In a population-based cirrhotic cohort, infection-related ACLF was a negative predictor of survival in decompensated disease. Infection-related ACLF was frequent and related to cirrhosis severity and infection acquisition type, as well as to high inpatient mortality, in particular in patients with significant comorbidity.

Cirrhosis is a well-known risk factor for hepatocellular cancer, but the true risk in autoimmune hepatitis (AIH) is scarcely studied. Other cancers may arise after prolonged use of immune-modulating drugs. The aim of this study was to investigate the cancer risk in a large cohort of AIH patients.Six hundred and thirty-four Swedish patients in a well-defined cohort were matched to the Cause of Death Registry and the Cancer Registry. Standard incidence ratios were calculated by relating the incidences in the cohort to an age-matched material from the Swedish background population.A higher overall incidence of malignancies than the background population was found, counting from the date of diagnosis (standard incidence ratio (SIR) 2.08, 95% CI 1.68-2.55). The highest risk was found for hepatocellular carcinoma (HCC). We found 10 cases (4.0%) in 248 patients with cirrhosis, which gives an incidence rate of 0.3%. Standard incidence ratio for developing hepatobiliary cancer was 54.55 (95% CI 19.92-99.99). HCC only occurred in cirrhotic patients. There was also an increased risk for non-melanoma skin cancer (SIR 9.87, 95% CI 6.26-14.81).A slightly enhanced risk for malignancies in general compared to the background population was found. The risk of hepatobiliary cancer was increased, but the annual risk over the observational period was well under the postulated 1.5% when surveillance in cirrhotic patients is considered to be cost-effective.

HLA class II markers and clinical heterogeneity in Swedish patients with primary biliary cirrhosis.

Population-based data on the occurrence of healthcare-associated (HCA) and hospital-acquired (HA) bacterial infections in cirrhosis, their predictors, and their impact on outcome are limited.All patients with incident cirrhosis in 2001-2010 residing in an area of 600,000 inhabitants were retrospectively identified. All serious bacterial infections (resulting in or occurring during an inpatient hospital episode) during this period were registered. Acquisition type, site of infection, occurrence of infection-related acute-on-chronic liver failure (ACLF), acute kidney injury (AKI) and bacterial resistance were analysed. Patients were followed longitudinally until death, transplant or end of 2011.A total of 398 serious infections occurred in 241/633 (38%) patients. Forty-seven per cent were HCA and 21% HA. Proton pump inhibitor (PPI) use was more common in HA (80%) vs. HCA (64%) vs. community-acquired (44%) infections (P0.001). In regression analysis, decompensated status, use of antibiotics and PPIs at infection diagnosis were independent predictors of HCA/HA infections (P0.05). After adjustment for confounders, HCA/HA infections were significantly related to infection-related ACLF (P0.05), but not severe sepsis, AKI or infection-related mortality (P0.05). Antibiotic-resistant infections were more frequent among HA (17%) than HCA (6%) or community-acquired (8%) infections (P0.05). Antibiotic-resistant HCA/HA infections were independently related to severe sepsis (P0.05).In a population-based cirrhotic cohort, two-thirds of serious bacterial infections were HCA or HA. Decompensated liver disease, antibiotics and PPIs were predictors of serious HCA/HA infections, which were associated with the development of ACLF. Antibiotic resistance was frequent, especially in HA infections, and contributed to risk of severe sepsis.

Background: Ursodeoxycholic acid (UDCA) has been shown to improve serum levels of liver enzymes and bilirubin in primary biliary cirrhosis (PBC). However, it is still uncertain whether UDCA treatment also improves symptoms, liver histology, and survival without liver transplantation. Methods: We randomized 116 patients with PBC to receive 0.5 g UDCA (n = 60) or placebo (n = 56) daily for 2 years. During the next 2 years, 80% of the UDCA-treated patients and 65% of the placebo-treated patients continued to take UDCA. Results: UDCA improved serum enzyme values but not survival, symptoms, serum bilirubin levels, or liver histology. There was no significant difference in response between initially symptomatic and asymptomatic patients. Conclusions: UDCA in a dosage of 7.7 mg/kg body weight is of little benefit in PBC. This does not exclude the possibility that larger doses have beneficial effects.

Objective. Development of ascites in patients with liver cirrhosis is an ominous sign with a poor outcome. A liver transplantation must be considered, and it then becomes important to know if there are any factors indicating a worsened prognosis. Material and methods. We used official registers for a follow-up study of at least 5 years considering the prognosis of 155 prospectively recruited in-patients with cirrhotic ascites from medical units at nine Swedish university hospitals. All patients had undergone at least one diagnostic ascites tap, and had initially been questioned about background factors and physically examined according to a standardized case record form, followed by sampling of blood, urine, and ascites. Results. Death occurred within 1 year after inclusion in 53% of the cases, and was primarily liver-related in 70%. In a multivariable analysis, the two ordinary variables that showed the strongest correlation with risk of death were serum potassium and abdominal tenderness. All 22 patients with a serum potassium concentration of at least 4.8 mmol/L (maximum 5.8 mmol/L) died within 1 year after inclusion. Potassium concentration was related to renal function and potassium-saving drugs. Conclusion. This follow-up study of a prospectively recruited cohort of in-patients with cirrhotic ascites confirms their poor prognosis. Awareness of an elevated serum potassium value, which would reflect a threatened renal function, seems essential, because it may offer a simple way to identify cases with the worst prognosis. An area for further research should be to explore the significance of including serum potassium in prognostic models.

A cohort of 559 patients in Sweden who satisfied predetermined criteria for the diagnosis of primary biliary cirrhosis was followed with respect to the incidence of cancer during the period of 1958 to 1988. The mean follow-up time from the time of primary biliary cirrhosis diagnosis was 9.0 +/- 5.4 yr. During the follow-up period, 148 patients died and the primary cause of death was liver insufficiency. An overall excess risk for cancer, standardized incidence ratio 1.6; 95% confidence interval, 1.1 to 2.2, was found in the cohort. In contrast to previous reports, we found no excess risk for breast cancer (standardized incidence ratio, 0.9; 95% confidence interval, 0.3 to 2.1). The number of hepatocellular cancers in the primary biliary cirrhosis cohort did not significantly differ from expected (standardized incidence ratio, 2.91; 95% confidence interval, 0.4 to 10.5).

Thirty-two consecutive patients with a histological diagnosis of chronic active hepatitis were examined with liver biopsy, laboratory tests and ultrasonography of the hepato-duodenal ligament to investigate the possible correlation between enlarged lymph nodes in the hepato-duodenal ligament and biochemical activity, histological activity and/or humoral immunoreactivity. We found a significant correlation between lymph-node size and serum alkaline phosphatase in the total material. In the hepatitis C-virus-associated group of patients a significant correlation between the size of the lymph nodes and gamma-glutamyl transpeptidase was found. In the autoimmune group there was a trend towards a negative correlation between lymph-node size and albumin.

Background Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have a high risk of developing colorectal cancer and dysplasia. Ursodeoxycholic acid (UDCA) has been suggested to have chemopreventive effects on the development of colorectal cancer and dysplasia but long-term data and larger trials are lacking. Aim To evaluate the effect of high dose (17-23 mg/kg/day) UDCA on colorectal neoplasia in a cohort of patients with PSC and IBD. Methods From our previous 5-year randomised controlled trial of UDCA vs. placebo in PSC, we performed a follow-up of 98 patients with concomitant IBD from entry of the trial 1996-1997 until 2009 for development of colorectal cancer or dysplasia. Results The total follow-up time was 760 person-years. Dysplasia/cancer-free survival was compared between placebo-(n = 50) and UDCA-treated (n = 48) patients. There was a similar frequency of dysplasia or cancer after 5 years between patients originally assigned to UDCA or placebo (13% vs. 16%) and no difference in dysplasia/cancer-free survival (P = 0.46, log rank test). At the end of 2009 no difference in cancer-free survival was detected, 30% of the placebo patients compared with 27% of UDCA patients had developed colorectal cancer or dysplasia. Conclusions Long-term high dose ursodeoxycholic acid does not prevent colorectal cancer or dysplasia in patients with primary sclerosing cholangitis-associated inflammatory bowel disease.

Objectives. Autoimmune hepatitis (AIH) is a liver disease which, if untreated, may lead to liver cirrhosis and hepatic failure. Limited data exist regarding factors predicting the long-term outcome. The aims of this study were to investigate symptoms at presentation, prognostic features, management and treatment in relation to long-term outcome of AIH. Material and methods. A cohort of 473 Swedish patients with AIH was characterized regarding initial symptoms and signs, factors predicting death and future need for liver transplantation. Survival and causes of death were retrieved from Swedish national registers. Results. At diagnosis, fatigue was a predominant symptom (69%), 47% of the patients were jaundiced and 30% had liver cirrhosis. Another 10% developed cirrhosis during follow-up. Markedly elevated alanine aminotransferase levels at presentation were correlated with a better outcome. A high international normalized ratio (INR) at diagnosis was the only risk factor predicting a need for later liver transplantation. Histological cirrhosis, decompensation and non-response to initial treatment were all factors that correlated with a worse outcome. Overall life expectancy was generally favourable. However, most deaths were liver-related, e.g. liver failure, shock and gastrointestinal bleeding. Conclusions. Cirrhosis at diagnosis, a non-response to initial immune-suppressive treatment or elevated INR values were associated with worse outcome and a need for later liver transplantation. In contrast, an acute hepatitis-like onset with intact synthetic capacity indicated a good response to treatment and favourable long-term prognosis. Lifetime maintenance therapy is most often required.

Objective. Autoimmune hepatitis (AIH) is a chronic liver disease, which if untreated can lead to cirrhosis and hepatic failure. The aim of the study was to investigate the incidence, prevalence, diagnostic tradition and clinical initial presentation of AIH. Material and methods. Analyses were performed in 473 patients identified as having probable or definite AIH. Results. The incidence of AIH was 0.85/100,000 (95% CI 0.69-1.01) inhabitants, which is somewhat lower than reported previously. The point prevalence amounted to 10.7/100,000 (95% CI 8.8-13.1), and 76% of the cases were females. The age-related incidence curve was bimodal but men were found to have only one incidence peak in the late teens, whereas women had a peak after menopause. AIH was presented as a spectrum of clinical settings from detected en passant to acute liver failure. Almost 30% of patients already had liver cirrhosis at diagnosis. Autoantibodies indicative of AIH type 1 were found in 79% of cases. Other concomitant autoimmune diseases were frequently found (49%). Conclusions. The incidence and prevalence figures confirm that AIH is a fairly uncommon disease in the Swedish population. Symptoms at presentation were unspecific, but almost half of the patients were jaundiced, with around 30% having liver cirrhosis. The majority of Swedish AIH patients had AIH type 1.

Background & Aims: The importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC. Methods: Subjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register. Results: The risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6-84.4), 11.1 (3.3-37.8), and 2.3 (0.9-6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3-4.9) and for Crohn's disease 1.4 (0.8-2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9-18.9). Conclusions: First-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC.

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.

Purpose: We investigated whether a low-field MR unit (0.2 T) could demonstrate and determine the size of the lymph nodes in the hepato-duodenal ligament that were previously found on ultrasound. Material and Methods: Eighteen patients were examined with ultrasound, MR and liver biopsy on consecutive days. Results: Two-thirds of the enlarged nodes detected by ultrasound were also detected with the low-field MR technique. However, the size of the nodes was slightly larger on ultrasound. Conclusion: Compared to low-field MR, ultrasound appears to be superior in the evaluation of lymph nodes in the liver hilus.

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.

AIMS--To study sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis (PSC). METHODS--One hundred and twelve biopsy specimens (that is, 56 pairs) from 44 patients with PSC, confirmed by cholangiography, were evaluated blindly. Six different features, qualitative grading of four other features and staging according to Ludwig were assessed. RESULTS--Quantitative sampling variability was confined mainly to just one grade or stage, although 11% (six of 56) of the biopsy specimen pairs differed by more than one stage (7% (one of 15) in pairs > 2 cm in length). Qualitative sampling variabilities were between 18 and 71%. Advanced disease (stages 3 or 4) was missed in 40% (two of five) of the biopsy specimens while cirrhosis was missed in 37%. CONCLUSION--Paired liver biopsy specimens should be taken in clinical studies of PSC using liver histology for evaluation or prognosis.

Ormarsdottir S, Ljunggren O, Mallmin H, Olsson R, Prytz H, Loof L (University Hospital, Uppsala; Sahlgrenska University Hospital, Gothenburg; University Hospital, Lund; and Central Hospital, Vasteras, Sweden). Longitudinal bone loss in postmenopausal women with primary biliary cirrhosis and well-preserved liver function. J Intern Med 2002; 252: 537–541. Objectives/design. Increased rate of bone loss has been reported in women with primary biliary cirrhosis (PBC) and varying degree of liver dysfunction. Whether bone loss is increased in patients without liver dysfunction is unclear. The aim of this study was to estimate retrospectively the rate of bone loss in postmenopausal women with PBC and well-preserved liver function. Subjects/interventions. Forty-three women with PBC, and classified as Child-Pugh class A, were included. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at the lumbar spine and the femoral neck. Results. Median time between measurements of BMD was 26 months (range, 12–48 months). Twenty women were not receiving any bone protective treatment, i.e. hormone replacement therapy (HRT), bisphosphonates or vitamin D/calcium supplementation, whilst 23 women received such treatment. Mean annual bone loss in the former group was 0.38 ± 2.56% and 0.42 ± 2.29% at the lumbar spine and the femoral neck, respectively. Women receiving treatment, however, increased their BMD by 1.92 ± 3.76% and 0.15 ± 2.75% at the lumbar spine and the femoral neck, respectively. At the lumbar spine the difference with regard to changes in BMD between untreated and treated women was statistically significant (P = 0.02). Women who received HRT (n = 11) increased their BMD at the lumbar spine by 2.95 ± 3.91%, P = 0.03 when compared with untreated women. Conclusion. Bone loss in postmenopausal women with PBC and well-preserved liver function is not increased above normal. Treatment with bone protective treatment, mainly HRT, improves BMD at the lumbar spine.

This study aims at describing the natural history and outcome of small duct primary sclerosing cholangitis (PSC).Thirty-two patients with small duct PSC were studied. The average time taken for diagnosis was 69 (1-168) months. The median follow-up time was 63 (1-194) months.All patients including one who underwent liver transplantation because of end-stage liver disease and hepatocellular carcinoma were alive at follow-up. None developed cholangiocarcinoma. In 27 patients repeated cholangiographic examinations were done after a median time of 72 (12-192) months from first ERCP. Four developed features of large duct PSC.Small duct PSC rarely progresses to large bile duct PSC and it seems to have a benign course in most patients and no development of cholangiocarcinoma was found.

Plasma thiols have been the object of growing interest because numerous studies have indicated that even a mild degree of hyperhomocysteinemia is associated with an increased risk of developing occlusive vascular diseases (1)(2)(3)(4)(5). However, the mechanism behind the vascular injuries is still unknown. Studies of the possible pathogenetic mechanism of increased plasma homocysteine concentrations are difficult because little is known about the mechanism for the formation of different homocysteine species in vivo. We recently published a method that measures reduced and total fractions of homocysteine, cysteine, glutathione, and cysteinylglycine(6). In a preliminary study, we found that patients suffering from stroke have hyperhomocysteinemia, whereas their reduced homocysteine was within the health-related reference interval(7). We hypothesized that the increased concentrations of the oxidized forms of homocysteine in plasma were attributable to a hyperoxidative state in the plasma. We also observed (8) that patients suffering from renal failure had concentrations of reduced homocysteine within the reference interval despite increased total homocysteine. The redox state of homocysteine in plasma may be influenced by other thiols (9), such as glutathione, which is involved in maintaining the intracellular thiols in reduced form. In the present study, we therefore investigated the relationships between homocysteine, cysteine, and glutathione in 29 healthy subjects and 15 patients with renal or liver failure. We used a newly developed preparation procedure, especially designed to minimize several known pitfalls that frequently influence plasma glutathione determinations. Increased hemolysis during sample collection causes falsely increased plasma glutathione measurements because of the high glutathione contents in the blood cells. Plasma glutathione also decreases with time because of the activity of γ-glutamyltransferase in plasma. Furthermore, reduced glutathione disappears within minutes in cell-free plasma because of oxidation(7)(10)(11)(12). In the present study, …

G A A b st ra ct s patients has not been examined. The objective of this analysis was to assess the efficacy and tolerability of rifaximin in maintaining remission from HE in cirrhotic patients with HCV. Methods: Breakthrough HE events and tolerability were assessed from a 6-month, randomized, double-blind, placebo-controlled trial of RFX 550 mg BID in cirrhotic patients (n= 299) with a recent history of recurrent HE but in remission at enrollment (Conn Score [CS], 0 or 1). Breakthrough overt HE was defined as an increase in CS to ≥2, or an increase in both CS and asterixis score of 1 grade each for patients entering with a CS of 0. Lactulose was permitted throughout the study. The incidence of adverse events (AEs) was reported. Results: HCV was the etiology of advanced liver disease in 42.8% (128 of 299) of patients. Demographic and baseline characteristics were generally similar between HCV and nonHCV patients. In HCV patients, breakthrough HE events occurred in 26.2% (16 of 61) of RFX patients vs. 47.8% (32 of 67) of PBO patients, corresponding to relative reduction in risk of a breakthrough HE episode of 52.2% (Figure, P=0.014). In cirrhotic patients with other etiologies (eg, alcohol-related, NAFLD/NASH), there were also significant treatmentrelated differences, with 19.0% (15 of 79) of RFX patients experiencing a breakthrough HE event vs. 44.6% (41 of 92) of PBO patients (P,0.001). In HCV patients, the most commonly reported AEs were nausea (RFX:18.0% of patients, PBO:19.4% of patients), fatigue (RFX:14.8%, PBO:13.4%), and peripheral edema (RFX:14.8%, PBO:7.5%). Conclusions: In patients with HCV and recurrent HE, RFX was efficacious and well-tolerated, with a clinical profile similar to that observed for cirrhotic patients with other etiologies of advanced liver disease.

BACKGROUND/AIMS--The course of primary sclerosing cholangitis (PSC) is highly variable and unpredictable. This study describes the natural history and outcome of PSC. These data were used to construct a prognostic model for patients with PSC. METHODS--A total of 305 Swedish patients with PSC were studied. The median follow up time was 63 (1-194) months and all patients could be traced for follow up. Some 79 patients died or had a liver transplant. The prognostic significance of clinical, biochemical, and histological findings at the time of diagnosis were evaluated using multivariate analysis. RESULTS--The estimated median survival from time of diagnosis to death or liver transplantation was 12 years. Cholangiocarcinoma was found in 24 (8%) of the patients and 134 (44%) of the patients were asymptomatic at the time of diagnosis. The estimated survival rate was significantly higher in the asymptomatic group (p < 0.001). However, 29 (22%) of the asymptomatic patients became symptomatic during the study period. It was found that age, serum bilirubin concentration, and histological stage at the time of diagnosis were independent predictors of a bad prognosis. These variables were used to construct a prognostic model. CONCLUSIONS--This prognostic model developed from a large homogeneous population of PSC patients should be of value for the timing of transplantation and patient counselling in PSC.

The aim of this study was to investigate whether changes in lymph node size in the hepatoduodenal ligament reflect changes in biochemical and histologic markers of cholestasis, hepatocellular damage, and humoral immunoreactivity in patients with primary biliary cirrhosis (PBC).Twenty-three consecutive patients were examined with repeated liver biopsies, laboratory tests, and ultrasonographic examinations of the hepatoduodenal ligament. The effect of treatment with ursodeoxycholic acid (UDCA) on these factors was also studied.A correlation was found between changes in lymph node size and changes in markers of hepatocellular damage, cholestasis, and humoral immunoreactivity and also with intralobular inflammation. In the UDCA-treated patients the node size decreased slightly during 2 years of treatment, whereas it was unchanged in the control group (p = 0.0528).Changes in the size of the lymph nodes in the hepatoduodenal ligament may reflect inflammation and cholestasis in PBC and thus be a valuable indicator in the follow-up of patients with this disease.

Objectives To see if budesonide, a second generation glucocorticosteroid with a high topical effect and a high first-pass metabolism of 90% in the healthy liver, can induce biochemical remission in autoimmune chronic active hepatitis before being metabolized, and further to study the effect on endogenous plasma cortisol levels and corticosteroid-related side effects. Patients and design Thirteen patients with autoimmune chronic active hepatitis (11 females) were treated openly for up to 9 months by oral budesonide capsules. The initial dose was 6-8 mg (mean 6.3 mg) daily for 6-10 weeks, and then the dose was individualized. Results The pre-treatment values of alanine aminotransferase and immunoglobulin (IgG) were 7.1 +/- 1.2 mukat/L (mean +/- S.E.M.) and 26.4 +/- 3.9 g/L, respectively. After 6 weeks of treatment, significant decreases in alanine aminotransferase (to 2.1 +/- 0.9 mukat/L) and immunoglobulin (to 18.4 +/- 2.4 g/L) were recorded. After 9 months the corresponding values (n = 9) were 1.2 +/- 0.9 mukat/L and 15.9 +/- 1.3 g/L, respectively. The mean value of plasma cortisol remained within normal ranges or was only slightly subnormal for the whole group (364 +/- 44 nmol/L at start, 165 +/- 46 after 6 weeks and 138 +/- 48 after 9 months). However, significantly reduced plasma cortisol levels were found in patients with biopsy-proven liver cirrhosis. Conclusion Oral budesonide appears to decrease liver inflammation in autoimmune chronic active hepatitis while causing a low frequency of systemic side effects and a marginal reduction in plasma cortisol in noncirrhotic patients over a study period of 9 months.

Liver biopsies from 88 patients with different liver diseases were studied for beta-hexosaminidase activity. Liver specimens with normal light microscopical morphology showed no immunohistochemical reactivity for beta-hexosaminidase. Increased reactions were noted, mainly in hepatocytes, in biopsies from the patients with different liver diseases. A very large interindividual variation of biochemical liver beta-hexosaminidase activity occurred even within the same diagnostic group, and no group of patients showed any significant increase of liver beta-hexosaminidase activity compared with the patients with normal liver histology. Livers with positive immunohistochemistry showed increased biochemical values for beta-hexosaminidase. In patients with cholestasis due to alcohol abuse, the immunohistochemical reaction was intense and the biochemical beta-hexosaminidase activity was significantly increased compared with non-alcoholic cholestatic cases. Furthermore, blood samples taken from 50 patients at the same time as the liver biopsies. These patients showed significantly increased serum beta-hexosaminidase activity compared with normal controls, but no correlation was found between beta-hexosaminidase activities in the liver and serum of these patients.

Thirty-five consecutive patients with primary biliary cirrhosis were examined using liver biopsy, laboratory tests and ultrasonography of the hepato-duodenal ligament to investigate the possible correlation between enlarged lymph nodes in the hepato-duodenal ligament and biochemical activity, histologic activity or stage and/or humoral immunoreactivity. We found a positive correlation between the size of the largest lymph node and laboratory values of cholestasis, hepatocellular damage and increased humoral immunoreactivity. On the other hand, we found a negative association between lymph node size and hepatocellular function. When twelve of the patients were reexamined after at least 10 months, in the majority of the patients changes in lymph node size were accompanied by similar changes in markers of cholestasis, hepatocellular damage and immunoreactivity. Prognostic index was also directly associated with lymph node size in most of these patients. No association between lymph node size and histologic stage was observed.

We observed a decrease in serum bilirubin, alkaline phosphatases (ALP) and IgM in five patients with primary biliary cirrhosis (PBC) treated with Prednimustin (Sterecyt®) for 6 months. In contrast to pretreatment findings, C3 activation was undetectable during treatment in three patients where normalization of serum IgM was achieved. After discontinuation of Prednimustin, bilirubin and ALP levels rapidly returned to pretreatment values, although IgM remained normal for up to 6 months in some patients. We conclude that Prednimustin might be of value in patients with symptomatic PBC where liver transplantation is not an option, and that it should be evaluated in a controlled study. However, the rapid reactivation of the disease after conclusion of treatment must be considered.

In 41 patients with alcoholic liver disease, antibodies to 12 common Escherichia coli O antigens (expressed as number of O antibody reactions with an agglutination titre of greater than or equal to 40) and to immunoglobulins IgG, IgA, and IgM were studied for 8 weeks. In 18 patients (8 with cirrhosis, 10 with fatty liver) who continued drinking during this period no significant changes were found. In 23 patients (11 with cirrhosis, 12 with fatty liver) who stopped or reduced drinking, a significant decrease in the levels of E. coli O antibodies and IgA was found (p less than 0.05 and p less than 0.01, respectively). In these 41 patients and in an additional 43 patients with alcoholic liver disease the amount of E. coli O antibodies was compared with type of histological lesion. The levels of E. coli O antibodies were significantly higher in cirrhosis with alcoholic hepatitis (22 cases) than in cirrhosis without alcoholic hepatitis (17 cases) (p less than 0.05). In these 17 patients antibody levels were significantly higher than in 41 patients with fatty liver without alcoholic hepatitis (p less than 0.02). In all patients a significant correlation between the number of positive reactions to E. coli O antigens and serum IgA concentration was found (p less than 0.01). No microbes were cultured from the liver biopsies, and no E. coli O antigens were demonstrated in the liver tissue by immunohistochemistry. Our results support the hypothesis that the high levels of E. coli O antibodies in alcoholic liver diseases are due to failure of the liver to extract circulating antigens and gut-derived endotoxins.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-base status was determined in 86 patients with cirrhosis of the liver. Group I comprised 55 patients living more than 3 months after examination (stable). Another 18 stable patients with a surgical porta-caval shunt (p.c.a.) formed group II. Group III consisted of 12 terminal patients without p.c.a. examined within the last week of life. With respect to liver function group II was intermediate between I and III. The most common acid-base disturbance in group I was compensated respiratory alkalosis (20%) followed by compensated metabolic alkalosis (15%). 50% of group II presented compensated respiratory alkalosis. 85% of group III showed metabolic acidosis, which was compensated in only half of the patients. Respiratory alkalosis seemed more related to impairment of liver function than to portasystemic shunting. The genesis of the terminal metabolic acidosis was complex. Renal function was reduced in 92% of group III, and lactic acidosis was found in 36%. In this group hepatic function was most severely impaired, and 60% were hypotensive. These disturbances were not related to aetiology or treatment of the liver disease.