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1.  The changing pattern of epidemiology in hepatocellular carcinoma 
Digestive and Liver Disease  2010;42(Suppl 3):S206-S214.
Primary liver cancer (PLC) represents approximately 4% of all new cancer cases diagnosed worldwide. The purpose of this review is to describe some of the latest international patterns in PLC incidence and mortality, as well as to give an overview of the main etiological factors. We used two databases, GLOBOCAN 2002 and the World Health Organization (WHO) mortality database to analyze the incidence and mortality rates for PLC in several regions around the world. The highest age adjusted incidence rates (>20 per 100,000) were reported from countries in Southeast Asia and sub-Saharan Africa that are endemic for HBV infection. Countries in Southern Europe have medium-high incidence rates, while low-incidence areas (<5 per 100,000) include South and Central America, and the rest of Europe.
Cirrhosis is present in about 80–90% of HCC patients and is thereby the largest single risk factor. Main risk factors include HBV, HCV, aflatoxin and possibly obesity and diabetes. Together HBV and HCV account for 80–90% of all HCC worldwide. HBV continues to be the major HCC risk factor worldwide, although its importance will most likely decrease during the coming decades due to the widespread use of the HBV vaccine in the newborns. HCV has been the dominant viral cause in HCC in North America, some Western countries and Japan. Obesity and diabetes are increasing at a fast pace throughout the world, and if they are proven to be HCC risk factors, they would account for more HCC cases in the future.
PMCID: PMC3392755  PMID: 20547305
Cirrhosis; Epidemiology; GLOBOCAN; Hepatitis; Liver cancer
2.  Determinants of Serum Alpha-Fetoprotein Levels in Hepatitis C Infected Patients 
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.
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.
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.
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.
PMCID: PMC3311729  PMID: 22155556
biomarker; risk; liver cancer; disease progression
3.  Risk Factors of Cholangiocarcinoma 
Hepatology (Baltimore, Md.)  2011;54(1):173-184.
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.
PMCID: PMC3125451  PMID: 21488076
4.  Risk of Colorectal Cancer Among Caucasian and African American Veterans with Ulcerative Colitis 
Inflammatory bowel diseases  2011;18(6):1011-1017.
African Americans are at an increased risk of developing sporadic colorectal cancer (CRC) compared to Caucasians. Ulcerative colitis (UC) is a risk factor for developing CRC; however, risk differences for CRC between African Americans and Caucasians with UC are unknown.
We performed a cohort study of patients with a diagnosis of UC during fiscal years 1998 to 2009 using the national Veterans Affairs administrative datasets. Cumulative CRC incidence rates and incidence rate ratios were calculated and Cox proportional hazards models were used to examine the association between race and the CRC risk.
The cohort comprised of 20,949 patients with UC. A total of 168 incident cases of CRC were identified during 112,243 patient-years (PY) of follow-up; overall CRC incidence rate was 163/100,000 PY (95% confidence interval [CI] 139–187/100,000 PY). The CRC incidence rates were 158/100,000 PY (95% CI 134–181/100,000 PY) and 180/100,000 PY (95% CI 155–205/100,000 PY) in Caucasians and African Americans, respectively, with an incidence rate ratio of 1.17 (95% CI 0.69–1.97). The 3, 5, and 10-year cumulative incidence rates for CRC were 0.36%, 0.76%, 1.79% for African Americans and 0.41%, 0.76%, 1.43% for Caucasians. African Americans were not at an increased risk for CRC (adjusted hazard ratio: 1.10, 95% CI 0.65–1.87) compared to Caucasians.
In a national cohort of UC patients the risk of developing CRC in African Americans was no higher than in Caucasians. The reasons for lack of racial differences compared to sporadic CRC are not clear; access to care, genetic factors, and molecular pathways require further study.
PMCID: PMC3976425  PMID: 22334479
inflammatory bowel disease; race; disparity; colorectal cancer
5.  Prevalence of oesophageal eosinophilia and eosinophilic oesophagitis: a prospective study in unselected patients presenting to endoscopy 
Oesophageal eosinophilia (EE) is encountered in clinical practice as oesophageal biopsies are being obtained in patients with GI symptoms other than classical symptoms of eosinophilic oesophagitis (EoE). The prevalence, determinants and clinical relevance of EE identified irrespective of symptoms are unclear.
To determine the prevalence and risk factors of EE with or without EoE in a non-selected group of patients undergoing endoscopy and in primary care patients.
A cross-sectional study in a single VA center in which we obtained at least one oesophageal biopsy from patients presenting to elective endoscopy, as well as a sample of patients eligible for screening colonoscopy recruited from primary care clinics. EE was defined by > 15 eosinophils in a single HPF; and EoE was defined as definite, probable or none depending on the presence of EE, acid-suppressive therapy and oesophageal symptoms.
EE was identified in 33 of 1357 patients (2.4%, 95% CI: 1.7–3.4); of whom 9 had definite EoE (0.66%, 95% CI: 0.23–1.10), 17 had probable EoE (1.25%), and the only 7 patients had EE without EoE. The prevalence of EE was 2.3% among patients undergoing elective endoscopy and 0.1% among patients eligible for screening colonoscopy. Seasonal allergies (adjusted OR: 2.78; 95%CI 1.26 – 6.11) and oesophageal strictures (4.50; 0.90 – 22.40) were associated with EE.
The prevalence of EE was 2.3% among unselected patients presenting to endoscopy most of whom have EoE. EE was present in 0.1% in primary care patients none of whom had EoE.
PMCID: PMC3602156  PMID: 23441936
Epidemiology; H. pylori; Dysphagia; Eosinophilia; Risk Factors
6.  The Incidence and Prevalence of Inflammatory Bowel Disease Among U.S. Veterans: A National Cohort Study 
Inflammatory bowel diseases  2013;19(5):1059-1064.
Temporal trends in incidence and prevalence of Crohn’s disease (CD) and ulcerative colitis (UC) in the United States have been reported only in regional populations. The Veterans Affairs (VA) health care system encompasses a national network of clinical care facilities. The aim of this study was to identify temporal trends in the incidence and prevalence of CD and UC among VA users using national VA data sets.
Veterans with CD and UC were identified during fiscal years 1998 to 2009 in the national VA outpatient and inpatient files. Incident and prevalent cases were identified by diagnosis code, and age-standardized and gender-standardized annual prevalence and incidence rates were estimated using the VA 1998 population as the standard population.
The total of unique incident cases were 16,842 and 26,272 for CD and UC, respectively; 94% were men. The average annual age-standardized and gender-standardized incidence rate of CD was 33 per 100,000 VA users (range, 27–40), whereas the average for UC was 50 per 100,000 VA users (range, 36–65). In 2009, the age-standardized and gender-standardized point prevalence rate of CD was 287 per 100,000 VA users, whereas the point prevalence of UC was 413 per 100,000 VA users.
Prevalence of CD and UC increased 2-fold to 3-fold among VA users between 1998 and 2009. The incidence of UC decreased among VA users from 1998 to 2004 but has remained stable from 2005 to 2009. The incidence of CD has remained stable during the observed time period.
PMCID: PMC3972034  PMID: 23448789
Crohn’s disease; ulcerative colitis; epidemiology
7.  Natural History of Pediatric-onset Inflammatory Bowel Disease 
There has been no systematic review of natural history studies of pediatric-onset inflammatory bowel disease (IBD). We conducted a systematic review focused on understanding the long-term risks of growth failure, disease reclassification and extension, hospitalizations, cancer and death among patients with childhood IBD.
PubMed searches and subsequent data abstraction were performed by 2 independent investigators. Studies published full in english with a 5-year minimum average follow-up in at least 30 patients with IBD onset before age 18 years.
We evaluated 41 total studies (only 2 population-based studies) with 3505 Crohn’s disease (CD) patients, 2071 ulcerative colitis (UC) patients, and 461 indeterminate colitis (IC). Growth failure was reported in CD (10% and 56%) more often than UC 0% to 10%) or non-IBD controls. Improvements in growth occurred after surgical resection in patients with CD. There was an increase in disease reclassification over time from UC and indeterminate colitis diagnosis to CD diagnosis. Patients with CD had higher number of hospitalizations and hospital days per year in comparison with UC patients in most studies. The reported surgery rates in CD ranged between 10% and 72%; the colectomy rates in UC ranged between 0% and 50%. Cancers were reported in 6 CD patients during a total 18,270 patient-years (PY) follow-up, and 8 UC patients in 18,115 PY. Deaths directly related to IBD were 63 during 39,719 PY.
Childhood-onset IBD patients had growth failure reported in patients with CD more often than those with UC, had a reclassification of disease type to CD over time. Higher rates of surgery and hospitalizations were found with CD than with UC. The risk of cancer and death is low in this population.
PMCID: PMC3972042  PMID: 22772738
natural history; pediatric IBD; long-term risk; growth failure; disease reclassification; disease extension; hospitalization; cancer; death
8.  Medications (NSAID, Statins, PPI) and the Risk of Esophageal Adenocarcinoma in Patients with Barrett’s Esophagus 
Gastroenterology  2010;138(7):2260-2266.
Background & Aims
Limited evidence suggests that proton pump inhibitors (PPI), non-steroidal anti inflammatory drugs (NSAID)/aspirin and statins may be associated with low risk of esophageal neoplasia. However, the possible effect these medications may have on the risk of esophageal adenocarcinoma (EAC) in patients with existing Barrett’s esophagus (BE) is unclear.
We conducted a nested case-control study in a cohort of patients with BE identified in the national Department of Veterans Affairs (VA) computerized databases. Cases with incident EAC were matched by incidence density sampling to controls with BE who remained without EAC at the date of the EAC diagnosis for the corresponding case. We identified prescriptions for PPI, NSAID/aspirin, and statins that were filled between BE diagnosis and EAC diagnosis. Incidence density ratios were calculated using conditional logistic regression models that adjusted for race, outpatient encounters, a disease comorbidity index, and socio-economic status.
In a cohort of 11,823 patients with first time BE diagnosis, we examined 116 EAC cases and 696 matched controls. Most cases and controls had at least one filled PPI prescription (95% vs. 94%, p=0.5). In this setting of almost universal PPI use, filled NSAID/aspirin prescriptions were associated with a reduced risk of EAC (adjusted incidence density ratio: 0.64; 95% CI, 0.42–0.97). Filled statin prescriptions were also associated with a reduction in EAC risk (0.55; 95% CI, 0.36–0.86), with a significant trend toward greater risk reduction with longer duration of statin use. However, the strong inverse associations with even short periods of use raise concerns of uncontrolled confounding.
This observational study indicates that in patients with Barrett’s esophagus using PPI, NSAID/aspirin or statin therapy might reduce the risk of developing esophageal adenocarcinoma.
PMCID: PMC2883678  PMID: 20188100
epidemiology; chemoprevention; GERD; VA; Medicare
9.  The Epidemiology of Obesity 
PMCID: PMC2833287  PMID: 20202574
obesity; epidemiology of obesity; complications of obesity
10.  Obesity increases oesophageal acid exposure 
Gut  2006;56(6):749-755.
Obesity has been associated with gastro‐oesophageal reflux disease (GERD); however, the mechanism by which obesity may cause GERD is unclear.
To examine the association between oesophageal acid exposure and total body or abdominal anthropometric measures.
A cross‐sectional study of consecutive patients undergoing 24 h pH‐metry was conducted. Standardised measurements of body weight and height as well as waist and hip circumference were obtained. The association between several parameters of oesophageal acid exposures and anthropometric measures were examined in univariate and multivariate analyses.
206 patients (63% women) with a mean age of 51.4 years who were not on acid‐suppressing drugs were enrolled. A body mass index (BMI) of >30 kg/m2 (compared with BMI<25 kg/m2) was associated with a significant increase in acid reflux episodes, long reflux episodes (>5 min), time with pH<4, and a calculated summary score. These significant associations have affected total, postprandial, upright and supine pH measurements. Waist circumference was also associated with oesophageal acid exposure, but was not as significant or consistent as BMI. When adjusted for waist circumference by including it in the same model, the association between BMI>30 kg/m2 and measures of oesophageal acid exposure became attenuated for all, and not significant for some, thus indicating that waist circumference may mediate a large part of the effect of obesity on oesophageal acid exposure.
Obesity increases the risk of GERD, at least partly, by increasing oesophageal acid exposure. Waist circumference partly explains the association between obesity and oesophageal acid exposure.
PMCID: PMC1954847  PMID: 17127706
11.  Statins Are Associated with a Reduced Risk of Hepatocellular Carcinoma in a Large Cohort of Patients with Diabetes 
Gastroenterology  2009;136(5):1601-1608.
Experimental studies indicate a potential cancer prevention effect for statins. Given the increasing prevalence of statin use, and the rising incidence of hepatocellular carcinoma (HCC), the potential association between statins and HCC is an important issue to examine.
We conducted a matched case-control study nested within a cohort of patients with diabetes. Cases comprised incident HCC as defined by those occurring at least 6 months following entry in the cohort. Controls were identified by incidence density sampling from patients who remained at risk at the date of the HCC diagnosis matched on age and gender. We identified filled statin prescriptions as well as several potential confounding conditions, medications as well as propensity score to use statins. Odds ratios (OR) as estimates of the relative risk for HCC associated with statin use and 95% CIs were obtained using conditional logistic regression.
We examined 1303 cases and 5212 controls. The mean age was 72 years and 99% were men. A significantly smaller proportion of cases (34.3%) had at least one filled prescriptions for statins than controls (53.1%). There were no significant associations between HCC and non statin cholesterol or triglyceride lowering medications. The unadjusted OR for any statin prescription was 0.46 (95% CI: 0.40–0.517) and the adjusted OR was 0.74 (0.64, 0.87). To reduce the potential confounding effect of existing liver disease, we ran the analyses in a subgroup of patients without recorded liver disease; the ORs were slightly attenuated but remained highly significant both for any statin prescription (0.63 (0.50–0.78).
Statin use is associated with a significant reduction in the risk of hepatocellular carcinoma among patients with diabetes.
PMCID: PMC2677134  PMID: 19208359
12.  Prevalence of colorectal polyps in pediatric colonoscopy 
Digestive diseases and sciences  2011;57(4):10.1007/s10620-011-1972-8.
The available data regarding the prevalence, types, and clinical determinants of colonic polyps in children is limited.
We aimed to estimate the prevalence of colorectal polyps in a large cohort of children.
We conducted a cross-sectional study to determine the presence, number, and location of colorectal polyps reported in all children (0–20 years) who underwent colonoscopy at 14 pediatric facilities between January 2000 and December 2007 recorded in Pediatric Endoscopy Database System Clinical Outcomes Research Initiative (PEDS-CORI). We compared procedures with and without polyps with respect to procedure indication, age, sex, and race. We also reviewed a sample of histopathologic reports from one participating center.
We analyzed 13,115 colonoscopy procedures performed in 11,637 patients. Colorectal polyps were reported in 810 procedures (6.1%; 95% CI: 5.7% to 6.5%) performed in 705 patients, and in 12% of patients with lower GI bleeding. Children with colorectal polyps were significantly younger (8.9y vs. 11.9y; p<0.0001), male (58.3% vs. 49.0%; p<0.001), non-white race (27.5% vs. 21.9%; p<0.001), and had lower GI bleeding (54.4% vs. 26.6%; p<0.001) as compared to children without polyps. In a sample of 122 patients with polyps from a single center, the histological types were solitary juvenile in 91 (70.5%), multiple juvenile in 20 (15.5%), adenoma in 14 (10.9%) and hyperplastic polyps in 4 patients (3.1%).
Colorectal polyps are detected in 6.1% overall and in 12.0% among those with lower gastrointestinal bleeding during pediatric colonoscopy. Approximately 26% are multiple juvenile or adenoma.
PMCID: PMC3878076  PMID: 22147243
colonic polyps; hematochezia; colonoscopy
13.  WNT Signaling Pathway Gene Polymorphisms and Risk of Hepatic Fibrosis and Inflammation in HCV-Infected Patients 
PLoS ONE  2013;8(12):e84407.
Chronic hepatitis C infection is the leading cause of hepatocellular carcinoma (HCC), a highly lethal malignancy with rapidly increasing prevalence in the United States. Little is known about genetic variations and HCC risk. This study aimed to determine if genetic variation in Wnt signaling pathway genes are associated with advanced hepatic fibrosis and inflammation risk in a hepatitis C virus (HCV) infected population.
We performed a genetic association cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 58 candidate genes and risk of FibroSURE-Acti Test determined advanced fibrosis (F3/F4-F4 advanced cases vs. F0-F3 mild controls) and inflammation (A2/A3-A3 advanced cases vs. A0-A2 mild controls). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) employing multivariate logistic regression. Haplotypes were inferred by the HAPLO.STAT program, interactions were evaluated using multifactor dimensionality reduction (MDR) analysis.
Among 425 chronically HCV-infected male veterans, 155 (37%) had advanced fibrosis and 180 (42%) had advanced inflammation. Of 3016 SNPs evaluated, eight were significantly associated with fibrosis risk (e.g., SFRP2 rs11937424: OR = 2.19, 95% CI 1.48-3.23, P = 0.00004), and seven were significantly associated with inflammation risk (e.g., SFRP1 rs16890282: OR = 2.15, 95% CI 1.39-3.16, P = 0.0004). MDR analysis identified overweight/obese, SOST rs1405952, SFRP2 rs11937424, and FZD4 rs11234870 as the best interaction model for predicting risk of fibrosis; whereas race/ethnicity, FZD1 rs1346665, and TBX3 rs1520177 as the best interaction model for predicting risk of inflammation.
Polymorphisms in several genes involved in the Wnt signaling pathway were associated with hepatic fibrosis or inflammation risk in HCV-infected males. Additional studies in other multi-ethnic HCV cohorts are needed to validate our findings in males and to assess if similar associations exist in chronically HCV-infected females.
PMCID: PMC3875538  PMID: 24386373
14.  Non-Alcoholic Fatty Liver Disease and Hepatocellular Cancer: A Systematic Review 
Non-alcoholic fatty liver disease (NAFLD) has been implicated as a possible cause of hepatocellular carcinoma (HCC) in several general review articles. We performed the first systematic review of the epidemiologic literature.
We searched PubMed for original reports published between 1/1992–12/2011 evaluating the association between NAFLD, non-alcoholic steatohepatitis (NASH) and cryptogenic cirrhosis (CC) presumptively NASH-related and the risk of HCC. Studies were categorized as offering potential direct evidence (e.g., cohort studies) or indirect evidence (e.g., case-control or cross-sectional studies or case-series) of an association.
A total of 17 cohort studies [3 population-based, 9 clinic-based (6 limited to cirrhotics), and 5 natural history], 18 case-control and cross-sectional studies, and 26 case-series were study-eligible. NAFLD or NASH cohorts with few or no cirrhosis cases demonstrated a minimal HCC risk (cumulative HCC mortality between 0%–3% for study periods up to two decades). Consistently increased risk was observed in NASH-cirrhosis cohorts (cumulative incidence between 2.4% over 7-years to 12.8% over 3-years). However, HCC risk was substantially lower in NASH-cirrhosis (NASH-C) cohorts than in HCV-related cirrhosis cohorts. The determinants of elevated risk among NASH-C cohorts were unclear as most studies were underpowered to perform multivariate analysis.
This systematic review shows that despite several limitations, the epidemiologic evidence supports an association between NAFLD or NASH and an increased HCC risk that seems to be predominantly limited to individuals with cirrhosis.
PMCID: PMC3501546  PMID: 23041539
epidemiology; hepatology; gastroenterology; endocrinology; obesity; metabolic syndrome
15.  Utilization of Surveillance for Hepatocellular Carcinoma among Patients with Cirrhosis in the United States 
Hepatology (Baltimore, Md.)  2010;52(1):10.1002/hep.23615.
Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended but may not be performed. The extent and determinants of HCC surveillance are unknown.
We conducted a population-based US cohort study of those over 65 years of age to examine utilization and determinants of pre-diagnosis surveillance in patients with HCC who were previously diagnosed with cirrhosis. Patients diagnosed with HCC during 1994-2002 were identified from the linked Surveillance, Epidemiology, and End-Results registry-Medicare databases. We identified alpha-fetoprotein and ultrasound tests performed for HCC surveillance, and examined factors associated with surveillance.
We identified 1,873 HCC patients with a prior diagnosis of cirrhosis. In the 3 years before HCC, 17% received regular surveillance and 38% received inconsistent surveillance. In a subset of 541 patients in whom cirrhosis was recorded for 3 or more years prior to HCC, only 29% received routine surveillance and 33% inconsistent surveillance. Among all patients who received regular surveillance, approximately 52% received both alpha-fetoprotein and ultrasound, 46% received alpha-fetoprotein only, and 2% received ultrasound only. Patients receiving regular surveillance were more likely to have lived in urban areas and had higher incomes than those who did not receive surveillance. Before diagnosis, approximately 48% of patients were seen by a gastroenterologist/hepatologist or by a physician with an academic affiliation; they were approximately 4.5-fold and 2.8-fold, respectively, more likely to receive regular surveillance than those seen by a primary care physician only. Geographic variation in surveillance was observed and explained by patient and physician factors.
Less than 20% of patients with cirrhosis who developed HCC received regular surveillance. Gastroenterologists/hepatologists or physicians with an academic affiliation are more likely to perform surveillance.
PMCID: PMC3835698  PMID: 20578139
Hepatocellular carcinoma; cirrhosis; AFP; ultrasound; surveillance
16.  Utilization and outcomes of palliative therapy for hepatocellular carcinoma: A population-based study in the United States 
Journal of clinical gastroenterology  2012;46(1):10.1097/MCG.0b013e318224d669.
To evaluate the utilization and determinants of receiving palliative treatment for HCC, and its effect on survival.
Palliative treatment for hepatocellular carcinoma (HCC), including transarterial chemoembolization (TACE) and systemic chemotherapy, is available for patients who do not receive potentially curative therapy. The utilization and outcomes of these therapies in clinical practice are unknown.
We conducted a population-based cohort study using Surveillance, Epidemiology, and End-Results registry data linked to Medicare claims of HCC patients >65 years diagnosed during 2000–2005 who did not receive liver transplant, resection, or ablation. The proportions of patients who received TACE or systemic chemotherapy were calculated by tumor stage, liver disease status, and non-HCC co-morbidity. Determinants of receiving palliative therapy were examined in logistic regression models and propensity scores were calculated. Cox proportional hazards models were used to evaluate mortality risk.
We identified 3,163 HCC patients (median age: 75 yrs, 67% men) who did not receive potentially curative treatment. Approximately 12.5% received TACE and 11.0% chemotherapy. In patients with early or intermediate stage HCC, no liver decompensation, and little or no co-morbidity, only 22.8% received TACE and 13.8% chemotherapy. Median survival was significantly higher among patients who received TACE (14.0 months) compared to chemotherapy (5.0 months) or no therapy (2.0 months). A significant reduction in overall mortality was observed for TACE (54%) and chemotherapy (33%).
Utilization of palliative treatment for HCC is low, which could not be explained by clinical features. However, misclassification could have occurred due to the data source. Receipt of TACE or systemic chemotherapy was associated with a reduction in mortality.
PMCID: PMC3832893  PMID: 22157221
Hepatocellular carcinoma; palliative treatment; chemotherapy
17.  Racial Differences in the Association between Adiposity Measures and the Risk of Hepatitis C-related Liver Disease 
African-Americans have lower reported likelihood of HCV-related cirrhosis than Whites. It is unknown if relative differences in the distribution of adipose tissue, lean mass, and other anthropometric measurements may explain these observed interethnic differences in disease risk.
To evaluate the association between anthropometric measurements and advanced liver disease in a cross-sectional study of African-American and White male veterans.
We used the validated FibroSURE-ActiTest to assess hepatic pathology, and direct segmental multichannel bioelectric impedance analysis for anthropometric measurements. Race-stratified logistic regression was employed to evaluate risk of high fibrosis progression rate (FPR) and advanced inflammation (A2-A3).
Among 330 eligible males (59% African-American), there were 43 White and 57 African American males with high FPR, and 70 African American and 59 White with advanced inflammation. % body fat (%BF) was a stronger predictor of high FPR risk than was a high BMI in African-Americans (ORadj=2.08, 95% CI= 0.83–5.23 for highest %BF vs. lowest tertile and. ORadj=1.50, 95% CI=0.60–3.75 for obese vs. normal BMI, respectively), but not in Whites. Highest lean leg mass was associated with a non-significant increased risk of both high FPR and advanced inflammation in African-Americans (ORhighFPRadj=1.73, 95% CI 0.73–4.10; ORAdvancednflammationAdj=1.65, 95% CI 0.76–3.56) vs. a decreased risk of both in Whites (ORhighFPRadj=0.62, 95% CI 0.21–1.79; ORAdvancednflammationAdj=0.58, 95% CI 0.22–1.48).
Interethnic differences in non-traditional anthropometric measurements like %BF suggests their potential role in understanding interethnic differences in HCV-related liver disease risk in males.
PMCID: PMC3437036  PMID: 22955261
epidemiology; veterans; infectious diseases; anthropometry; insulin resistance; cirrhosis; obesity; hepatology
18.  Statin Therapy and Serum Transaminases Among a Cohort of HCV-Infected Veterans 
Digestive diseases and sciences  2010;55(1):190-195.
We sought to determine the effect of statin therapy on serum AST and ALT levels in a cohort of HCV-infected veterans with well-characterized liver disease.
We examined liver biopsy records of consecutive HCV-infected patients and identified 20 patients who were prescribed statins. We matched them on age, stage of fibrosis, and time between HCV diagnosis and statin start dates with up to four HCV-infected patients who did not use statins. ALT and AST values from up to four time points within 1 year of follow-up were abstracted from the medical record. We compared median ALT and AST levels using Wilcoxon–Mann–Whitney tests and assessed changes in ALT and AST over time between the statin and non-statin groups using a non-parametric repeated measures ANOVA model, adjusting for the matching factors, receipt of HCV treatment, BMI, and diabetes.
Patients prescribed statins had higher median BMIs, were more likely to have diabetes, and had higher total cholesterol levels. Median baseline ALT levels were higher among those prescribed statins (P = 0.04) while median baseline AST levels were lower among statin users (P = 0.03). From baseline to follow-up, the median decreases in both ALT (−13.5 vs. −4.0) and AST (−4.5 vs. −0.5) were significantly larger among statin users compared to non-statin users (P = 0.03 and P = 0.0007, respectively) even after adjustment.
Among HCV-infected patients AST and ALT levels for those prescribed statins decreased over a 6 to 12-month follow-up period compared to patients not taking statins.
PMCID: PMC3698853  PMID: 19731022
Hepatitis C virus; Statins; Transaminases; Veterans
19.  The Association between Barrett’s Esophagus and Helicobacter pylori Infection: A Meta-Analysis 
Helicobacter  2012;17(3):163-175.
The effect of Helicobacter pylori on Barrett’s esophagus is poorly understood. We conducted a meta-analysis to summarize the existing literature examining the effect that H pylori has on Barrett’s esophagus.
We performed a comprehensive search to identify studies pertaining to the association between H pylori and Barrett’s esophagus. We conducted meta-regression analyses to identify sources of variation in the effect of H pylori on Barrett’s esophagus.
Our analysis included a total of 49 studies that examined the effect of H pylori on Barrett’s esophagus and 7 studies that examined the effect of cag A positivity on Barrett’s esophagus. Overall, H pylori, and even more so cag A, tended to be protective for Barrett’s esophagus in most studies; however there was obvious heterogeneity across studies. The effect of H pylori on Barrett’s esophagus varied by geographic location and in the presence of selection and information biases. Only 4 studies were found without obvious selection and information bias, and these showed a protective effect of H pylori on Barrett’s esophagus (Relative Risk = 0.46 [95% CI: 0.35, 0.60]).
Estimates for the effect of H pylori on Barrett’s esophagus were heterogeneous across studies. We identified selection and information bias as potential sources of this heterogeneity. Few studies without obvious selection and information bias have been conducted to examine the effect of H pylori on Barrett’s esophagus, but in these, H pylori infection is associated with a reduced risk of Barrett’s esophagus.
PMCID: PMC3335759  PMID: 22515353
20.  Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma 
Gastroenterology  2012;142(6):1264-1273.e1.
Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiological studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the US.
PMCID: PMC3338949  PMID: 22537432
Liver cancer; association; virology; genetics
21.  Higher Serum Testosterone is associated with Increased Risk of Advanced Hepatitis C-related Liver Disease in Males 
Hepatology (Baltimore, Md.)  2011;55(3):759-768.
Males have strikingly increased risk of advanced liver disease. However, the association between testosterone and risk of hepatitis C virus (HCV)-related advanced liver disease is unknown.
We performed a cross-sectional study in male veterans with chronic HCV. Blood samples were obtained to measure total serum testosterone and perform the FibroSURE-ActiTest. Other risk factor data were obtained through systematic questionnaires (e.g., alcohol), physical measurements (e.g., BMI) and serological tests (e.g., viral load). The association between total testosterone and risk of advanced hepatic fibrosis (F3 and F3/F4) and inflammatory activity (A3 and A2/3) measured by FibroSURE-ActiTest was evaluated with logistic regression.
A total of 308 eligible study participants were prospectively recruited (mean age 57, 52% African-American). There were 105 cases with advanced fibrosis and 203 mild fibrosis controls; and 88 cases with advanced inflammatory activity and 220 mild activity controls. Mean total serum testosterone was significantly higher in advanced fibrosis cases as well as advanced inflammatory activity cases compared to mild disease controls (6.0 ng/ml vs. 5.3 ng/ml and 5.9 ng/ml vs. 5.4 ng/ml, respectively). We observed a significant 27% increase in advanced fibrosis risk and 16% increase in advanced inflammatory activity risk for each 1 ng/ml increase in total serum testosterone. Total testosterone in the upper tertile was associated with an even greater excess risk of advanced fibrosis than advanced inflammatory activity (ORadjusted advanced fibrosis=3.78, 95% CI 1.88–7.61 vs. ORadjusted advanced inflammatory activity=2.64, 95% CI 1.29–5.45, respectively).
Total serum testosterone is associated with an increased risk of both advanced hepatic fibrosis and advanced hepatic inflammatory activity in HCV-infected men. Testosterone may be important in the pathogenesis of HCV-related advanced liver disease in males.
PMCID: PMC3399504  PMID: 21858849
epidemiology; digestive system; hormones; steroids; reproductive and urinary physiological phenomena; diagnosis
22.  Plasma soluble receptor for advanced glycation end-products and risk of colorectal adenoma 
Receptor for advanced glycation end products (RAGE) plays an important role in promoting chronic inflammation with activation of NF-κB. Soluble form of RAGE (sRAGE) represents a naturally occurring competitive inhibitor of RAGE-mediated events. In a colonoscopy-based case-control study, we examined the associations of plasma levels of sRAGE, sTNF-αRI, sTNF-αRII, sIL-6R, EGF, IFNα2, G-CSF, MCP1, TNFβ, and VEGF with risk of colorectal adenoma. We prospectively identified 158 cases with colorectal adenoma and 203 polyp-free controls who were frequency-matched according to age, sex, race, and time of blood draw. Exposure information was collected using a questionnaire and fasting plasma samples were obtained before the colonoscopy. We used Luminex bead-based multiplex assays to determine level of biomarkers. Multivariate logistic regression model was used to estimate odds ratio (OR) and its 95% confidence interval (CI). Cases had insignificant lower levels of sRAGE, and higher levels of EGF and VEGF than controls. When the highest compared with the lowest category, the OR (95% CI) of colorectal adenoma was 0.55 (0.31-0.96) (P trend = 0.03) for sRAGE and 1.75 (1.05-2.93) (P trend =0.04) for VEGF, adjusting for age, smoking status, hypertension and type 2 diabetes. The inverse association between sRAGE and colorectal adenoma was seen only among those without hypertension (P interaction = 0.02). An inverse association between sRAGE and colorectal adenoma was in line with an inverse association between sRAGE and colorectal cancer previously reported. This study supported the involvement of RAGE-NF-kB related inflammatory mechanism in the formation of colorectal adenoma.
PMCID: PMC3508542  PMID: 23205181
Case-control; colorectal adenoma; risk; inflammation; sRAGE; VEGF; NF-kB
23.  Level of Alpha-Fetoprotein Predicts Mortality among Patients with Hepatitis C-Related Hepatocellular Carcinoma 
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.
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.
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.
Serum level of AFP at the time of diagnosis with HCV-related HCC is an independent predictor of mortality.
PMCID: PMC3200479  PMID: 21820396
liver disease; risk; prognosis; epidemiology; blood test
24.  Dietary history and physical activity and risk of advanced liver disease in veterans with chronic hepatitis C infection 
Digestive Diseases and Sciences  2010;56(6):1835-1847.
The role of customary diet and physical activity in development of advanced HCV-related liver disease is not well-established.
We conducted a retrospective association study in 91 male veterans with PCR-confirmed chronic HCV and biopsy-determined hepatic pathology. Respondents completed the Block Food Frequency and the International Physical Activity questionnaires. We conducted three independent assessments based on hepatic pathology: fibrosis (advanced=F3-F4 vs. mild=F1-F2), inflammation (advanced=A2-A3 vs. mild=A1) and steatosis (advanced=S2-S3 vs. mild=S1). Each assessment compared estimated dietary intake and physical activity in veterans with advanced disease to that in analogous veterans with mild disease. Multivariate models adjusted for total calories, age, race/ethnicity, biopsy-to-survey lag-time, BMI, pack-years smoking, and current alcohol use.
Average veteran age was 52, with 48% African-American. Advanced fibrosis was more prevalent than advanced inflammation or steatosis (52.7% vs. 29.7% vs. 26.4% respectively). The strongest multivariate association was the suggestive 14-fold significantly decreased advanced fibrosis risk with lowest dietary copper intake (OR=0.07, 95% CI 0.01–0.60). Other suggestive associations included the 6.5-fold significantly increased advanced inflammation risk with lower vitamin E intake and 6.2-fold significantly increased advanced steatosis risk with lower riboflavin intake. The only physical activity associated with degree of hepatic pathology was a 2-fold greater weekly MET-minutes walking in veterans with mild compared to advanced steatosis (p=0.02).
Several dietary factors and walking may be associated with risk of advanced HCV-related liver disease in male veterans. However, given our modest sample size, our findings must be considered as provisional pending verification in larger prospective studies.
PMCID: PMC3383839  PMID: 21188525
Nutrition Assessment; Exercise; Infectious Diseases; Military Personnel; Epidemiology; Gastroenterology
25.  Barrett’s esophagus in children and adolescents without neurodevelopmental or tracheoesophageal abnormalities: a prospective study 
Gastrointestinal endoscopy  2011;73(5):875-880.
There have been no prospective large-scale studies to evaluate the prevalence and determinants of Barrett’s esophagus (BE) in children who are free from neurodevelopmental disorders and tracheoesophageal abnormalities.
A prospective cross-sectional study
Three pediatric GI Centers in Houston, TX, Phoenix AZ, and Portland ME between February, 2006 and December, 2007.
Children and adolescents consecutively presenting for elective upper endoscopy. Patients with neurodevelopmental and tracheoesophageal disorders were excluded.
Endoscopic pictures of all cases with suspected BE were independently reviewed and verified by 2 experienced investigators. Esophageal biopsies were obtained in all patients, and targeted biopsies were also obtained from suspected BE.
Main Outcome Measurements
Endoscopically suspected BE and histologically confirmed BE.
A total of 840 patients (mean age, 9.5 years) were enrolled and had complete questionnaire and endoscopic data. Twelve patients were suspected of having BE (prevalence of 1.43% (95% CI: 0.73–2.45)) and only 1 patient has intestinal metaplasia for a prevalence of 0.12% (95% CI 0–0.65), while the rest had gastric (n=6) or squamous (n=5). Patients with suspected BE had higher mean BMI (23.0 vs. 19.1, p=0.05) and more chest pain (50% vs. 13%, p<0.01) than patients without BE or reflux esophagitis. There was a trend of higher frequency of dysphagia, heartburn and regurgitation in patients with suspected BE.
The accuracy of BE prevalence estimates is limited by the small number of cases.
BE is rare in children without neurodevelopmental delay or tracheoesophageal anomalies presenting for elective upper endoscopy.
PMCID: PMC3083476  PMID: 21354565

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