Primary sclerosing cholangitis (PSC) is a disease of unclear cause characterized by cholestasis, ... more Primary sclerosing cholangitis (PSC) is a disease of unclear cause characterized by cholestasis, fibrosis of the intrahepatic and/or extrahepatic bile ducts, leading eventually to cirrhosis of the liver, end-stage liver disease, and an increased risk for bile duct and colon cancer. 1 About 70% to 80% of patients with PSC have the inflammatory bowel disease ulcerative colitis (UC). The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 people per year and 0 to 16.2 per 100,000 people, respectively. The estimated median survival from the time of PSC diagnosis until liver transplantation or liver diseaserelated death is 12 to 15 years. The diagnosis of PSC is made when there is evidence of cholestasis and stricturing of the intrahepatic and/or extrahepatic bile ducts on magnetic resonance cholangiography. Small-duct PSC is characterized by cholestasis and a normal cholangiogram; in these cases, liver biopsy is required for diagnosis. No therapy for PSC has been proven to halt the progression of the disease. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has been extensively studied in PSC. The value of UDCA in PSC is questionable. In the Scandinavian clinical trial, the use of UDCA at a dose of 17 to 23 mg/kg/day was associated with improvement in liver biochemistries, but no statistically significant effect on survival or prevention of cholangiocarcinoma (CCA), although this study was underpowered to detect a significant effect on the clinical endpoints that had been sought. In the high-dose ursodiol clinical trial, the use of higher doses of UDCA (28 to 30 mg/kg/day) showed the expected improvement of liver biochemistries. 5 However, this study was terminated at 5 years because of the higher rates of serious adverse events in the UDCA group. In this article, we take the opportunity to briefly discuss the previously examined agents and the emerging potential treatments for PSC.
Primary sclerosing cholangitis (PSC) is a disease of unclear cause characterized by cholestasis, ... more Primary sclerosing cholangitis (PSC) is a disease of unclear cause characterized by cholestasis, fibrosis of the intrahepatic and/or extrahepatic bile ducts, leading eventually to cirrhosis of the liver, end-stage liver disease, and an increased risk for bile duct and colon cancer. 1 About 70% to 80% of patients with PSC have the inflammatory bowel disease ulcerative colitis (UC). The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 people per year and 0 to 16.2 per 100,000 people, respectively. The estimated median survival from the time of PSC diagnosis until liver transplantation or liver diseaserelated death is 12 to 15 years. The diagnosis of PSC is made when there is evidence of cholestasis and stricturing of the intrahepatic and/or extrahepatic bile ducts on magnetic resonance cholangiography. Small-duct PSC is characterized by cholestasis and a normal cholangiogram; in these cases, liver biopsy is required for diagnosis. No therapy for PSC has been proven to halt the progression of the disease. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has been extensively studied in PSC. The value of UDCA in PSC is questionable. In the Scandinavian clinical trial, the use of UDCA at a dose of 17 to 23 mg/kg/day was associated with improvement in liver biochemistries, but no statistically significant effect on survival or prevention of cholangiocarcinoma (CCA), although this study was underpowered to detect a significant effect on the clinical endpoints that had been sought. In the high-dose ursodiol clinical trial, the use of higher doses of UDCA (28 to 30 mg/kg/day) showed the expected improvement of liver biochemistries. 5 However, this study was terminated at 5 years because of the higher rates of serious adverse events in the UDCA group. In this article, we take the opportunity to briefly discuss the previously examined agents and the emerging potential treatments for PSC.
Background The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) a... more Background The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known. Methods The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age-and gendermatched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC). Results We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.7 years. Seventy-eight patients received prednisone for induction of remission, and 53 received at least one other immunosuppressive agent for maintenance of remission. Of the IgG4-SC group, 10 died (median time from diagnosis until death was 6.5 years): 2 due to cirrhosis, 3 due to cholangiocarcinoma (CCA), and 5 due to non-hepatobiliary causes. Eleven patients in the PSC group underwent liver transplantation, while none did in the IgG4-SC group. The incidence of a hepatobiliary adverse event (cirrhosis or CCA) was 3.4 times greater in the PSC compared to the IgG4-SC group (events per 1000 person-years: 52.6; 95% CI 38-73; vs. 15.6; 95% CI 7-32). The probability of development of a hepatobiliary adverse event within 10 years was 11% in the IgG4-SC compared to 45% in the PSC group (P = 0.0001). The overall survival tended to be higher in the IgG4-SC compared to the PSC group (10-year: 79% vs. 68%, respectively; P = 0.11). Conclusions In a cohort of IgG4-SC patients, 88% of whom were treated with immunosuppressive drugs, the risk of cirrhosis and CCA was significantly lower compared to an age-and gender-matched group with PSC.
Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by choles... more Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.
Background: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). ... more Background: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. Areas of Uncertainty: The etiopathogenesis of PSC remains an enigma. Data Sources: We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documen...
The expectation exists that medical education will continue to improve even during financially ch... more The expectation exists that medical education will continue to improve even during financially challenging times. The authors reviewed their recent experiences in effecting positive changes and improvements in Mayo Medical School during a time of fiscal constraint. They successfully implemented numerous changes, including a major curriculum reform, while modestly reducing overall
The expectation exists that medical education will continue to improve even during financially ch... more The expectation exists that medical education will continue to improve even during financially challenging times. The authors reviewed their recent experiences in effecting positive changes and improvements in Mayo Medical School during a time of fiscal constraint. They successfully implemented numerous changes, including a major curriculum reform, while modestly reducing overall
Background Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholang... more Background Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. Methods Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. Results Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was "very good" (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and "moderate" (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. Conclusions Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.
Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflamma... more 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. 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. Of the 7121 patients in the cohort, 2616 met the primary endpoin...
Although highly sensitive and specific, the revised International Autoimmune Hepatitis Group (IAI... more Although highly sensitive and specific, the revised International Autoimmune Hepatitis Group (IAIHG) diagnostic criteria for autoimmune hepatitis (AIH) are cumbersome to use in clinical practice and rely upon a number of autoantibodies that are costly and are not widely available. The simplified scoring system for AIH attempts to rectify the complexity of the IAIHG criteria. To date, there have been few studies assessing the specificity of the simplified score for AIH when applied to patients with cholestatic liver diseases. The purpose of this study was to examine the specificity of the simplified scoring system for AIH as compared to the revised IAIHG criteria in a large cohort of patients with primary sclerosing cholangitis (PSC). The patient population consisted of 147 patients enrolled in two prospective trials at the Mayo Clinic examining the use of ursodeoxycholic acid in PSC. All of the patients underwent baseline blood work (including standard serologic testing to exclude o...
Purpose Standard dose (13-15 mg/kg) ursodeoxycholic acid (UCDA) is ineffective in the treatment o... more Purpose Standard dose (13-15 mg/kg) ursodeoxycholic acid (UCDA) is ineffective in the treatment of nonalcoholic steatohepatitis (NASH), however, its immunomodulatory and hepatoprotective effects are dose related. Therefore, we examined the impact of high-dose (28-32 mg/kg) UCDA on aminotransaminase levels in a pilot study of patients with NASH. Methods Twelve patients with biopsy-proven NASH and elevated aminotransaminases were prescribed high-dose UCDA for 6 months. Liver function tests were monitored during and after treatment with the study endpoint defined as normalization of aminotransaminase levels. Results Normalization of aspartate aminotransaminase (AST) levels was observed in two (17%) patients, however, no patient normalized their alanine aminotransaminase (ALT) levels. A trend towards a minor reduction in median (range) ALT values from baseline to end of treatment was noted [124 (66-229) vs. 101 (53-188) IU/l, p = 0.07], whereas AST levels remained unchanged [85 (40-132) vs. 98 (28-147) IU/l, p = 0.83]. One patient discontinued treatment prematurely due to diarrhea. No significant change in fasting glucose, triglyceride or HDL cholesterol was observed with treatment. No significant change in ALT or AST levels was observed in the 6-month period after cessation of treatment. Conclusion High-dose UCDA does not normalize aminotransaminase levels in patients with NASH. Other inexpensive well-tolerated agents for the treatment of NASH need to be investigated.
Background & Aims: Primary sclerosing cholangitis (PSC) is typically associated with inflammatory... more 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 6 years. 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%).
Recurrence of primary sclerosing cholangitis (PSC) following liver transplantation has been sugge... more Recurrence of primary sclerosing cholangitis (PSC) following liver transplantation has been suggested; however, it has not been fully defined because of numerous complicating factors and the lack of diagnostic criteria. In the present study, we investigated the recurrence of PSC by developing strict criteria and applying them to a large cohort of PSC patients who underwent liver transplantation. Between March 1985 and June 1996, 150 PSC patients underwent liver transplantation at the Mayo Clinic; mean follow up was 55 months. The incidence of nonanastomotic biliary strictures and hepatic histologic findings suggestive of PSC were compared between patients transplanted for PSC and a non-PSC transplant control group. Our definition of recurrent PSC was based on characteristic cholangiographic and histologic findings that occur in nontransplant PSC patients. By using strict criteria, 30 patients with other known causes of posttransplant nonanastomotic biliary strictures were excluded leaving 120 patients for analysis of recurrence of PSC. We found evidence of PSC recurrence after liver transplantation in 24 patients (20%). Of these, 22 out of 24 patients showed characteristic features of PSC on cholangiography and 11 out of 24 had compatible hepatic histologic abnormalities with a mean time to diagnosis of 360 and 1,350 days, respectively. Both cholangiographic and hepatic histologic findings suggestive of PSC recurrence were seen in nine patients. The higher incidence and later onset of nonanastomotic biliary strictures in patients with PSC compared with a non-PSC control group is supportive of the fact that PSC does recur following liver transplantation. We were unable to identify specific clinical risk factors for recurrent PSC, and the overall patient and graft survival in patients with recurrent PSC was similar to those without evidence of recurrence. Our observations provide convincing evidence that PSC frequently recurs in the hepatic allograft using strict inclusion and exclusion criteria.
Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase ac... more Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UD CA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and y-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial.
The aim of this study was to determine the safety and potential efficacy of B-cell depletion with... more The aim of this study was to determine the safety and potential efficacy of B-cell depletion with the anti-CD20 monoclonal antibody rituximab in patients with primary biliary cirrhosis (PBC) and an incomplete response to ursodeoxycholic acid (UDCA). This open-label study enrolled six patients with PBC and incomplete responses to UDCA to be treated with 2 doses of 1000 mg rituximab separated by 2 weeks and followed for 52 weeks. The primary endpoints were safety and changes in B-cell function. Two patients received only 1 dose of rituximab, one due to activation of latent varicella and the other due to a viral upper respiratory infection. Serum levels of total IgG, IgM, and IgA as well as anti-mitochondrial autoantibodies (AMAs) IgA and IgM decreased significantly from baseline by 16 weeks and returned to baseline levels by 36 weeks. Stimulation of B cells with CpG produced significantly less IgM at 52 weeks after treatment compared with B cells at baseline. In addition, transient decreases in memory B-cell and T-cell frequencies and an increase in CD25 high CD4 1 T cells were observed after treatment. These changes were associated with significant increases in mRNA levels of FoxP3 and transforming growth factor-b (TGF-b) and a decrease in tumor necrosis factor-a (TNF-a) in CD4 1 T cells. Notably, serum alkaline phosphatase levels were significantly reduced up to 36 weeks following rituximab treatment. Conclusion: These data suggest that depletion of B cells influences the induction, maintenance, and activation of both B and T cells and provides a potential mechanism for treatment of patients with PBC with an incomplete response to UDCA.
Primary sclerosing cholangitis (PSC) is a disease of unclear cause characterized by cholestasis, ... more Primary sclerosing cholangitis (PSC) is a disease of unclear cause characterized by cholestasis, fibrosis of the intrahepatic and/or extrahepatic bile ducts, leading eventually to cirrhosis of the liver, end-stage liver disease, and an increased risk for bile duct and colon cancer. 1 About 70% to 80% of patients with PSC have the inflammatory bowel disease ulcerative colitis (UC). The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 people per year and 0 to 16.2 per 100,000 people, respectively. The estimated median survival from the time of PSC diagnosis until liver transplantation or liver diseaserelated death is 12 to 15 years. The diagnosis of PSC is made when there is evidence of cholestasis and stricturing of the intrahepatic and/or extrahepatic bile ducts on magnetic resonance cholangiography. Small-duct PSC is characterized by cholestasis and a normal cholangiogram; in these cases, liver biopsy is required for diagnosis. No therapy for PSC has been proven to halt the progression of the disease. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has been extensively studied in PSC. The value of UDCA in PSC is questionable. In the Scandinavian clinical trial, the use of UDCA at a dose of 17 to 23 mg/kg/day was associated with improvement in liver biochemistries, but no statistically significant effect on survival or prevention of cholangiocarcinoma (CCA), although this study was underpowered to detect a significant effect on the clinical endpoints that had been sought. In the high-dose ursodiol clinical trial, the use of higher doses of UDCA (28 to 30 mg/kg/day) showed the expected improvement of liver biochemistries. 5 However, this study was terminated at 5 years because of the higher rates of serious adverse events in the UDCA group. In this article, we take the opportunity to briefly discuss the previously examined agents and the emerging potential treatments for PSC.
Primary sclerosing cholangitis (PSC) is a disease of unclear cause characterized by cholestasis, ... more Primary sclerosing cholangitis (PSC) is a disease of unclear cause characterized by cholestasis, fibrosis of the intrahepatic and/or extrahepatic bile ducts, leading eventually to cirrhosis of the liver, end-stage liver disease, and an increased risk for bile duct and colon cancer. 1 About 70% to 80% of patients with PSC have the inflammatory bowel disease ulcerative colitis (UC). The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 people per year and 0 to 16.2 per 100,000 people, respectively. The estimated median survival from the time of PSC diagnosis until liver transplantation or liver diseaserelated death is 12 to 15 years. The diagnosis of PSC is made when there is evidence of cholestasis and stricturing of the intrahepatic and/or extrahepatic bile ducts on magnetic resonance cholangiography. Small-duct PSC is characterized by cholestasis and a normal cholangiogram; in these cases, liver biopsy is required for diagnosis. No therapy for PSC has been proven to halt the progression of the disease. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has been extensively studied in PSC. The value of UDCA in PSC is questionable. In the Scandinavian clinical trial, the use of UDCA at a dose of 17 to 23 mg/kg/day was associated with improvement in liver biochemistries, but no statistically significant effect on survival or prevention of cholangiocarcinoma (CCA), although this study was underpowered to detect a significant effect on the clinical endpoints that had been sought. In the high-dose ursodiol clinical trial, the use of higher doses of UDCA (28 to 30 mg/kg/day) showed the expected improvement of liver biochemistries. 5 However, this study was terminated at 5 years because of the higher rates of serious adverse events in the UDCA group. In this article, we take the opportunity to briefly discuss the previously examined agents and the emerging potential treatments for PSC.
Background The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) a... more Background The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known. Methods The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age-and gendermatched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC). Results We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.7 years. Seventy-eight patients received prednisone for induction of remission, and 53 received at least one other immunosuppressive agent for maintenance of remission. Of the IgG4-SC group, 10 died (median time from diagnosis until death was 6.5 years): 2 due to cirrhosis, 3 due to cholangiocarcinoma (CCA), and 5 due to non-hepatobiliary causes. Eleven patients in the PSC group underwent liver transplantation, while none did in the IgG4-SC group. The incidence of a hepatobiliary adverse event (cirrhosis or CCA) was 3.4 times greater in the PSC compared to the IgG4-SC group (events per 1000 person-years: 52.6; 95% CI 38-73; vs. 15.6; 95% CI 7-32). The probability of development of a hepatobiliary adverse event within 10 years was 11% in the IgG4-SC compared to 45% in the PSC group (P = 0.0001). The overall survival tended to be higher in the IgG4-SC compared to the PSC group (10-year: 79% vs. 68%, respectively; P = 0.11). Conclusions In a cohort of IgG4-SC patients, 88% of whom were treated with immunosuppressive drugs, the risk of cirrhosis and CCA was significantly lower compared to an age-and gender-matched group with PSC.
Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by choles... more Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.
Background: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). ... more Background: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. Areas of Uncertainty: The etiopathogenesis of PSC remains an enigma. Data Sources: We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documen...
The expectation exists that medical education will continue to improve even during financially ch... more The expectation exists that medical education will continue to improve even during financially challenging times. The authors reviewed their recent experiences in effecting positive changes and improvements in Mayo Medical School during a time of fiscal constraint. They successfully implemented numerous changes, including a major curriculum reform, while modestly reducing overall
The expectation exists that medical education will continue to improve even during financially ch... more The expectation exists that medical education will continue to improve even during financially challenging times. The authors reviewed their recent experiences in effecting positive changes and improvements in Mayo Medical School during a time of fiscal constraint. They successfully implemented numerous changes, including a major curriculum reform, while modestly reducing overall
Background Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholang... more Background Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. Methods Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. Results Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was "very good" (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and "moderate" (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. Conclusions Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.
Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflamma... more 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. 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. Of the 7121 patients in the cohort, 2616 met the primary endpoin...
Although highly sensitive and specific, the revised International Autoimmune Hepatitis Group (IAI... more Although highly sensitive and specific, the revised International Autoimmune Hepatitis Group (IAIHG) diagnostic criteria for autoimmune hepatitis (AIH) are cumbersome to use in clinical practice and rely upon a number of autoantibodies that are costly and are not widely available. The simplified scoring system for AIH attempts to rectify the complexity of the IAIHG criteria. To date, there have been few studies assessing the specificity of the simplified score for AIH when applied to patients with cholestatic liver diseases. The purpose of this study was to examine the specificity of the simplified scoring system for AIH as compared to the revised IAIHG criteria in a large cohort of patients with primary sclerosing cholangitis (PSC). The patient population consisted of 147 patients enrolled in two prospective trials at the Mayo Clinic examining the use of ursodeoxycholic acid in PSC. All of the patients underwent baseline blood work (including standard serologic testing to exclude o...
Purpose Standard dose (13-15 mg/kg) ursodeoxycholic acid (UCDA) is ineffective in the treatment o... more Purpose Standard dose (13-15 mg/kg) ursodeoxycholic acid (UCDA) is ineffective in the treatment of nonalcoholic steatohepatitis (NASH), however, its immunomodulatory and hepatoprotective effects are dose related. Therefore, we examined the impact of high-dose (28-32 mg/kg) UCDA on aminotransaminase levels in a pilot study of patients with NASH. Methods Twelve patients with biopsy-proven NASH and elevated aminotransaminases were prescribed high-dose UCDA for 6 months. Liver function tests were monitored during and after treatment with the study endpoint defined as normalization of aminotransaminase levels. Results Normalization of aspartate aminotransaminase (AST) levels was observed in two (17%) patients, however, no patient normalized their alanine aminotransaminase (ALT) levels. A trend towards a minor reduction in median (range) ALT values from baseline to end of treatment was noted [124 (66-229) vs. 101 (53-188) IU/l, p = 0.07], whereas AST levels remained unchanged [85 (40-132) vs. 98 (28-147) IU/l, p = 0.83]. One patient discontinued treatment prematurely due to diarrhea. No significant change in fasting glucose, triglyceride or HDL cholesterol was observed with treatment. No significant change in ALT or AST levels was observed in the 6-month period after cessation of treatment. Conclusion High-dose UCDA does not normalize aminotransaminase levels in patients with NASH. Other inexpensive well-tolerated agents for the treatment of NASH need to be investigated.
Background & Aims: Primary sclerosing cholangitis (PSC) is typically associated with inflammatory... more 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 6 years. 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%).
Recurrence of primary sclerosing cholangitis (PSC) following liver transplantation has been sugge... more Recurrence of primary sclerosing cholangitis (PSC) following liver transplantation has been suggested; however, it has not been fully defined because of numerous complicating factors and the lack of diagnostic criteria. In the present study, we investigated the recurrence of PSC by developing strict criteria and applying them to a large cohort of PSC patients who underwent liver transplantation. Between March 1985 and June 1996, 150 PSC patients underwent liver transplantation at the Mayo Clinic; mean follow up was 55 months. The incidence of nonanastomotic biliary strictures and hepatic histologic findings suggestive of PSC were compared between patients transplanted for PSC and a non-PSC transplant control group. Our definition of recurrent PSC was based on characteristic cholangiographic and histologic findings that occur in nontransplant PSC patients. By using strict criteria, 30 patients with other known causes of posttransplant nonanastomotic biliary strictures were excluded leaving 120 patients for analysis of recurrence of PSC. We found evidence of PSC recurrence after liver transplantation in 24 patients (20%). Of these, 22 out of 24 patients showed characteristic features of PSC on cholangiography and 11 out of 24 had compatible hepatic histologic abnormalities with a mean time to diagnosis of 360 and 1,350 days, respectively. Both cholangiographic and hepatic histologic findings suggestive of PSC recurrence were seen in nine patients. The higher incidence and later onset of nonanastomotic biliary strictures in patients with PSC compared with a non-PSC control group is supportive of the fact that PSC does recur following liver transplantation. We were unable to identify specific clinical risk factors for recurrent PSC, and the overall patient and graft survival in patients with recurrent PSC was similar to those without evidence of recurrence. Our observations provide convincing evidence that PSC frequently recurs in the hepatic allograft using strict inclusion and exclusion criteria.
Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase ac... more Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UD CA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and y-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial.
The aim of this study was to determine the safety and potential efficacy of B-cell depletion with... more The aim of this study was to determine the safety and potential efficacy of B-cell depletion with the anti-CD20 monoclonal antibody rituximab in patients with primary biliary cirrhosis (PBC) and an incomplete response to ursodeoxycholic acid (UDCA). This open-label study enrolled six patients with PBC and incomplete responses to UDCA to be treated with 2 doses of 1000 mg rituximab separated by 2 weeks and followed for 52 weeks. The primary endpoints were safety and changes in B-cell function. Two patients received only 1 dose of rituximab, one due to activation of latent varicella and the other due to a viral upper respiratory infection. Serum levels of total IgG, IgM, and IgA as well as anti-mitochondrial autoantibodies (AMAs) IgA and IgM decreased significantly from baseline by 16 weeks and returned to baseline levels by 36 weeks. Stimulation of B cells with CpG produced significantly less IgM at 52 weeks after treatment compared with B cells at baseline. In addition, transient decreases in memory B-cell and T-cell frequencies and an increase in CD25 high CD4 1 T cells were observed after treatment. These changes were associated with significant increases in mRNA levels of FoxP3 and transforming growth factor-b (TGF-b) and a decrease in tumor necrosis factor-a (TNF-a) in CD4 1 T cells. Notably, serum alkaline phosphatase levels were significantly reduced up to 36 weeks following rituximab treatment. Conclusion: These data suggest that depletion of B cells influences the induction, maintenance, and activation of both B and T cells and provides a potential mechanism for treatment of patients with PBC with an incomplete response to UDCA.
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Papers by Keith Lindor