Nathan Shores

HCV Infection Selectively Impairs Type I but Not Type III IFN Signaling

A stable and persistent Hepatitis C virus (HCV) replication cell culture model was developed to examine clearance of viral replication during long-term treatment using interferon-α (IFN-α), IFN-λ, and ribavirin (RBV). Persistently HCV-infected cell culture exhibited an impaired antiviral response to IFN-α+RBV combination treatment, whereas IFN-λ treatment produced a strong and sustained antiviral response that cleared HCV replication. HCV replication in persistently infected cells induced chronic endoplasmic reticulum (ER) stress and an autophagy response that selectively down-regulated the functional IFN-α receptor-1 chain of type I, but not type II (IFN-γ) or type III (IFN-λ) IFN receptors. Down-regulation of IFN-α receptor-1 resulted in defective JAK-STAT signaling, impaired STAT phosphorylation, and impaired nuclear translocation of STAT. Furthermore, HCV replication impaired RBV uptake, because of reduced expression of the nucleoside transporters ENT1 and CNT1. Silencing ER stress and the autophagy response using chemical inhibitors or siRNA additively inhibited HCV replication and induced viral clearance by the IFN-α+RBV combination treatment. These results indicate that HCV induces ER stress and that the autophagy response selectively impairs type I (but not type III) IFN signaling, which explains why IFN-λ (but not IFN-α) produced a sustained antiviral response against HCV. The results also indicate that inhibition of ER stress and of the autophagy response overcomes IFN-α+RBV resistance mechanisms associated with HCV infection.

Racial disparity and their impact on hepatocellular cancer outcomes in inner-city New Orleans

BACKGROUNDnThe role of socioeconomic factors that affect survival, particularly for hepatocellular cancer (HCC), has yet to be fully analyzed. This study attempts to elucidate those racial and socioeconomic factors that affect differences in survival for patients with HCC.nnnMETHODSnIn a retrospective cohort study of 206 patients with HCC diagnosed in an inner-city urban center from 2003 to 2011, outcomes by race (African Americans versus white) were analyzed. Additional attention was paid to socioeconomic factors. Continuous variables were compared with the Student t-test, and categorical variables were compared with the χ(2) or Fisher exact test. Multivariate analysis was conducted using a logistic regression model. Patient death and survival data were analyzed with Kaplan-Meier and Cox proportional hazards.nnnRESULTSnComparison of 138 white and 68 African-American patients revealed that African-American patients were more likely to present with larger tumor size at the time of diagnosis (4.7 vs 3.7 cm; Pxa0<xa0.05). African-American patients were also more likely to be intravenous drug users (25.4% vs 11.6%; P < .05) and have cirrhosis from hepatitis C (81% vs 60%; P < .01). African-American patients were less likely to have private insurance compared with white patients (68% vs 92%; Pxa0<xa0.01). Despite these findings in our inner-city practice, there was no difference in liver transplantation rates or survival rates between the 2 groups.nnnCONCLUSIONnDespite presentation with less-favorable tumor characteristics, African-American patients are able to achieve survival that is comparable with their white counterparts when treated in a program that is attuned to the challenges faced by their specific population.

Epidemiology of Metastatic Hepatocellular Carcinoma, A Nationwide Perspective

BackgroundHepatocellular carcinoma (HCC) is the most common primary tumor of the liver.AimsThe aim of this study was to describe the prevalence, trends, and predictors of metastatic HCC on a national scale.MethodsWe used two nationwide datasets for our study: the University Health Consortium (UHC) and the Nationwide Inpatient Sample (NIS) databases. We included adults with a primary diagnosis of HCC from 2000 to 2011. We collected information regarding demographics, insurance, HCC risk factors, liver decompensation, and the sites and frequencies of metastases. Multivariable regression analysis was used to examine predictors of metastatic HCC. Trend analysis was performed to examine the change in metastatic HCC prevalence over time.ResultsWe included 25,671 and 26,054 HCC patients from UHC and NIS, respectively. Prevalence of metastatic HCC was 18xa0% with lung being the most frequent site (31xa0%). Compared with Caucasian, African American ethnicity was an independent predictor of metastasis in both the NIS [OR 1.13 (1.02–1.25)] and UHC [OR 1.4 (1.3–1.6)] databases. Lack of long-term insurance was associated with significantly higher prevalence of metastasis in both the NIS [OR 1.6 (1.4–1.9)] and UHC [OR 1.9 (1.6–2.2)] databases. There has been an increased prevalence of metastatic HCC over the last decade with an annual percentage change of +1.25 and +1.60xa0% (pxa0=xa00.03 and pxa0=xa00.08) for the NIS and UHC databases, respectively.ConclusionsMetastasis is not rare among HCC patients and is rising in prevalence over the last decade. Lungs were the most common metastatic site. Ethnicity and insurance status are independent predictors of metastasis.

Donor risk index for African American liver transplant recipients with hepatitis C virus

African American (AA) liver transplant (LT) recipients with hepatitis C virus (HCV) have higher rates of graft loss than other racial/ethnic groups. The Donor Risk Index (DRI) predicts graft loss but is neither race‐ nor disease‐specific and may not be optimal for assessing donor risk for AA HCV‐positive LT recipients. We developed a DRI for AA with HCV with the goal of enhancing graft loss predictions. All U.S. HCV‐positive adult AA first deceased donor LTs surviving ≥30 days from March 2002 to December 2009 were included. A total of 1,766 AA LT recipients were followed for median 2.8 (interquartile range [IQR] 1.3‐4.9) years. Independent predictors of graft loss were donor age (40‐49 years: hazard ratio [HR] 1.54; 50‐59 years: HR 1.80; 60+ years: HR 2.34, Pu2009<u20090.001), non‐AA donor (HR 1.66, Pu2009<u20090.001), and cold ischemia time (CIT) (HR 1.03 per hour >8 hours, Pu2009=u20090.03). Importantly, the negative effect of increasing donor age on graft and patient survival among AAs was attenuated by receipt of an AA donor. A new donor risk model for AA (AADRI‐C) consisting of donor age, race, and CIT yielded 1‐year, 3‐year, and 5‐year predicted graft survival rates of 91%, 77%, and 68% for AADRI <1.60; 86%, 67%, and 55% for AADRI 1.60‐2.44; and 78%, 53%, and 39% for AADRI >2.44. In the validation dataset, AADRI‐C correctly reclassified 27% of patients (net reclassification improvement Pu2009=u20090.04) compared to the original DRI. Conclusion: AADRI‐C identifies grafts at higher risk of failure and this information is useful for risk‐benefit discussions with recipients. Use of AA donors allows consideration of older donors. (Hepatology 2013;58:1263–1269)

United States Women Receive More Curative Treatment for Hepatocellular Carcinoma Than Men

AbstractBackgroundPrevious database studies have found gender disparities favoring men in rates of liver transplantation, which resolve in cohorts examining only patients with hepatocellular carcinoma (HCC).nAimsOur study aims to use two large, multicenter United States (US) databases to assess for gender disparity in HCC treatment regardless of transplant listing status.nMethodsWe performed a retrospective database analysis of inpatient admission data from the University Health Consortium (UHC) and the Nationwide Inpatient Sample (NIS), over a 9- and 10-year period, respectively. Adults with a primary discharge diagnosis of HCC, identified using the International Classification of Diseases 9th Edition (ICD-9) code, were included. Series of univariate and multivariate analyses were performed to examine gender disparities in metastasis, liver decompensation, treatment type, and inpatient mortality after controlling for other possible predictors.ResultsWe included 26,054 discharges from the NIS database and 25,671 patients from the UHC database in the analysis. Women with HCC appear to present less often with decompensated liver disease (ORxa0=xa00.79, pxa0<xa00.001). Furthermore they are more likely to receive invasive HCC treatment, with significantly higher rates of resection across race and diagnoses (ORxa0=xa01.34 and 1.44, pxa0<xa00.001). Univariate analyses show that US women have lower unadjusted rates of transplant; however, the disparity resolves after controlling for other clinical and demographic factors.ConclusionsUS women more often receive invasive treatment for HCC (especially resection) than US men with no observed disparity in transplantation rates when adjusted for pre-treatment variables.

Mixed Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Spindle Cell and Clear Cell Features in the Extrahepatic Bile Duct

Mixed adenoneuroendocrine carcinomas, spindle cell carcinomas, and clear cell carcinomas are all rare tumors in the biliary tract. We present the first case, to our knowledge, of an extrahepatic bile duct carcinoma composed of all three types. A 65-year-old man with prior cholecystectomy presented with painless jaundice, vomiting, and weight loss. CA19-9 and alpha-fetoprotein (AFP) were elevated. Cholangioscopy revealed a friable mass extending from the middle of the common bile duct to the common hepatic duct. A bile duct excision was performed. Gross examination revealed a 3.6u2009cm intraluminal polypoid tumor. Microscopically, the tumor had foci of conventional adenocarcinoma (CK7-positive and CA19-9-postive) surrounded by malignant-appearing spindle cells that were positive for cytokeratins and vimentin. Additionally, there were separate areas of large cell neuroendocrine carcinoma (LCNEC). Foci of clear cell carcinoma merged into both the LCNEC and the adenocarcinoma. Tumor invaded through the bile duct wall with extensive perineural and vascular invasion. Circumferential margins were positive. The patients poor performance status precluded adjuvant therapy and he died with recurrent and metastatic disease 5 months after surgery. This is consistent with the reported poor survival rates of biliary mixed adenoneuroendocrine carcinomas.

Leptospirosis with acute liver injury

A 61-year-old man with no significant medical history presented with fever, muscle pain, and weakness. He was found to be in multiorgan failure due to leptospirosis, a condition known as Weils disease. A timely workup, combined with early initiation of antibiotics, led to effective treatment for this patient.

Cutaneous Metastases from Primary Hepatobiliary Tumors as the First Sign of Tumor Recurrence following Liver Transplantation

Cutaneous metastasis from hepatobiliary tumors is a rare event, especially following liver transplantation. We report our experience with two cases of cutaneous metastases from both hepatocellular carcinoma and mixed hepatocellular/cholangiocarcinoma following liver transplantation, along with a review of the literature.

Mastabol induced acute cholestasis: A case report

A 26-year-old male presented with three weeks of jaundice after the self-initiation of the injectable anabolic steroid, Mastabol [Dromastanolone Di-Propionate (17 beta-Hydroxy-2alpha-methyl-5alpha-androstan-3-one propionate)]. He reported dark urine, light stools, and pruritus. He denied abdominal pain, intravenous drug use, intranasal cocaine, blood transfusions, newly placed tattoos, or sexually transmitted diseases. He used alcohol sparingly. Physical exam revealed jaundice with deep scleral icterus. The liver was palpable 2 cm below the right costal margin with no ascites. The peak bilirubin was 23.6 mg/dL, alkaline phosphatase was 441 units/L, and aspartate aminotransferase/alanine aminotransferase were 70 units/L and 117 units/L respectively. A working diagnosis of acute intrahepatic cholestasis was made. Liver biopsy revealed a centrilobular insult with neutrophilic infiltrates and Ito cell hyperplasia consistent with acute drug induced cholestasis. The patients clinical symptoms resolved and his liver enzymes, bilirubin, and alkaline phosphatase normalized. Anabolic steroids with 17 alpha carbon substitutions have been associated with a bland variety of cholestatic injury with little hepatocellular injury. Cholestasis, under these circumstances, may be secondary to the binding of drugs to canalicular membrane transporters, accumulation of toxic bile acids from canalicular pump failure, or genetic defects in canalicular transport proteins. Mastabol is an injectable, 17 beta hydroxyl compound with no alpha alkyl groups at the 17 carbon position. As such, it has been reported to have little potential toxic effects on the liver. This is the first known reported case of Mastabol-induced cholestatic liver injury. It highlights the need for physicians to consider such widely available substances when faced with hepatic injury of unclear etiology.

Racial disparity in New Orleans: A faith-based approach to an age-old problem

RECENTLY IN THE UNITED STATES, HEALTH CARE REFORM has become a central focus of heated debate and controversy. Sweeping legislation was introduced and passed by the Obama administration in attempt to achieve universal health care with the intent of providing equal access to care through national policy. Although a laudable goal, this policy does not ensure equivalent quality of care delivered to the most vulnerable communities in our nation. Historically, racial disparity in health care delivery results in delay in diagnosis, and often inferior patient outcomes at a substantial increase in cost of care. In the same stride, strong criticism has turned to the mounting and unsustainable costs of health care on the national budget. Despite the best intentions, current proposed changes in policy and infrastructure development, national health care policy may be woefully inadequate. Health care in certain socioeconomic groups, regions, or individual institutions function well and provide excellent care. Other regions or even individual institutions struggle under their community’s payor mix to provide adequate care. Governmental support in the form of disproportionate share has been applied to decrease this financial disparity. Unfortunately, this gap is often wider than perceived and innercity institutions absorb the sickest and most complex patients with the least primary care associated with the lowest payor mix. This self-fulfilling prophecy leads rise to multiple at-risk populations