Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.

Risk and Surveillance of Cancers in Primary Biliary Tract Disease.

Primary biliary diseases have been associated in several studies with various malignancies. Understanding the risk and optimizing surveillance strategy of these malignancies in this specific subset of patients are an important facet of clinical care. For instance, primary sclerosing cholangitis is associated with an increased risk for cholangiocarcinoma (which is very challenging to diagnose) and when IBD is present for colorectal cancer. On the other hand, primary biliary cirrhosis patients with cirrhosis or not responding to 12 months of ursodeoxycholic acid therapy are at increased risk of hepatocellular carcinoma. In this review we will discuss in detail the risks and optimal surveillance strategies for patients with primary biliary diseases.

Comparison of Adenoma Detection Rates in Afro-Caribbeans and Non-Hispanic Whites Undergoing First Screening Colonoscopy.

OBJECTIVES: The African American population has a higher prevalence of advanced colon adenomas when compared with non-Hispanic whites and Hispanics, but the risk in other black populations has not been evaluated. Although the Afro-Caribbean population is a significant demographic segment in some regions of the United States, the data are limited on the prevalence of colon adenomas in this group and there is no comparison with a non-Hispanic white population. The objective of our study was to compare the prevalence of adenomas in Afro-Caribbean versus non-Hispanic white populations. METHODS: A total of 880 Afro-Caribbean patients and 1828 non-Hispanic white patients undergoing their first screening colonoscopy between January 2008 and August 2014 was included in the study. RESULTS: A total of 2708 patients met entry criteria for the study. The adenoma detection rate among Afro-Caribbeans was 29% and 31% among non-Hispanic whites. There was no statistically significant difference in the prevalence of adenomas in the two groups (P = 0.28), and the rate of advanced adenomas also was similar in both groups (8.6% in Afro-Caribbeans, 9.2% in non-Hispanic whites; P = 0.60). A multivariate analysis also found no difference in the occurrence of adenomas (P = 0.60) or advanced adenomas (P = 0.99) between Afro-Caribbeans and non-Hispanic whites. CONCLUSIONS: We found a similar adenoma detection rate and advanced adenoma prevalence among Afro-Caribbeans and non-Hispanic whites undergoing their first screening colonoscopy. As such, the Afro-Caribbean population may not have the same risk of colorectal neoplasia as what has been described for African Americans. Based on these results, it is appropriate to initiate colorectal cancer screening for Afro-Caribbeans at age 50 as recommended for non-Hispanic whites.

Long-term outcomes in antimitochondrial antibody negative primary biliary cirrhosis.

OBJECTIVES: Antimitochondrial antibodies (AMA) are a sensitive and specific marker for primary biliary cirrhosis (PBC). AMAs are present in 95% of patients with PBC. However, 5% do not have AMAs and data on these patients is scarce. We aim to evaluate the long-term outcomes of patients with AMA negative PBC. METHODS: A retrospective chart review of 71 AMA negative PBC patients. Disease presentation, laboratory results, and clinical endpoints were recorded. AMA negative patients were matched on year of diagnosis to a control group of 71 AMA positive patients. RESULTS: Ninety-six percent of the AMA negative patients were of female gender with a median age at diagnosis of 55 years and a length of follow-up of 7.5 years vs. 86% females, a median age of 56 and a follow-up of 8.3 years in the control group. Mean total bilirubin and alkaline phosphatase levels were 0.7 mg/dL vs. 0.6 and 570 U/L vs 341, in AMA negative vs. AMA positive patients at presentation, respectively (p = NS). AMA negative patients did not differ in terms of age, serum IgM levels, ANA status, or length of follow-up. Notably, AMA negative patients had a significantly reduced survival free of liver-related complications including transplantation and death compared to AMA positive patients (p = 0.0182). CONCLUSION: In this large experience, AMA negative PBC patients had a significantly worse prognosis compared to AMA positive PBC patients. The reason for the difference in prognosis is unclear, as it may be true difference or reflect delays in case detection among AMA negative patients.

Body mass index and colon cancer screening: the road ahead.

Screening for colorectal cancer (CRC) has been associated with a decreased incidence and mortality from CRC. However, patient adherence to screening is less than desirable and resources are limited even in developed countries. Better identification of individuals at a higher risk could result in improved screening efforts. Over the past few years, formulas have been developed to predict the likelihood of developing advanced colonic neoplasia in susceptible individuals but have yet to be utilized in mass screening practices. These models use a number of clinical factors that have been associated with colonic neoplasia including the body mass index (BMI). Advances in our understanding of the mechanisms by which obesity contributes to colonic neoplasia as well as clinical studies on this subject have proven the association between BMI and colonic neoplasia. However, there are still controversies on this subject as some studies have arrived at different conclusions on the influence of BMI by gender. Future studies should aim at resolving these discrepancies in order to improve the efficiency of screening strategies.

Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study.

BACKGROUND & AIMS: Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points. METHODS: We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death). RESULTS: Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P < .0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤ 1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels >1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment. CONCLUSIONS: Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trials.

The natural history of primary biliary cirrhosis.

Our understanding of the natural history of primary biliary cirrhosis (PBC) has been evolving especially following the introduction of ursodeoxycholic acid (UDCA). A clearer understanding of disease pathophysiology and earlier diagnosis with increased prevalence of the disease worldwide has led to increased interest and improved outcomes in patients with PBC. In this article, the authors touch briefly on features of the disease and describe the natural history of PBC prior to and after the introduction of UDCA.

Association between serum IgE level and adverse clinical endpoints in primary sclerosing cholangitis.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is an idiopathic hepatobiliary disorder associated with an increased risk for cholangiocarcinoma (CCA) and a median survival time of 12 years. Reliable predictors of CCA and other major adverse events in PSC are currently lacking. Recently, serum IgE was found to be associated with CCA in a Japanese cohort of PSC patients. Our aim in this study was to determine whether IgE levels predict time to CCA, liver transplantation, or death in a Western (USA-based) cohort of PSC patients. MATERIAL AND METHODS: Thirty-eight patients with PSC and IgE levels were identified and categorized into low or high IgE groups based on the sample median. Groups were compared with respect to clinical characteristics and adverse endpoint-free survival, and the association between IgE and endpoints was assessed with multivariate proportional-hazards models. RESULTS: The median sample age at PSC diagnosis was 41 years, and median serum IgE level was 47.6 kU/L. Low and high IgE groups differed significantly only with respect to IgG subclasses, which were higher among the latter (p < 0.05). There were no significant differences in composite endpoint-free (p = 0.83) or CCA-free survival (p = 0.20). In multivariate analyses, only Mayo PSC risk score and MELD score were significant predictors of endpoint-free survival (p < 0.05). CONCLUSIONS: Serum IgE level is associated with several IgG subclass levels but not time to CCA, liver transplantation, or death among PSC patients in a USA-based cohort. While Mayo PSC risk score and MELD score can predict these outcomes, more specific predictors of CCA are needed.

Neoplasia in the ileoanal pouch following colectomy in patients with ulcerative colitis and primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is typically associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). PSC-IBD patients are at an increased risk for colorectal neoplasia. The ileal pouch-anal anastomosis (IPAA) is a treatment option for patients with medically refractory UC or neoplasia. However, little is known about the development of pouch neoplasia in PSC-UC patients following an IPAA. We aim to describe the incidence of pouch neoplasia in PSC-UC patients after an IPAA. METHODS: We conducted a retrospective chart review of patients with a confirmed diagnosis of PSC and IBD who underwent colectomy with IPAA followed by pouch surveillance between 1995 and 2012. RESULTS: Sixty-five patients were included in the cohort and were followed up from the time of colectomy/IPAA for a median of 6years. The most common indications for surgery were low-grade dysplasia (LGD) and refractory colitis. Only 3 patients developed evidence of neoplasia (LGD n=1, high-grade dysplasia n=1, adenocarcinoma n=1). The cumulative 5-year incidence of pouch neoplasia was 5.6% (95% confidence intervals [CI], 1.8%-16.1%). CONCLUSION: Based on our short-term follow-up, surveying the pouch frequently appears to be an unnecessary practice in PSC-IBD patients. Longer follow-up will be needed to develop an optimal surveillance strategy for the development of dysplasia and cancer in such patients.

Is it necessary to assess for fat-soluble vitamin deficiencies in pediatric patients with newly diagnosed celiac disease?

BACKGROUND: The purpose of this study was to identify the frequency of fat-soluble vitamin deficiencies in children with celiac disease (CD) and to determine the value of routine testing for these deficiencies. METHODS: We conducted a retrospective medical record review of patients with a confirmed diagnosis of CD and fat-soluble vitamin levels measured at diagnosis between 1995 and 2012 at Mayo Clinic. Patients' demographics, fat-soluble vitamin levels, and pertinent clinical factors at the time of diagnosis were collected. RESULTS: Eighty-three patients were included in the final analysis: 51 girls and 32 boys, with an average age at diagnosis of 12.8 years in girls and 13.0 years in boys. The most commonly reported symptoms were abdominal pain in 49 patients and diarrhea in 30 patients. Family history of CD was reported in 32 patients. Average vitamin levels for vitamin E, 25-hydroxyvitamin D (25 (OH) D), and vitamin A were 7.5 mg/L, 32.8 ng/mL, and 334.5 µg/dL, respectively. No patients had vitamin A deficiency, 2 patients had vitamin E deficiency, and 9 patients had mild-to-moderate vitamin D deficiency (none had severe deficiency). Both patients with vitamin E deficiency were symptomatic and had complete villous atrophy. Thirty-one patients had insufficiency of 25 (OH) D, which was less than the reported frequency of vitamin D insufficiency in the general pediatric population in the United States in 2004. None of the patients were receiving vitamin supplements at the time of diagnosis. CONCLUSIONS: Fat-soluble vitamin deficiencies are uncommon in children with new diagnosis of CD. Routine measuring of fat-soluble vitamins levels may not be necessary.

Clinical management of autoimmune biliary diseases.

Autoimmune biliary disease is an umbrella term that encompasses several distinct entities such as primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune hepatitis and overlap syndromes. The general approach to the diagnosis of these disorders involves investigating symptomatic patients presenting with a cholestatic biochemical profile. Asymptomatic patients are often diagnosed during investigation of other accompanying or discrete diseases. The distinction between the various entities is necessary for directing clinical management in this group of patients with an underlying autoimmune pathophysiology. Goals of management comprise treating symptoms, preventing complications and suppressing the underlying pathogenetic processes. Liver transplantation plays a vital role in the management of this group of patients and has shown a dramatic improvement in outcomes. Medical therapies such as ursodeoxycholic acid have shown mixed effects with excellent outcomes in primary biliary cirrhosis and less impressive results in primary sclerosing cholangitis. In this manuscript we aim to discuss in detail the management of these autoimmune biliary disorders and describe the effects of different therapies on outcomes on the different subsets of patients.

Secondary sclerosing cholangitis: pathogenesis, diagnosis, and management.

Secondary sclerosing cholangitis (SSC) is an aggressive and rare disease with intricate pathogenesis and multiple causes. Understanding the specific cause underlying each case of SSC is crucial in the clinical management of the disease. Radiologic imaging can help diagnose SSC and hence institute management in a timely manner. Management may encompass simple interventions, such as supportive therapy, antibiotics, and monitoring, or more serious measures, such as surgery, endoscopic intervention, or liver transplantation. Patients with AIDS cholangiopathy have limited therapeutic options and worsened survival. The disease should always be highly suspected in patients with primary sclerosing cholangitis with questionable diagnosis.

Pathogenesis and management of pruritus in cholestatic liver disease.

Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.

Long-term outcomes of patients with primary biliary cirrhosis and hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive tumor that frequently develops in patients with primary biliary cirrhosis (PBC). We determined the mortality of patients with PBC who develop HCC, and which interventions (surgery, radiofrequency ablation, chemoembolization, alcohol injection, or transplantation) increase survival times. We investigated whether the Milan criteria predict outcomes of these patients and are effective in selection for liver transplantation. METHODS: We evaluated data from 38 patients who had a confirmed diagnosis of PBC and HCC between March 1993 and February 2011. Patients were grouped based on whether or not they met the Milan criteria. Survival was assessed using the Kaplan-Meier analysis. RESULTS: Eighteen of the 38 patients (47.3%) died during the follow-up period; 49.4% survived for 5 years and 31.7% survived for 10 years. Thirty-five patients (92.0%) underwent one or a combination of interventions. Liver transplantation improved survival (risk ratio, 0.06; P < .0001), whereas surgery approached significance in causing deterioration (risk ratio, 2.87; P = .07). Mortality did not appear to be affected by meeting the Milan criteria (P = .84). CONCLUSIONS: Five- and 10-year survival times for patients with PBC who developed HCC were 49.4% and 31.7%, respectively. Patients who meet the Milan criteria receive liver transplantation as often as those who do not; we did not observe a difference in survival time between groups. Patients with PBC who develop HCC appear to benefit from aggressive therapies.

Recent developments in the management of idiopathic cholestatic liver disease.

In recent years, the clinical management of patients with idiopathic cholestatic liver disease has shown significant progress. Advancement of diagnostic and therapeutic approaches and better understanding of the pathophysiology underlying these diseases have all contributed considerably to this progress. In this review, we aim to touch briefly on several developments that have occurred in this regard and to discuss novel findings and interventions valuable to clinical practice.