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.

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.

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.

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.

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.

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.

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.

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.

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.