Kelly W. Burak

Incidence and Risk Factors for Cholangiocarcinoma in Primary Sclerosing Cholangitis

Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC); however, marked variability in the incidence of CCA in PSC is reported. Furthermore, limited information exists on risk factors for the development of CCA in PSC. The aim of this study was to determine the incidence of CCA in patients with PSC and to evaluate baseline risk factors for the later development of CCA. From a previous study of the natural history of PSC, we identified 161 patients with PSC who did not have CCA at study entry. Patients were followed until a diagnosis of CCA was established, liver transplantation was performed, or death occurred. Patients were followed for a median of 11.5 yr (interquartile range 4.0–16.1 yr). Fifty-nine patients (36.6%) died, 50 patients (31.1%) underwent liver transplantation, and 11 patients (6.8%) developed CCA. The rate of CCA developing was approximately 0.6% per year. Compared to the incidence rates of CCA in the general population, the relative risk of CCA in PSC was significantly increased (RR = 1,560; 95%CI = 780, 2,793; p < 0.0001). On univariate analysis, a history of variceal bleeding (p < 0.001), proctocolectomy (p = 0.01), and lack of symptoms (p = 0.02) were significant risk factors for CCA with the Mayo Risk Score being marginally significant (p = 0.051). Multivariate analysis determined only variceal bleeding to be a significant risk factor for CCA (RR 24.2; 95%CI: 3.3–67.1). No association was found between the duration of PSC and the incidence of CCA. In conclusion, approximately 7% of PSC patients later developed CCA over a mean follow-up of 11.5 yr, which is dramatically higher than the rates in the general population. Variceal bleeding is a major risk factor for the later development of CCA.

Is there a role for liver biopsy in primary sclerosing cholangitis

OBJECTIVE:Liver biopsies are performed in patients with primary sclerosing cholangitis (PSC) to stage disease and to rule out coexisting liver disease. The purpose of this study was to examine how often routine liver biopsies provide important information in patients with PSC.METHODS:We reviewed the charts of 138 patients with a cholangiographic diagnosis of PSC to determine whether information from liver biopsy had an impact on clinical management.RESULTS:A total of 30 patients did not have a liver biopsy, whereas 29 patients had a biopsy before cholangiography. In 79 patients the liver biopsy was performed after the diagnosis of PSC was established by cholangiography (median time from cholangiography to liver biopsy, 21 days). In 78 of 79 patients (98.7%) the liver biopsy revealed no atypical findings and did not affect clinical management. In one patient the liver biopsy revealed findings of an overlap syndrome with autoimmune hepatitis, and the patient was treated with corticosteroids and azathioprine. This patient had biochemical features consistent with autoimmune hepatitis. One patient developed a bile leak after liver biopsy, requiring hospitalization (complication rate 0.9%).CONCLUSIONS:Liver biopsies rarely contribute new information that affects the management of patients with PSC. Given the risks of the procedure, liver biopsies for patients with a diagnosis of PSC established by cholangiography may not routinely be necessary.

Management of chronic hepatitis C: Consensus guidelines

Since the last consensus conference on the management of chronic viral hepatitis, a number of studies looking at modifications of the standard course of treatment have been published. These changes have been sufficiently substantive to warrant review to determine whether any changes in the recommended treatment algorithms are needed. A consensus development conference was held in January 2007, and the present document highlights the results of the presentations and discussion about these issues. It reviews the epidemiology of hepatitis C in Canada, treatment of acute hepatitis C and new algorithms in chronic hepatitis C, including retreatment of previous treatment failures. In addition, sections on management of hepatitis C in special populations have been updated. There is also a section on the use of hematopoietic growth factors to help manage patients on therapy. The document should be read in conjunction with the previous document to identify changes. Some recommendations made in the previous document remain and are not discussed here.

Prediction of cardiac complications after liver transplantation.

Background. Orthotopic liver transplantation (OLT) stresses the cardiovascular system, and cardiac complications after OLT are common. Methods. Hundred ninety-seven patients (≥40 years) who had OLT from 2002 to 2007 were reviewed to identify predictors of cardiac complications within 6 months after transplantation. Results. Median age was 56 years (40–75 years); 69% men. Reasons for OLT were hepatitis C virus (HCV) 45.5%, alcohol 22%, hepatocellular carcinoma (HCC) 8%, primary biliary cirrhosis 10%, and others 14.5%. Eighty-two patients suffered one or more cardiac complications within 6 months after OLT (pulmonary edema=61 [overt heart failure=7], arrhythmia=13, pulmonary hypertension=7, pericardial effusion=2, and right atrial thrombus=1). Cardiac causes were the leading cause of death (n=5; 23.8% of all mortality). By multivariate analysis, after adjusting for age and sex, independent predictors were adverse intraoperative cardiovascular events (adjusted odds ratio; 95% confidence interval: 5.89, 1.82–19.14), history of cardiac disease (2.42, 0.89–6.6), and i-MELD (integrated model for end-stage liver disease) score (1.08, 1.02–1.14), whereas adverse intraoperative cardiovascular events (5.73, 1.96–16.78) and i-MELD (1.07, 1.01–1.13) predicted pulmonary edema. None of the following variables predicted complications: age, sex, OLT indication, body mass index, blood pressure, alcohol and smoking history, pre-OLT investigations (chest X-ray, electrocardiogram, echocardiography, coronary angiography, pulmonary arterial pressure, and 2-methoxy isobutyl isonitrile scan), immunosuppressive treatment, or intraoperative variables (transfusion amount, cadaveric vs. living graft or cold ischemia and rewarming times). Conclusions. Cardiac complications after OLT are common and were the leading cause of death after surgery. Adverse intraoperative cardiovascular events, previous cardiac disease, and advanced liver disease as quantified by i-MELD score predicted postoperative cardiac complications.

Epidemiology and natural history of primary biliary cirrhosis in a Canadian health region: A population‐based study

The recent epidemiology and outcomes of primary biliary cirrhosis (PBC) in North America are incompletely described, partly due to difficulties in case ascertainment. In light of their availability, broad coverage, and limited expense, administrative databases may facilitate such investigations. We used population‐based administrative data (inpatient, ambulatory care, and physician billing databases) and a validated International Classification of Diseases coding algorithm to describe the epidemiology and natural history of PBC in the Calgary Health Region (population ≈1.1 million). Between 1996 and 2002, the overall age/sex‐adjusted annual incidence of PBC was 30.3 cases per million (48.4 per million in women, 10.4 per million in men). Although the incidence remained stable, the prevalence increased from 100 per million in 1996 to 227 per million in 2002 (P < 0.0005). Among 137 incident cases with a total follow‐up of 801 person‐years from diagnosis (median 5.8 years), 27 patients (20%) died and six (4.4%) underwent liver transplantation. The estimated 10‐year probabilities of survival, liver transplantation, and transplant‐free survival were 73% (95% confidence interval [CI] 60%–83%), 6% (95% CI 2.5%–12.6%), and 68% (95% CI 55%–78%), respectively. Survival in PBC patients was significantly lower than that of the age/sex‐matched Canadian population (standardized mortality ratio 2.87; 95% CI 1.89–4.17); male sex (hazard ratio [HR] 3.80; 95% CI 1.85–7.82) and an older age at diagnosis (HR per additional year, 1.06; 95% CI 1.03–1.10) were independent predictors of mortality. Conclusion: This population‐based study demonstrates that the burden of PBC in Canada is high and growing. Survival of PBC patients is significantly lower than that of the general population, emphasizing the importance of developing new therapies for this condition. (HEPATOLOGY 2009.)

The pathogenesis of hepatitis C virus is influenced by cytomegalovirus

We investigated the effect of beta-herpesviruses on allograft failure and mortality, hepatitis C virus (HCV) replication, and liver histologic characteristics among 92 HCV-infected liver transplant recipients. Reactivation of cytomegalovirus (CMV) but not of human herpesvirus 6 (HHV-6) was independently associated with allograft failure and mortality (risk ratio, 3.71; 95% confidence interval, 1.64-8.39); allograft failure and mortality was observed in 48% of patients with CMV disease, 35% of patients with subclinical CMV infection, and 17% of patients without CMV infection (P=.0275). CMV reactivation was highly predictive of mortality (P<.001), regardless of whether it remained subclinical or evolved into CMV disease. Patients with CMV disease had a higher fibrosis stage (P=.05) and had a trend toward a higher hepatitis activity index (P=.10) and HCV load (P=.10) at 16 weeks after liver transplantation. The pathogenesis of HCV is influenced by its interaction with CMV but not with HHV-6.

Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy.

There are limited therapeutic options available for patients with autoimmune hepatitis in whom conventional treatment fails. A case series of five patients unresponsive to or unable to take azathioprine, 6-mercaptopurine or corticosteroids who were treated with mycophenolate mofetil (MMF) is reported. While on MMF, alanine aminotransferase normalized or remained normal in all patients. MMF had a steroid-sparing effect and histological remission was demonstrated in one patient after seven months of MMF. One patient experienced an uncomplicated episode of pyelonephritis. In conclusion, MMF can effectively induce and maintain remission in refractory autoimmune hepatitis patients.

Management of chronic hepatitis B: Consensus guidelines

The present document presents the proceedings of the consensus development conference on the management of viral hepatitis held in January 2007 under the auspices of the Canadian Association for the Study of the Liver and the Association of Medical Microbiology and Infectious Disease Canada. Several new agents have become available since the last such document was published in 2004, and new information has become available to help assess risk of adverse outcomes and who should be treated. In addition, the participants at the meeting identified a number of structural barriers that exist uniquely in Canada and that prevent physicians from properly managing their patients. The conference discussed the selection of patients for treatment and the drugs that can be used to treat these patients, as well as the treatment of hepatitis B in special populations. The present document should be read in conjunction with the companion document on the management of chronic hepatitis C.

Maintenance Therapy With Peginterferon Alfa-2b Does Not Prevent Hepatocellular Carcinoma in Cirrhotic Patients With Chronic Hepatitis C

BACKGROUND & AIMS Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program. METHODS Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event. RESULTS There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P=.016). There were no new safety observations. CONCLUSIONS Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

Successful treatment of refractory type 1 autoimmune hepatitis with methotrexate

BACKGROUND/AIMS Autoimmune hepatitis is a heterogeneous disorder that typically responds to glucocorticoids with or without azathioprine. Treatment options for patients not responding to standard therapy are limited. METHODS We describe a 52-year-old female who presented with jaundice, marked elevation in liver enzymes, positive antinuclear antibody and a liver biopsy consistent with autoimmune hepatitis. Liver enzymes did not normalize with prednisone alone. When azathioprine was added, the disease flared. The patient refused cyclosporine. Methotrexate 7.5 mg po per week resulted in normalization of liver enzymes, improved liver histology, and has maintained remission with a steroid-sparing effect. RESULTS/CONCLUSION In this patient methotrexate was used successfully to treat type 1 autoimmune hepatitis. This suggests that methotrexate may have a role in treatment of autoimmune hepatitis refractory to standard therapy.