Cholangiocarcinoma is the second most common primary hepatic malignancy after hepatocellular cancer. It accounts for approximately 10–25% of all hepatobiliary malignancies. There are considerable geographic and demographic variations in the incidence of cholangiocarcinoma. There are several established risk factors for CC including parasitic infections, primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and toxins. Other less-established, potential risk factors include inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol drinking, tobacco smoking, and host genetic polymorphisms. In studies where the distinction between ICC and ECC was used, some potential risk factors seem to have differential effect on CC depending on site. Therefore, the consistent use of more refined classification would allow better understanding of risk factors for cholangiocarcinoma.

Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1- and 3-year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re-transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic-type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.

Background and Aims It has been reported that the incidence of intrahepatic cholangiocarcinoma (ICC) has increased in the USA, while extrahepatic cholangiocarcinoma (ECC) has decreased or remained stable. However, neither the recent trends nor the effects of the misclassification of Klatskin tumors are known. Methods Using the Surveillance, Epidemiology, and End Results program databases, we calculated the average annual age-adjusted incidence rates (AA-IRs) of ICC and ECC in 4-year time periods (1992–1995, 1996–1999, 2000–2003, 2004–2007). These AA-IRs were calculated with misclassified as well as correctly classified Klatskin tumors. AA-IRs were also calculated based on age, sex, and race. Multivariable Poisson regression models were used to evaluate the secular trends of ICC and ECC. Results The AA-IR of ICC was 0.92 in 1992–1995 and 0.93 in 2004–2007, while the AA-IR of ECC increased from 0.70 in 1992–1995 to 0.95 in 2004–2007. There was no significant trend in AA-IR of ICC (p = 0.07), while there was a significant increase in ECC across the 4-year time periods (p < 0.001). Klatskin tumors comprised 6.7 % of CCs with approximately 90 and 45 % misclassified as ICC during 1992–2000 and 2001–2007, respectively. Adjusted Poisson models showed no significant differences in the temporal trend of ICC or ECC due to misclassification of Klatskin tumors. Conclusions The incidence of ICC has remained stable between 1992 and 2007 with only slight fluctuations, while the incidence of ECC has been increasing. Misclassification of Klatskin tumors does not appear to play a significant role in the trends of CCs.

Background The delivery of treatment for hepatocellular carcinoma (HCC) could be influenced by place of HCC diagnosis (hospitalization vs. outpatient), subspecialty referral following diagnosis, as well as physician and facility factors. We conducted a study to examine the effect of patient and non-patient factors on the place of HCC diagnosis, referral, and treatment in Veterans Administration (VA) hospitals in the United States. Methods Using the VA Hepatitis C Clinical Case Registry, we identified HCV-infected patients who developed HCC during 1998–2006. All cases were verified and staged according to Barcelona Clinic Liver Cancer (BCLC) criteria. The main outcomes were place of HCC diagnosis, being seen by a surgeon or oncologist, and treatment. We examined factors related to these outcomes using hierarchical logistic regression. These factors included HCC stage, HCC surveillance, physician specialty, and facility factors, in addition to risk factors, co-morbidity, and liver disease indicators. Results Approximately 37.2% of the 1,296 patients with HCC were diagnosed during hospitalization, 31.0% were seen by a surgeon or oncologist, and 34.3% received treatment. Being seen by a surgeon or oncologist was associated with surveillance (adjusted odds ratio (aOR)=1.47;95%CI:1.20–1.80) and varied by geography (1.74;1.09–2.77). Seeing a surgeon or oncologist was predictive of treatment (aOR=1.43;95%CI:1.24–1.66). There was a significant increase in treatment among patients who received surveillance (aOR=1.37; 95%CI:1.02–1.71), were seen by gastroenterology (1.65;1.21–2.24) or were diagnosed at a transplant facility (1.48;1.15–1.90). Conclusions Approximately 40% of patients were diagnosed during hospitalization. Most patients were not seen by a surgeon or oncologist for treatment evaluation and only 34% received treatment. Only receipt of HCC surveillance was associated with increased likelihood of outpatient diagnosis, being seen by a surgeon or oncologist, and treatment.

The effect of hepatitis B virus (HBV) co-infection in patients with hepatitis C virus (HCV) remains unclear. We used the National Veterans Affairs HCV Clinical Case Registry to identify patients with confirmed HCV viremia during 1997–2005. We defined HBV co-infection as a positive test for hepatitis B surface antigen, HBV DNA, or hepatitis B e antigen. We defined cirrhosis and HCC based on the validated ICD9 codes and determined mortality through the end of 2009. We performed Cox proportional hazard regression analyses to examine the effect of HBV co-infection stratified by HBV DNA status (positive or negative) on the risk of cirrhosis, HCC, and death adjusting for patients’ age, gender, race, HIV infection, alcohol or drug use, Deyo Score, and antiviral treatment. Among 99,548 patients with HCV infection, 1370 patients (1.4%) had HBV co-infection. Of the co-infected patients, 677 (49.4%) patients had at-least 1 HBV DNA test done and 303 patients (44.7%) tested positive for HBV DNA. The incidence rates of cirrhosis, HCC, and death were significantly higher in patients with HBV co-infection and detectable HBV DNA compared to HCV mono-infection (36.8, 6.9, and 41.7 versus 17.4, 3.6, and 31.4 per 1,000 person-years, respectively; p<0.05 for all comparisons). After adjustment for demographic, clinical, and treatment factors, patients with detectable HBV DNA had a significantly higher risk for cirrhosis, (hazard ratio [HR] =1.89 95% CI=1.46–2.45), HCC (HR=2.12, 95%CI=1.26–3.60), and death (HR=1.62, 95%CI=1.33–1.99), respectively, compared to HCV mono-infected patients. There were no differences in the risk of cirrhosis, HCC, or overall mortality between co-infected patients with undetectable HBV DNA and those with HCV mono-infection (HRs=1.18, 95% CI=0.90–1.55; 1.54, 95% CI=0.93–2.56; 1.08, 95% CI=0.88–1.33, respectively). In conclusion, we found that while only a small number of HCV patients were co-infected with HBV, patients with documented HBV viremia were at a significantly higher risk for cirrhosis, HCC, and overall death than HCV mono-infected patients. Absence of HBV replication was associated with a clinical course similar to that of HCV mono-infected patients.

Background and Aim There is sparse epidemiologic data on co-infection of hepatitis B (HBV) and hepatitis C (HCV) in the United States. Therefore, the aim of this study was to determine the prevalence and predictors of HBV co-infection in a large United States population of HCV patients. Methods We used the National Veterans Affairs HCV Clinical Case Registry to identify patients tested for HCV during 1997–2005. Patients were categorized based on HCV exposure (any two +HCV tests or one test with a diagnostic code), HCV infection (+RNA or genotype), HBV exposure (any +HBV test, excluding +HBsAb only) and HBV infection (+HBsAg, HBV DNA, or HBeAg). The prevalence of HBV exposure among patients with HCV exposure and that of HBV infection among patients with HCV infection were determined. Multivariable logistic regression evaluated potential demographic and clinical predictors of HBV co-infection. Results Among 168,239 patients with HCV exposure, 58,415 patients had HBV exposure for a prevalence of 34.7% (95% CI 34.5–35.0). Among 102,971 patients with HCV infection, 1,431 patients had HBV co-infection for a prevalence of 1.4% (95% CI 1.3–1.5). Independent associations with HBV co-infection compared with HCV mono-infection were age ≤ 50 years, male sex, positive HIV status, history of hemophilia, sickle cell anemia or thalassemia, history of blood transfusion, cocaine and other drug use; there was decreased risk in patients of Hispanic ethnicity. Conclusions This is the largest cohort study in the United States on the prevalence of HBV co-infection in HCV patients. Among veterans with HCV, exposure to HBV is common (~35%), but HBV co-infection is relatively low (1.4%). Several possible risk factors were identified.

Background & Aims Little information is available about what factors determine serum levels of α-fetoprotein (AFP) levels (e.g., demographic, virological, or clinical features) among individuals who do not develop hepatocellular cacrcinoma (HCC). This information might improve AFP-based algorithms for HCC detection. Methods We examined data from patients in the national Veterans’ Affairs Hepatitis C Virus (HCV) Clinical Case Registry who received at least 1 AFP test (258,275 AFP tests in 76,357 patients; 1.9% developed HCC). We constructed hierarchical multivariate models of AFP levels. Potential predictors of AFP values included patients’ sex, race, cirrhosis status, model for end-stage liver disease (MELD) score, HCV genotype, level of alanine aminotransferase (ALT) within 30 days before the AFP test, time to diagnosis of HCC, and time elapsed from the HCV index date. Results Significant determinants for increased levels of AFP included presence of cirrhosis, higher MELD scores and increased levels of ALT. AFP levels were also affected by the interaction between ALT levels and the presence and time to development of HCC. Among patients that did not have HCC, the AFP level increased with the level of ALT; the AFP values in the presence of ALT (37–56 U/L), ALT (57–92 U/L), or ALT > 92 U/L were 16%, 35%, and 68% higher, respectively, than AFP values at ALT (0–36 U/L). However, patients who developed HCC within 30 days of receiving the AFP test had a lower rate of increase in AFP with each higher category of ALT level, with increases of 31%, 39% and 37% for the same respective ALT categories. Conclusions In patients with chronic HCV infection, AFP and ALT values correlate; however, among patients with HCC, levels of AFP increase disproportionately to, or unaccompanied by, increases in levels of ALT. The prognostic and diagnostic value of AFP levels might be increased by adjusting for ALT values.

Background & Aims Hepatocellular carcinoma (HCC) can result from hepatitis C (HCV)-related liver disease and is the fastest-growing cause of cancer-related death in the United States. Alpha-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV-related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC. Methods In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998 to January 1, 2007 (n=1480 patients). Mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as <10 ng/ml (18%), 10–<100 ng/ml (30%), 100–<1000 ng/ml (22%), or ≥1000 ng/ml (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment. Results The median survival times were significantly lower among patients with higher levels of AFP: 709 d for patients with <10 ng/ml, 422 d for 10–<100 ng/ml, 208 d for 100–<1000 ng/ml, and 68 d for ≥1000 ng/ml. In the multivariate analysis, increased levels of AFP (10–<100, 100–<1000, ≥1000) were significantly associated with increased mortality, compared to a serum level of AFP <10; hazard ratios were 1.50, 2.23, and 4.35, respectively. Conclusions Serum level of AFP at the time of diagnosis with HCV-related HCC is an independent predictor of mortality.