Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic, usually slowly progressive cholestatic liver diseases that may eventually lead to liver cirrhosis and liver failure. The natural history of PBC has been extensively documented, with reported median 7-year survival rates of approximately 25%. In the 1980’s ursodeoxycholic acid (UDCA) was introduced in the treatment of PBC. Although several randomized controlled trials have been performed, the therapeutic effect of UDCA remains controversial, mainly because individual trials failed to show significant improvement in survival and meta-analyses came to different conclusions with respect to this end-point (chapter 1). Currently, given the facts that UDCA is widely used in the treatment of PBC and the disease is relatively rare, it is unlikely that new, decisive randomized controlled trials will be initiated. Since 1990, we prospectively studied the long-term course of patients with PBC treated with UDCA. In chapter 2 we compared patient survival in our cohort of 300 patients to the prediction by the Mayo model. This prognostic model was developed and validated before the introduction of UDCA and predicts survival based on clinical and laboratory data. In addition, we compared survival of PBC patients to that of an age- and sex-matched sample from the Dutch population. Survival of PBC patients from our cohort was significantly increased compared to the Mayo model prediction. Survival for the large majority of patients with early PBC was comparable to that of the general population. However, a minority of patients, who can be identified by increased serum bilirubin and decreased albumin concentrations, has a prognosis that was significantly worse than age- and sex-matched controls. The study documents that the long-term outcome of PBC patients on UDCA is significantly better than the natural history of PBC and therefore adds support to the efficacy of UDCA therapy in PBC. Further studies should be considered to assess whether the efficacy of UDCA is also reflected by decreasing numbers of PBC patients undergoing liver transplantation. The diagnosis of PBC can usually be made on the basis of clinical and laboratory data, and in most cases liver biopsy may not be needed for establishing the diagnosis. However, at the time of diagnosis liver biopsy may be useful for staging the disease. In chapter 3 we aimed to develop a non-invasive method to stage the disease, based on routinely available, simple laboratory tests. We found that cirrhosis in patients with PBC can be predicted by using the serum bilirubin concentration and the platelet count. In addition, we found that prognosis for patients with a false-negative test result (i.e. cirrhotic patients not identified by the predictive model), is favorable and comparable to prognosis for non-cirrhotic patients. Our findings suggest that liver biopsy in patients with PBC should not remain routine practice. However, when there is any doubt about the correct diagnosis, e.g. in cases with features of an overlap-syndrome with autoimmune hepatitis, and also from a scientific point of view, liver biopsy remains an important and valuable diagnostic tool. . PBC, as other autoimmune disorders, has been associated with many other diseases. However, most of these associations have been described in case reports or case series, and significant bias may have occurred in these studies. There are no previous studies documenting the occurrence of all concurrent disorders. In chapter 4, we report the prevalence of other diseases in a large group of patients with PBC. We found that most patients had one or more concurrent disorders, however the prevalence of most disease entities was low, and lower than reported in the case studies. PSC is a disease which is highly associated with ulcerative colitis and Crohn's disease: approximately 75% of patients with PSC also have inflammatory bowel disease. It has previously been hypothesized that the presence of an inflamed bowel facilitates the development of PSC. However, although several cases of PSC developing after a colectomy performed for inflammatory bowel disease have been described, none of the reports convincingly show that liver tests were normal at the time of colectomy. In our large cohort of PSC patients, we were unable to identify any patient who developed PSC after previous colectomy (chapter 5). This finding supports the hypothesis that the presence of an inflamed bowel may indeed be important in the pathogenesis of PSC. If so, new therapeutic approaches may be considered addressing factors including gut permeability and portal bacteremia and endotoxinemia. We suggest that the generally accepted view that de novo PSC may well develop after colectomy requires further study. Recently, the occurrence of fatigue as a dominant symptom in cholestatic liver disease, especially in PBC, has become an area of interest. Although it is well recognized that patients with PSC also frequently suffer from fatigue, little information is available on the prevalence of fatigue in PSC and no previous studies have quantified the impact of fatigue in patients with this disease. We therefore studied the prevalence and severity of fatigue in patients with PSC (chapter 6). The severity and impact of fatigue were comparable to that in PBC, and were significantly increased when compared to healthy controls. In both diseases fatigue was not related to any marker of disease activity or liver function. Clinicians should be well aware that fatigue is an important and occasionally invalidating symptom in both PBC and PSC, also in non-advanced or early disease. In addition to fatigue, it has been reported previously that the prevalence of depressive disorders is markedly increased in patients with PBC. We studied the prevalence of depression in patients with PBC and PSC (chapter 7) and found that the prevalence of depression was comparable to that reported for the general population. Our discrepant outcome is likely the result of other diagnostic criteria: in all previous studies questionnaires were used to establish the diagnosis, whereas we diagnosed depression based on DSM-IV criteria after a formal, extensive psychiatric evaluation. These conflicting findings of our and previous studies underline the importance of questionnaire validation. We therefore aimed to validate the Beck Depression Inventory (BDI) as a screening tool for depression in patients with PBC and PSC (chapter 8). Although the BDI correctly identified the small number of patients with a depressive syndrome, the specificity of the test was low. Thus, the previously reported high prevalence of depression in PBC indeed appears to be the result of using screening instruments, such as the BDI, for diagnosis. In our opinion, for correct diagnosis of depression a structured psychiatric evaluation is mandatory. Because the prevalence of depression in fatigued patients with PBC and PSC is low, fatigue is not a symptom likely to be part of a depressive disorder. Previous studies have failed to elucidate the pathophysiology of fatigue in PBC and PSC and this remains unknown. We hypothesized that oxidative stress as a result of immune activation might be involved in the development of fatigue. In chapter 9 we describe a study confirming previous findings of increased oxidative stress in patients with cholestatic liver disease when compared to controls, and suggest that oxidative stress may indeed be related to immune activation. However, we could not find any relation between oxidative stress and severity of fatigue or quality of life scores. Unfortunately, given the high prevalence of the symptom in PBC and PSC, no effective treatment for fatigue has been defined. In particular, while UDCA improves liver tests and overall prognosis in PBC, previous studies have failed to demonstrate a clear beneficial effect on symptoms including fatigue. Fatigue is a common symptom of depression and depression usually responds to antidepressant drugs. We considered the possibility that fatigue and depression might share a common pathophysiological pathway and consequently that antidepressants could ameliorate fatigue. To test this hypothesis a randomized controlled trial in patients with PBC and PSC was performed, comparing the antidepressant fluvoxamine to placebo with respect to the effect on fatigue (chapter 10). No serious adverse events of fluvoxamine were observed but we were also unable to document a significant beneficial therapeutic effect. This finding does therefore not support the hypothesis that the pathophysiological mechanisms leading to fatigue and depression are related. Treatment of fatigue with an antidepressant in patients with PBC or PSC cannot be recommended. Previous studies in the early 1980's showed that marked abnormalities in serum amino acid concentrations occur in patients with PBC. However, these studies only included patients with advanced PBC. We initiated a study to confirm these abnormalities in patients with early PBC and PSC (chapter 11). We found that abnormalities in serum amino acid concentrations occur, largely irrespective of disease severity or activity. Thus, the previously reported abnormalities in amino acid concentrations in patients with PBC were confirmed in patients with early disease, while data in patients with PSC were not previously available. In addition to these abnormalities in amino acid concentrations, we found a relation between the serum tyrosine concentration and fatigue in PBC, suggesting that low tyrosine concentrations may be associated with fatigue and diminished quality of life. Further studies into the role of tyrosine in the development of fatigue in patients with cholestatic liver disease should be considered. Recently, a variant of the glucocorticoid receptor has been described, which may be associated with glucocorticoid resistance in ulcerative colitis and asthma. The problem of glucocorticoid resistance in PBC and PSC, both disorders of presumed autoimmune etiology, is relevant given the poor response to corticosteroid treatment. Further, abnormalities in the hypothalamo-pituitary-adrenal axis have been considered as a potential factor involved in fatigue, a common symptom in these disorders. No previous studies on glucocorticoid receptor variants in patients with liver diseases have been performed. Chapter 12 reports a pilot study exploring abnormalities in glucocorticoid receptor expression in patients with PBC and PSC. The expression of the beta variant of this receptor was significantly increased compared to controls, whereas the expression of the biologically active variant of the receptor was decreased. These preliminary findings may contribute to understanding the limited efficacy of corticosteroids in PBC and PSC.