The future of autoimmune liver diseases – Understanding pathogenesis and improving morbidity and mortality

Autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are rare diseases. These days, patients with PBC almost never require liver transplantation. When treated early with ursodeoxycholic acid patients have a normal life expectancy if the disease is diagnosed at an early stage and the patients respond to treatment. Patients with AIH often go into remission with first‐line therapy including corticosteroids alone or in combination with azathioprine. Nevertheless, about one quarter of patients already developed cirrhosis at diagnosis. Those who do not respond to first line standard of care (SOC) have significant liver‐related morbidity and mortality. No approved second‐ or third‐line treatments are available and the drugs are selected based on limited case series and personal experience. Larger trials are needed to develop efficient therapies for difficult‐to‐treat AIH patients. No treatment has been found to alter the natural course of disease in patients with PSC except for liver transplantation. Identifying PSC patients at risk of developing cholangiocarcinoma (CCA) is another unmet need. Current research in all AILD including AIH, PBC and PSC, focuses on improving our understanding of the underlying disease process and identifying new therapeutic targets to decrease morbidity and mortality.     

Virological and clinical characteristics of delta hepatitis in Central Europe

Summary.  Hepatitis D virus (HDV) or delta hepatitis has mainly been studied in Asian and Mediterranean cohorts, but data on virological and clinical characteristics of HDV-infected Central and Northern European patients are limited. We investigated virological patterns, as well as biochemical and clinical features of liver disease in 258 HDV infected patients recruited over a period of 15 years at Hannover Medical School. Virological parameters were compared to 2083 anti-HDV negative hepatitis B surface antigen (HBsAg) positive individuals. In this cohort, (i) HDV infection was associated with both suppressed hepatitis B virus (HBV) and hepatitis C virus (HCV) replication, (ii) the suppression of HBV-DNA and HCV-RNA was not related to HDV-RNA replication, (iii) mean HBsAg levels did not significantly differ between HBV-monoinfected patients and individuals with delta hepatitis, (iv) HCV coinfection was rather frequent as about one third of our delta hepatitis patients tested anti-HCV positive, however, without being associated with more advanced liver disease, (v) delta hepatitis patients presented in a high frequency with an advanced stage of liver disease, and (vi) the course of delta hepatitis did not differ between Turkish-born, Eastern European (EE)-born and German-born patients. In summary, in this cohort of patients which is the largest so far Central European single centre group of delta hepatitis patients, we confirm the presence of frequently severe disease and describe novel virological profiles which require consideration in the management of this difficult to treat group of patients.     

K-ras mutations in the bile of patients with primary sclerosing cholangitis

BACKGROUND AND AIMS: The development of cholangiocarcinoma (CCC) is a complication of primary sclerosing cholangitis (PSC). To date, no reliable factors have been described which can define those PSC patients at high risk for the development of CCC and the clinical diagnosis of CCC in PSC patients is difficult. Therefore, molecular markers of cholangiocarcinogenesis, such as K-ras mutations, may improve the early diagnosis of CCC or the timing of liver transplantation. METHODS: K-ras mutations were analysed by enriched polymerase chain reaction/restriction fragment length polymorphism in the bile fluid of 56 PSC patients and 20 patients with other cholestatic diseases. To assess the value of K-ras mutations as a risk factor for cholangiocarcinogenesis, patients were prospectively investigated over a mean period of 31.5 months. RESULTS: In contrast with the control group, 17 (30%) patients with PSC revealed K-ras mutations in bile fluid. The mean Mayo score was not significantly different between PSC patients with (mean score 0.70) and without (mean score 0.13; p=0.2) K-ras mutations. In contrast with the group of PSC patients without K-ras mutations, four CCCs and two dysplasia were diagnosed in the group of patients with K-ras mutations during the follow up investigation (p<0.001). CONCLUSIONS: Our results indicate that K-ras mutations in bile fluid of PSC patients represent frequent early events during cholangiocarcinogenesis. However, most of the PSC patients with K-ras mutations remained tumour free after a long follow up investigation which is in agreement with the fact that these mutations are not specific for malignancy but may also occur in normal bile duct mucosa or in dysplasias. Therefore, analysis of K-ras mutations in bile should not be used for diagnosis of CCC in PSC patients. However, the results of our prospective follow up investigation indicate that K-ras mutations in bile fluid of PSC patients have to be considered as risk factors for the development of CCC which may have implications for the timing of liver transplantation.     

Candidemia in Norway (1991 to 2003): results from a nationwide study

A long-term, nationwide prospective candidemia study has been ongoing in Norway since 1991. All medical microbiological laboratories in the country have participated. During the period 1991 to 2003 a total of 1,393 episodes of candidemia occurred in 1,348 patients. The incidence of candidemia episodes per 100,000 inhabitants increased from approximately 2 episodes in the early 1990s to 3 episodes in 2001 to 2003. The average annual incidences varied markedly between the age groups. The incidence was high in patients aged < 1 year and in patients aged > or = 70 years. In patients > or = 80 years of age, the incidence has increased during the last 3 years from an annual average of 6.5 to 15.6 cases/100,000 inhabitants in 2003. Four Candida species (C. albicans [70%], C. glabrata [13%], C. tropicalis [7%], and C. parapsilosis [6%]) accounted for 95.5% of the isolates. The species distribution has been constant during the 13-year study period. The distribution of the most important species varied with the age of the patient. In patients < 1 year of age, the majority of episodes were caused by C. albicans (91%). The occurrence of C. glabrata increased with age. In patients > or = 80 years of age, approximately 1/3 of all episodes were due to this species. All C. albicans strains were susceptible to fluconazole. The percentage of yeast isolates with decreased susceptibility to fluconazole (MICs > or = 16 microg/ml) was 10.7% during the first period of this study (1991 to 1996) and 11.7% during the second period (1997 to 2003).