Cynthia Levy

The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis.

CA 19-9 has been used with questionable accuracy to aid diagnosis of cholangiocarcinoma complicating primary sclerosing cholangitis. We aimed to characterize the test properties of CA 19-9 and of a change in CA 19-9 over time in predicting cholangiocarcinoma. Charts of 208 patients were reviewed. Fourteen patients had cholangiocarcinoma. Median CA 19-9 was higher with cholangiocarcinoma (15 vs. 290 U/ml, p < 0.0001). A cutoff of 129 U/ml provided: sensitivity 78.6%, specificity 98.5%, adjusted positive predictive value 56.6% and negative predictive value 99.4%. The median change over time was 664 U/ml in cholangiocarcinoma compared to 6.7 U/ml in primary sclerosing cholangitis alone (p < 0.0001). A cutoff of 63.2 U/ml for change in CA 19-9 provided: sensitivity 90%, specificity 98% and positive predictive value 42%. Only 2 patients with cholangiocarcinoma were the candidates for curative therapy. In conclusion, the positive predictive value of an elevated CA 19-9 was 56.6%; only advanced cases were detected by this method.

Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis

We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10−4) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10−13), 17q12-21 (combined P = 3.50 × 10−13) and MMEL1 (combined P = 3.15 × 10−8) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases.

Chronic hepatitis C and type II diabetes mellitus: A prospective cross-sectional study

An epidemiologic link between chronic hepatitis C (HCV) and type II diabetes mellitus (DM) has been established. Our aims were to prospectively determine the prevalence of DM in interferon-naïve patients with HCV in comparison with the general population, and to determine the association between DM and impaired fasting glucose (IFG) with histological stage in patients with HCV. A consecutive sample of 179 patients was included in this prospective cross-sectional study. The crude percentage of DM for the cohort was 14.5%, different from the crude rate of 7.8% for the general population (p= 0.0008) and from the rate of 7.3% observed in a matched control group with non-HCV liver disease. The prevalence of DM and IFG (DM/IFG) was higher among HCV-infected patients with advanced versus those with early histological disease (p= 0.0004). Advanced histological disease predicted DM/IFG after controlling for other identified risk factors for DM. Family history was the only other independent predictor of DM/IFG in HCV-infected patients. In conclusion, patients with HCV had a higher prevalence of DM compared to the general population. The presence of advanced histological disease in genetically predisposed HCV-patients is associated with a higher prevalence of DM/IFG. DM and IFG were not associated with anthropomorphic markers of obesity in HCV patients, suggesting a unique multifactorial pathogenesis of DM in HCV.

Ursodeoxycholic Acid and Long-Term Survival in Primary Biliary Cirrhosis

OBJECTIVE:At the population level, a detailed picture of the nature of adenocarcinoma at the distal esophagus and esophagogastric junction under modern treatment is lacking. We evaluated the fate of these patients and the results of various types of therapeutic procedures using unselected population-based data.METHODS:Primary data on patients with these adenocarcinomas in two health care districts in Finland were retrieved from the Finnish Cancer Registry. The fate of all 402 patients treated between 1990 and 1998 in 23 units was analyzed.RESULTS:The 5-yr survival rate of these patients was 12.5%. Median survival was 36.5 days (0 days– 68.1 months) with best supportive care (18.9%), 116.5 days (0 days–59.5 months) with palliative (33.8%), mainly either endoscopic or oncological treatment, 211 days (113 days–26.6 months) with exploratory surgery (4.7%), and 17.6 months (0–101.1) after esophageal resection (42.5%). The 5-yr and 8-yr survival rates in this unselected material after esophageal resection including 8.8% operative mortality were 29.0% and 26.0%. The best chance for cure and long-term survival came from esophagectomy with 2-field lymphadenectomy compared to less extensive operations (50.0% vs 23.2% survival at 5 yrs, p = 0.005). Between these groups no statistically significant difference (p = 0.4) existed in pathological TNM stages or in the distribution of node-negative tumors (47.6% vs 41.8%).CONCLUSIONS:Although overall prognosis for adenocarcinoma near the esophagogastric junction is poor, a substantial percentage of patients eligible for major surgery achieve long-term survival.

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.

Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid

Aliment Pharmacol Ther 2011; 33: 235–242

The natural history of hepatitis C cirrhosis after liver transplantation

Hepatitis C after liver transplantation leads to graft cirrhosis in up to 30% of patients within 5 years, but limited data exist regarding the clinical course of cirrhosis after transplantation. The aims of this study were to report the natural history of hepatitis C cirrhosis after liver transplantation and to identify risk factors for decompensation and survival. Hepatitis C patients underwent protocol liver biopsies yearly after liver transplantation. After cirrhosis was identified by biopsy, the outcomes of interest were the development of decompensation, death, or retransplantation for hepatitis C. Kaplan‐Meier and Cox regression analysis was used to determine survival and risk factors for decompensation and mortality. Out of 502 liver transplants performed for hepatitis C, 88 patients (18%) had cirrhosis within 3.7 years. Seventy‐one patients were compensated at diagnosis. The cumulative probability of decompensation 1 year after cirrhosis was 30%. A Model for End‐Stage Liver disease score ≥ 16 was predictive of decompensation and poor survival, whereas successful interferon treatment was found to reduce this risk (relative risk = 0.05). Once decompensation occurred, 1‐year survival was 46%. In conclusion, the results confirm an accelerated natural history of hepatitis C cirrhosis after liver transplantation and demonstrate poor survival after decompensation. The Model for End‐Stage Liver Disease can stratify risk for decompensation and survival, whereas successful antiviral therapy may be protective. Liver Transpl 15:1063–1071, 2009.

Management of internal fistulas in Crohn's disease.

Internal fistulas occur in 5–10% of patients with Crohns disease. The clinical presentation of each of the three main types of internal fistulas–enteroenteric, enterovaginal, and enterovesical fistulas–is important in determining the best management. Asymptomatic fistulas usually require no treatment, but fistulas that cause severe or persistent symptoms necessitate intervention. Previously regarded as a surgical condition requiring resection, some internal fistulas are amenable to a more conservative approach involving medical therapy, surgical repair, or both. So far, there have not been any prospective studies designed specifically to assess the efficacy of a medical treatment of internal fistulas, and information about treatment results is gleaned from trials in which patients with internal fistulas have been included and from retrospective reports. Drugs that have been reported to close internal fistulas partially or completely include azathioprine, 6-mercaptopurine, mycophenolate mofetil, cyclosporine A, tacrolimus, and infliximab. Reparative surgical techniques include transrectal and transvaginal mucosal advancement flaps, cutaneous advancement flap, and anal stricturectomy in combination with a rectal mucosal advancement sleeve. Prospective trials of medical therapy and combination medical and surgical therapy for internal fistulas are needed to provide evidence to support the use of these new therapeutic approaches.

Abnormal Hepatic Biochemistries in Patients With Inflammatory Bowel Disease

OBJECTIVES:The relationship between abnormal hepatic biochemistries and inflammatory bowel disease (IBD) is unclear. We determined the prevalence of abnormal hepatic biochemistries and chronic liver disease in a cohort of IBD patients, and we compared patients with normal and abnormal liver biochemistries.METHODS:Patients with IBD evaluated at our institution between January 1, 2000 and December 31, 2000 were identified. Data on gender, age, IBD subtype, extent and activity, medications, liver disease history, liver biochemistries, and vital status were collected. The χ2 test, Students t-test, and Cox proportional regression were used.RESULTS:We identified 544 patients with available hepatic biochemistries. Abnormal hepatic biochemistries were found in 159 (29%). Defined chronic liver disease was present in 5.8% of patients (primary sclerosing cholangitis in 4.6%). The prevalence of abnormal hepatic biochemistries was 27% for those with active IBD and 36% for those in remission (P = 0.06). Patients with abnormal hepatic biochemistries were less frequently on 5-aminosalicylates (35% vs 51%, P < 0.001), and a smaller proportion was alive at last follow-up (90.4% vs 98.5%, P < 0.0001). The age-adjusted risk of death was 4.8 times higher in patients with abnormal hepatic biochemistries, after excluding patients with any diagnosis of liver disease.CONCLUSIONS:Abnormal hepatic biochemistries were present in nearly one-third of our patients, and surprisingly, they were not associated with IBD activity. Abnormal hepatic biochemistries and chronic liver disease appeared to have a negative impact on vital status. Persistently abnormal hepatic biochemistries should be evaluated, and not attributed to IBD activity.

Use of herbal supplements for chronic liver disease

BACKGROUND & AIMS Complementary and alternative medicine (CAM) is becoming popular among patients with liver disease. Although there is a growing body of evidence regarding potential mechanisms of action of these and other herbs, caution must be used to interpret the results of the few clinical trials available. Our goal was to discuss the biologic rationale for the use of specific herbs (silymarin, glycyrrhizin, sho-saiko-to, Phyllanthus amarus , Picrorrhiza kurroa , Compound 861, CH-100, and LIV.52) in the treatment of chronic liver diseases, as well as the evidence for their efficacy and adverse effects according to clinical trials. METHODS Because of the relative paucity of clinical studies using herbs, every trial published in English was reviewed. RESULTS Although many trials suggest that these herbs can decrease serum transaminase levels, the effects on hepatic histopathology and long-term survival are either poorly studied or conflicting. LIV.52 has been withdrawn from the market because of deleterious effects in patients with liver disease. CONCLUSIONS Based on current evidence, we cannot recommend the use of herbal supplements for the routine treatment of any chronic liver disease and further well-designed clinical trials are necessary.