Clinical practice guidelines for IgG4-related sclerosing cholangitis.

IgG4-related sclerosing cholangitis (IgG4-SC) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4-related disease. Although clinical diagnostic criteria of IgG4-SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4-SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions (CQs) with clinical statements were developed regarding diagnosis (14 CQs) and treatment (4 CQs). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4-SC.

Variant Syndromes of Autoimmune Liver Diseases: Classification, Diagnosis and Management.

The term 'overlap syndrome' has been used to describe the presence of both autoimmune hepatitis and primary biliary cholangitis or primary sclerosing cholangitis in the past. As this term is misleading, the term 'variant syndrome' should be used preferably. Laboratory features, serology, histology and bile duct imaging contribute to the diagnosis of 'variant syndromes'. Patients with a suspected variant syndrome should receive a complete work-up with liver histology, serology and - if not conclusive, bile duct imaging. Liver histology is usually reliable to recognize secondary autoimmune hepatitis in patients with primary cholestatic disease. An histological activitiy index of >4 usually is commonly seen in patients with variant syndrome. Identification of variant syndrome is very important, as appropriate - in most cases additional - immunosuppressive treatment is necessary and most patients will respond promptly.

Patients with large-duct primary sclerosing cholangitis and Crohn's disease have a better outcome than those with ulcerative colitis, or without IBD.

BACKGROUND: Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). AIM: To compare PSC/CD with other PSC patients. METHODS: Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. RESULTS: Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. CONCLUSIONS: The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.

Primary Sclerosing Cholangitis: Multiple Phenotypes, Multiple Approaches.

Primary sclerosing cholangitis (PSC) is a heterogeneous, idiopathic, inflammatory disorder frequently associated with inflammatory bowel diseases. PSC patients may be classified into several subphenotypes. Investigations of pediatric, nonwhite, and female PSC patients have revealed distinguishing features. The natural history of PSC is variable in progression with numerous possible clinical outcomes. PSC patients may suffer bacterial cholangitis, cholangiocarcinoma, or colorectal adenocarcinoma. Treatments focusing on bile acid therapy and immunosuppression have not proven beneficial. Interest in PSC and international collaboration has led to improved understanding of the heterogeneity and the genetic structure and introduced possible effective therapeutics.

Comparative assessment of prognostic value for revised-Mayo risk model and Child-Pugh score in patients with primary sclerosing cholangitis.

BACKGROUND/AIMS: The aim of this study was to compare the utility of the revised Mayo risk model (rMRM) and Child-Pugh scores (CPSs) for predicting the prognosis of disease in patients with primary sclerosing cholangitis (PSC). MATERIALS AND METHODS: Patients were divided into 2 groups: Group I (37 patients; alive and not requiring liver transplantation) and Group II (8 patients; deceased or requiring liver transplantation). rMRM suggests the possible survival percentage over a 4-year period. Thus, rMRM scores and CPSs on the first visit were calculated from the data at the time of diagnosis for patients diagnosed with PSC <4 years ago. rMRM scores and CPSs of patients with >4 years of follow-up were calculated using data from the visit 4 years prior to their last follow-up. RESULTS: Bivariate analyses showed that need for liver transplantation/mortality was correlated with either first visit CPS (r=0.481, p=0.001) or rMRM (r=0.452, p=0.002). Analysis of the area under the curve showed that both models performed similarly in terms of predicting the need for liver transplantation/mortality (rMRM: 0.780; CPS: 0.762; p=0.8). There was a significant difference in Kaplan-Meier survival rates between Group I and Group II for both risk models (rMRM: p<0.001; CPS: p<0.001) when the decisive event was death or need for liver transplantation. CONCLUSION: Both rMRM and CPSs are useful in risk assessment of patients with PSC. The ability to predict prognosis is similar for both risk models.

Comparison of intraductal ultrasonography findings between primary sclerosing cholangitis and IgG4-related sclerosing cholangitis.

BACKGROUND AND AIM: Comparisons of intraductal ultrasonography (IDUS) findings between primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC) have not been elucidated. We aimed to clarify the differences in transpapillary IDUS findings between PSC and IgG4-SC. METHODS: We retrospectively compared transpapillary IDUS findings between 15 patients with PSC and 35 patients with IgG4-SC between 2004 and 2014. RESULTS: IDUS findings of circular-asymmetric wall thickness, irregular inner margin, diverticulum-like outpouching, unclear outer margin, heterogeneous internal echo, and disappearance of three layers were significantly higher in PSC than in IgG4-SC (P < 0.001). Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers were specific IDUS findings for PSC compared to IgG4-SC. Diverticulum-like outpouching on IDUS and endoscopic retrograde cholangiogram (ERC) was observed in 10 (67%) and five (33%) of 15 patients with PSC, respectively. However, based on IDUS and ERC, diverticulum-like outpouching was not observed in any patient with IgG4-SC. All five patients with diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS, and five (50%) of 10 patients without diverticulum-like outpouching on ERC had diverticulum-like outpouching on IDUS. CONCLUSIONS: The IDUS findings differed between PSC and IgG4-SC. Irregular inner margin, diverticulum-like outpouching, and disappearance of three layers are specific IDUS findings for PSC compared to IgG4-SC. IDUS is a more useful procedure than ERC for the early detection of diverticulum-like outpouching.

Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease.

BACKGROUND & AIMS: Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC. METHODS: Four classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions. RESULTS: HLA-DRB1*13:01 (OR = 2.0, 95% CI 1.2-3.4, P = 0.01) and HLA-B*08 (OR = 1.6, 95% CI 1.1-2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4-65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC. CONCLUSIONS: Small duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA-DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease.

Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related sclerosing cholangitis: a Japanese cohort.

BACKGROUND AND AIM: IgG4-related sclerosing cholangitis (IgG4-SC) must be precisely distinguished from primary sclerosing cholangitis and cholangiocarcinoma (CC) because the treatments are completely different. However, the pathological diagnosis of IgG4-SC is difficult. Therefore, highly specific non-invasive criteria such as serum IgG4 should be established. This study established a cut-off for serum IgG4 to differentiate IgG4-SC from respective controls using serum IgG4 levels measured in Japanese centers. METHODS: A total of 344 IgG4-SC patients were enrolled in this study. As controls, 245, 110, and 149 patients with pancreatic cancer, primary sclerosing cholangitis, and CC, respectively, were enrolled. IgG4-SC patients were classified into three groups: type 1 (stenosis only in the lower part of the common bile duct), type 2 (stenosis diffusely distributed throughout the intrahepatic and extrahepatic bile ducts), and types 3 and 4 (stenosis in the hilar hepatic region) with 246, 56, and 42 patients, respectively. Serum IgG4 levels were compared, and the cut-offs were established. RESULTS: The cut-off obtained from receiver operator characteristic curves showed similar sensitivity and specificity to that of 135 mg/dL when all IgG4-SC and controls were compared. However, a new cut-off value was established when subgroups of IgG4-SC and controls were compared. A cut-off of 182 mg/dL can increase the specificity to 96.6% (4.7% increase) for distinguishing types 3 and 4 IgG4-SC from CC. A cut-off of 207 mg/dL might be useful for completely distinguishing types 3 and 4 IgG4-SC from all CC. CONCLUSIONS: Serum IgG4 is useful for the differential diagnosis of IgG4-SC and controls.

Evolving concepts in primary sclerosing cholangitis.

Patients suffering from primary sclerosing cholangitis (PSC) show considerable differences regarding clinical manifestations (i.e. large duct versus small-duct PSC, presence or absence of concomitant inflammatory bowel disease), disease progression, risk for malignancy and response to therapy, raising the question whether PSC may represent a mixed bag of diseases of different aetiologies. The growing list of secondary causes and diseases 'mimicking' or even overlapping with PSC (e.g. IgG4-associated sclerosing cholangitis), which frequently causes problems in clear-cut discrimination from classic PSC and the emerging knowledge about potential disease modifier genes (e.g. variants of CFTR, TGR5 and MDR3) support such a conceptual view. In addition, PSC in children differs significantly from PSC in adults in several aspects resulting in distinct therapeutic concepts. From a clinical perspective, appropriate categorization and careful differential diagnosis are essential for the management of concerned patients. Therefore, the aim of the current review is to summarize current and evolving pathophysiological concepts and to provide up-to-date perspectives including future treatment strategies for PSC.

Validity of administrative data for the diagnosis of primary sclerosing cholangitis: a population-based study.

BACKGROUND/AIMS: Administrative databases could be useful in studying the epidemiology of primary sclerosing cholangitis (PSC); however, there is no information regarding the validity of the diagnostic code in administrative databases. The aims of this study were to determine the validity of administrative data for a diagnosis of PSC and generate algorithms for the identification of PSC patients. METHODS: The sensitivity (Se) and positive predictive value (PPV) of a PSC diagnosis based on administrative data from 2000 to 2003 were determined through chart review data. Algorithms were developed by considering variables associated with PSC and coding details. A logistic regression model was constructed using covariates associated with PSC. Based on this model, each subject was assigned a probability of having PSC. A cutoff value was selected that maximized the Se and specificity (Sp) of correctly predicting PSC cases. RESULTS: In the administrative data, the initial Se and PPV were 83.7 and 7.2% respectively. The optimal algorithm included one PSC code and one inflammatory bowel disease code and had Se 56% and PPV 59%. Overall, the algorithms yielded inadequate PPV and Se estimates to identify a cohort of true PSC cases. The predictive model was constructed using six covariates. For this model, the area under the receiver operating characteristic curve was 93.5%. A cutoff of 0.0729 was used, which maximized the Se 81.9% and Sp 90.7%; however, the PPV was 41.0%. CONCLUSION: An algorithm for the identification of true PSC cases from administrative data was not possible. We recommend that PSC receives a distinct ICD code from ascending cholangitis.

Systematic review: management options for primary sclerosing cholangitis and its variant forms - IgG4-associated cholangitis and overlap with autoimmune hepatitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) remains a challenging disease to manage. The main goals are prevention of disease progression and reduction of the increased cancer risk. AIMS: To review the management strategies for PSC and its variant forms based on published studies. METHODS: Publications were identified using Pubmed, Medline and Ovid search engines. RESULTS: Distinguishing PSC from variants, such as IgG4-associated cholangitis, and overlap with autoimmune hepatitis is essential to guide treatment decisions. There is no proven efficacious medical treatment for PSC. Ursodeoxycholic acid has been disappointing in low and moderate doses, and potentially dangerous in higher doses, although its role and optimal dose in chemoprevention requires investigation. The novel bile acid, 24-norursodeoxycholic acid, has shown promise in mouse models; human trials are in progress. Dominant strictures are optimally managed by dilatation and stenting to relieve obstructive complications, although exclusion of biliary malignancy is essential. Liver transplantation is the only proven therapy for those with advanced disease. Cholangiocarcinoma remains the most unpredictable and feared complication. In highly selected groups, neo-adjuvant chemoradiation with liver transplantation seems promising, but requires further validation. Screening for inflammatory bowel disease and surveillance for colorectal carcinoma should not be overlooked. CONCLUSIONS: The effective management of PSC and its variants is hindered by uncertainties regarding pathogenesis of disease and factors responsible for its progression. Genome studies may help to identify further targets for drug therapy and factors leading to malignant transformation.

Validation of a cholangiographic prognostic model in primary sclerosing cholangitis.

BACKGROUND AND STUDY AIMS: We previously developed a prognostic model for primary sclerosing cholangitis (PSC), which was primarily based on a cholangiographic classification of the intra- and extrahepatic biliary tree lesions. The aim of the present study was to validate the performance of this model in an external cohort. PATIENTS AND METHODS: The validation dataset consisted of patients with PSC from a single referral center in Oslo, Norway. The patients' cholangiograms were scored according to the Amsterdam classification. We then examined whether adjusting the value of the original coefficients of the predictors or adding new predictors would improve the fit of the original model in the validation cohort. In addition, we evaluated calibration (closeness between observed and expected survival) and discrimination using the concordance index. RESULTS: A total of 111 patients (mean age 35 +/- 13 years; 76 % male) were included in the validation study. Baseline clinical characteristics were comparable between the two cohorts. None of the coefficients that were re-estimated in the validation cohort differed significantly from the values of the original model. Observed and expected survival curves were in close agreement across different risk groups. Discrimination of the original model was preserved in the validation cohort: the concordance index was the same in both cohorts. CONCLUSIONS: The prognostic model showed adequate performance in an independent series of patients. Therefore, we updated the model using the data from both cohorts to provide more robust estimates of transplant-free survival for individual patients. A nomogram was constructed, which can be used to predict medium- and long-term prognosis in individual patients with PSC.

Intrahepatic IgG/IgM plasma cells ratio helps in classifying autoimmune liver diseases.

BACKGROUND/AIM: Plasma cells infiltrate in the liver is a prototype lesion of autoimmune liver diseases. The possible role of plasma cells isotyping (IgM and IgG) in the liver in the diagnostic definition of autoimmune liver disease, and particularly in variant syndromes such as autoimmune cholangitis and the primary biliary cirrhosis/autoimmune hepatitis overlap syndrome, is less defined. METHODS: We analysed the clinical, serological and histological features of 83 patients with autoimmune liver disease (40 primary biliary cirrhosis, 20 autoimmune hepatitis, 13 primary sclerosing cholangitis, 4 autoimmune cholangitis and 6 overlap syndrome) compared to 34 patients with chronic hepatitis C and evaluated the expression of IgM and IgG plasma cells in their liver by immunostaining. RESULTS: By Spearman's correlation, the mean-counts of IgM plasma cells in portal tracts were significantly correlated with female gender, serum alkaline phosphatase, gamma-glutamyl transferase and IgM values, positivity for anti-mitochondrial antibody-M2 and, on liver biopsy, with bile duct changes, orcein-positive granules and granulomas. Whereas IgG plasma cells resulted more correlated with alanine aminotransferase levels. IgG/IgM ratio lower than 1 was found no only in primary biliary cirrhosis but also in all patients with autoimmune cholangitis. Conversely, all patients with overlap syndrome showed IgG/IgM ratio higher than 1. CONCLUSION: Immunostaining for IgM and IgG plasma cells on liver tissue can be a valuable parameter for better diagnosis of autoimmune liver disease and also for variant or mixed syndromes.

Primary sclerosing cholangitis--the arteriosclerosis of the bile duct?

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of unknown aetiology affecting the large bile ducts and characterized by periductal fibrosis and stricture formation, which ultimately result in biliary cirrhosis and liver failure. Arteriosclerosis involves the accumulation of altered lipids and lipoproteins in large arteries; this drives inflammation and fibrosis and ultimately leads to narrowing of the arteries and hypoperfusion of dependent organs and tissues. Knowledge of the causative factors is crucial to the understanding of disease mechanisms and the development of specific treatment. Based on pathogenetic similarities between PSC and arteriosclerosis, we hypothesize that PSC represents "arteriosclerosis of the bile duct" initiated by toxic biliary lipids. This hypothesis is based on common molecular, cellular, and morphological features providing the conceptual framework for a deeper understanding of their pathogenesis. This hypothesis should stimulate translational research to facilitate the search for novel treatment strategies for both diseases.

[Autoimmune hepatitis and overlap syndrome: diagnosis]. / Autoimmunhepatitis und Overlap-Syndrom: Diagnostik.

Autoimmune hepatitis (AIH) is a rare autoimmune disease (incidence about 5% among all chronic liver disorders) that reflects a loss of tolerance to normal hepatic proteins. AIH is characterized by female preponderance, hypergammaglobulinemia, extrahepatic syndromes and a good response to immunosuppressive treatment. AIH may be subdivided into two or three subtypes. AIH type 1 is characterized by antinuclear autoantibodies (ANA) and/or smooth muscle antibodies (SMA). SMA are actin-specific, can occur without ANA and their presence relates strongly to AIH. AIH type 2 is defined by the presence of anti-liver-kidney microsomal antibodies (LKM-1). Patients with AIH type 2 are typically younger at the time of disease onset, exhibit higher inflammatory activity, suffer more frequent relapses under immunosuppressive treatment and are more likely to progress to cirrhosis. AIH type 3 is characterized by autoantibodies against the soluble liver antigen (SLA) and liver-pancreas antigen (LP), but ANA/SMA are frequently present and, therefore, some authors consider this autoantibody manifestation as belonging to AIH type 1. Antineutrophil cytoplasmic antibodies (ANCA) recognize cytoplasmic or nuclear components of neutrophilic granulocytes and are detected with high prevalence in patients with autoimmune liver diseases. They are associated with AIH type 1 but not with AIH type 2. However, 40-70% of patients with primary sclerosing cholangitis (PSC) also produce these autoantibodies. Autoimmune cholangitis is an idiopathic disorder with mixed hepatocellular and cholestatic findings that typically has antinuclear antibodies (ANA). It may be considered as an atypical form of primary biliary cirrhosis. It has been recognized that some forms of AIH may also occur with variable incidence and severity especially in patients with primary biliary cirrhosis (overlap AIH/PBC) or primary sclerosing cholangitis (AIH/PSC). On the basis of clinical, biochemical, serological, histological and radiological criteria a clear distinction between these conditions can be readily made in the majority of cases. An association of AIH-typical autoantibodies (anti-LKM-1, anti-SLA/LP) in association with antimitochondrial autoantibodies (AMA) almost confirm the overlap syndrome AIH/PBC. In PSC patients expressing typical ERCP findings and suffering from inflammatory bowel disease (IBD), the diagnosis of an overlap syndrome between PSC/AIH can be readily made in the presence of ANCA and AIH relevant autoantibodies. Apart from this kind of overlap syndrome involving different types of autoimmune disorders within the liver AIH can be also associated with other organspecific autoimmune disorders as documented in the autoimmune polyglandular syndrome type 1 (APS-1). In this disease homozygosity for a defect in a single gene (AIRE) leads to a broad spectrum of organ specific autoimmune diseases.

Sclerosing cholangitis and liver cirrhosis after extrabiliary infections: report on three cases.

OBJECTIVE: To describe three unusual cases of sclerosing cholangitis after severe extrahepatic/extrabiliary bacterial infections. DESIGN: Case report, clinical. SETTING: Tertiary care intensive care unit (ICU). PATIENTS: Three patients admitted to the ICU with infections from Gram-positive bacteria followed by sclerosing cholangitis and secondary biliary cirrhosis. MAIN RESULTS: Three unusual cases of persisting cholestasis that occurred after bacterial infections originating from extrahepatic/extrabiliary foci are described. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography revealed multiple strictures of the intrahepatic bile ducts as a sign of sclerosing cholangitis. All patients progressed to biliary cirrhosis within months after the onset of cholestasis. CONCLUSION: Infection-associated cholestasis is usually a functional disorder and subsides after effective treatment of the underlying inflammatory focus. In rare cases, however, extrahepatic/extrabiliary infections may lead to sclerosing cholangitis and secondary biliary cirrhosis via unknown mechanisms.

Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system.

BACKGROUND/AIM: Recently, the scoring system for the diagnosis of autoimmune hepatitis (AIH) was modified by the International AIH Group. Our aim was to determine the prevalence of AIH in patients with cholangiographically proven primary sclerosing cholangitis (PSC) using this new scoring system. METHODS: A total of 211 PSC patients were evaluated. RESULTS: Three (1.4%) patients scored more than 15 points ('definite' AIH); 13 (6%) patients scored between 10 and 15 points ('probable' AIH); the remaining 195 (93%) patients had less than 10 points, allowing the exclusion of AIH. The separation of patients with PSC plus AIH from patients with PSC alone was based mostly on serum levels of total globulins (p=0.01), IgG (p=0.001), titers of autoantibodies (p<0.001) and histologic score (p<0.001). Using the older scoring system, four (2%) patients met the criteria for the diagnosis of PSC plus 'definite' AIH and 40 (19%) the diagnosis of PSC plus 'probable' AIH. CONCLUSIONS: Overlap of PSC and AIH occurs rarely. The new scoring system seems to more precisely define the potential overlap syndrome between PSC and AIH, although further modification of the new scoring system may provide even better discrimination among these conditions.

Cholestatic liver diseases and health-related quality of life.

OBJECTIVE: Symptoms associated with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) negatively affect health-related quality of life (HRQL). The aim of this study was to measure HRQL in patients with chronic cholestatic liver diseases and to determine factors associated with more severe impairment. METHODS: We conducted a cross-sectional study in which we documented patients' demographic and clinical characteristics, and measured their HRQL using the Short Form-36 and Chronic Liver Disease Questionnaire. We assessed the association of HRQL impairment with disease severity (Child's-Pugh class and Mayo PBC Risk Score) and compared patients' HRQL with those of a healthy population, and patients with congestive heart failure, chronic obstructive pulmonary disease, and diabetes. RESULTS: One hundred and four patients with PBC and PSC participated, of whom 73% were women, with an average age of 55+/-12 yr. Of these patients, 61% had cirrhosis (37% Child's A, 23% Child's B, and 2% Child's C). Patients with cholestatic liver disease showed more HRQL impairment than the healthy population and were similar to patients with other chronic conditions. Additionally, patients who experienced severe itching showed profound HRQL impairment. In patients with PBC, Physical Component Summary (PCS) scores of the SF-36 and Chronic Liver Disease Questionnaire (CLDQ) scores fell from noncirrhotic to Child's A to Child's B/C and with worsening Mayo PBC Risk Scores. No other clinicodemographic data were associated with patients' well-being. CONCLUSIONS: Patients with cholestatic liver disease (PBC and PSC) showed substantial impairment of HRQL, which is further affected by worsening disease severity. Disease-specific measures were better able to discriminate patients with varying severities.