Hazard Ratios For Hepatocellular Carcinoma Research Articles

Time-varying Comparison of All-cause Mortality After Liver Transplantation Between Recipients With and Without Hepatocellular Carcinoma: A Population-based Cohort Study Using the United Kingdom Liver Transplant Registry.

Background.Accurately identifying time-varying differences in the hazard of all-cause mortality after liver transplantation (LT) between recipients with and without hepatocellular carcinoma (HCC) may inform patient selection and organ allocation policies as well as post-LT surveillance protocols.Methods.A UK population-based study was carried out using 9586 LT recipients. The time-varying association between HCC and post-LT all-cause mortality was estimated using an adjusted flexible parametric model (FPM) and expressed as hazard ratios (HRs). Differences in this association by transplant year were then investigated. Non–cancer-specific mortality was compared between HCC and non-HCC recipients using an adjusted subdistribution hazard model.Results.The HR comparing HCC recipients with non-HCC recipients was below one immediately after LT (1-mo HR = 0.76; 95% confidence interval [CI], 0.59-0.99; P = 0.044). The HR then increased sharply to a maximum at 1.3 y (HR = 2.07; 95% CI, 1.70-2.52; P < 0.001) before decreasing. The hazard of death was significantly higher in HCC recipients than in non-HCC recipients between 4 mo and 7.4 y post-LT. There were no notable differences in the association between HCC and the post-LT hazard of death by transplant year. The estimated non–cancer-specific subdistribution HR for HCC was 0.93 (95% CI, 0.80-1.09; P = 0.390) and not found to vary over time.Conclusions.FPMs can provide a more precise comparison of post-LT hazards of mortality between HCC and non-HCC patients. The results provide further evidence that some HCC patients have extra-hepatic spread at the time of LT, which has implications for optimal post-LT surveillance protocols.

The Importance of Metabolic Syndrome Status for the Risk of Non-Viral Hepatocellular Carcinoma: A Nationwide Population-Based Study.

The positive association between metabolic syndrome (MetS) and hepatocellular carcinoma (HCC) has been suggested. However, no studies have yet looked at how the risk of developing HCC varies with changes in MetS status. Therefore, we aimed to investigate the association between changes in MetS and subsequent HCC development. Data were obtained from the Korean National Health Insurance Service. In this study, 5,975,308 individuals who participated in health screenings both in 2009–2010 and 2011–2012 were included. Individuals with preexisting viral hepatitis, liver cirrhosis, or cancer diagnoses were excluded. Subjects were divided into four groups according to change in MetS status during the 2-year interval screening (from 2009 to 2011): sustained non-MetS, transition to MetS, transition to non-MetS, and sustained MetS. Cox regression analysis was used to examine the hazard ratios of HCC. The subjects were followed through December 31, 2018. During a median of 7.3 years of follow-up, 25,880 incident HCCs were identified. Compared to the sustained non-MetS group, age, sex, smoking, alcohol, regular exercise, and body mass index-adjusted hazard ratios (95% confidence interval) for HCC development were 1.01 (0.97–1.05) for the transition to MetS group, 1.05 (1.003–1.09) for the transition to non-MetS group, and 1.07 (1.03–1.10) for the sustained MetS group. Stratified analyses according to age, sex, smoking, alcohol intake, exercise, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease showed similar results. A significantly increased HCC risk was observed in the sustained MetS and transition to non-MetS groups. The baseline status of MetS was associated with the risk of HCC development. Strategies to improve MetS, especially targeting insulin resistance, might prevent HCC development.

Chronic hepatitis B virus infection and the risk of hepatocellular carcinoma by age and country of origin in people living in Sweden: A national register study.

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), and surveillance is recommended for patients without cirrhosis when risk exceeds an incidence rate (IR) of 0.2%. Populations in Asia and sub‐Saharan Africa have been associated with HCC at younger ages, but the risk after immigration to Western countries should be investigated. The aim of this study was to study HCC by age and country of origin in people with chronic HBV infection in Sweden. Through national registers, residents with chronic HBV diagnosis (1990–2015) were identified with information on country of origin, immigration/emigration, death, coinfections, antiviral therapy, and HCC. Observation time started at HBV diagnosis, and IR and hazard ratios for HCC were calculated by sex, age, and region of origin. Among 16,410 individuals (47% women), the origin and observation time (person years) were as follows: Western Europe, 2316 (25,415); Eastern Europe, 2349 (26,237); Middle East/North Africa, 4402 (47,320); sub‐Saharan Africa, 3677 (30,565); Asia, 3537 (35,358); and other, 129 (1277). There were 232 individuals with HCC (82% in men). The IR increased with age and exceeded 0.2% for Asian men from age group 40–49 years (IR, 0.63; 95% confidence interval, 0.39–1.00), for men of other origins from age group 50–59 years, and for women aged ≥60 years originating from Eastern Europe, Asia, and Middle East/North Africa. After exclusion of patients with cirrhosis or HBV treatment, the IR still exceeded 0.2% in Asian men aged 40–49 years. This study demonstrates that HBV‐infected men of Asian origin should be recommended HCC surveillance at younger ages, but there is a need for further studies of HCC incidence in African‐born men without cirrhosis living in the Western world.

Impact of overweight and obesity on the risk of hepatocellular carcinoma: a prospective cohort study in 14.3 million Koreans.

Whether obesity and being overweight, defined by body mass index (BMI), increase hepatocellular carcinoma (HCC) has been less apparent in Asian populations. Overall, 14,265,822 Korean adults who underwent routine health examinations during 2003-2006 were followed up for HCC. Multivariable-adjusted hazard ratios (HRs) associated with BMI were calculated. During 13.7 years (mean) of follow-up, 47,308 individuals developed HCC. HRs of HCC associated with BMIs of 25.0-26.4, 26.5-27.9, 28.0-29.4, 29.5-30.9 and ≥31 kg/m² compared to those for 23.5-24.9 kg/m² were 1.05, 1.20, 1.39, 1.59 and 2.13, respectively. For BMI < 25 kg/m², linear associations were not apparent. For BMI ≥ 25 kg/m2, the HR per 5 kg/m2 increase in BMI was 1.60 (total), 1.60 (men), and 1.59 (women). The corresponding HRs were 1.56, 1.61 and 1.60 for individuals aged <45, 45-64 and ≥65 years, respectively. Further adjustment for alanine transaminase (ALT) levels substantially reduced the HRs for high BMI, especially in men and younger adults. Overweight and obesity clearly increase HCC risk in Koreans. ALT levels are a mediator of the impact of obesity, but it may not accurately predict high BMI-induced liver damage that can potentially progress to HCC, especially in women and older adults.

Abstract 754: Serum iron markers in relation to hepatocellular carcinoma risk among patients with non-alcoholic fatty liver disease

Abstract Background: Hepatocellular carcinoma (HCC) is the 6th most commonly diagnosed cancer and the 3rd leading cause of cancer death in the US. Around 85-90% of primary liver cancer is HCC. Besides identified risk factors for HCC including chronic infection with hepatitis B and C virus (HBV and HCV), alcohol abuse, dietary aflatoxin exposure and hereditary hemochromatosis, nonalcoholic fatty liver disease (NAFLD) is as another important risk factor for HCC. NAFLD is a spectrum of liver disease that ranges from hepatic steatosis through non-alcoholic steatohepatitis (NASH) with or without fibrosis and may progress to cirrhosis or HCC. Iron is an essential metal and hepatocytes are its main storage site. Increased body iron from the intestine due to high dietary iron or hereditary or acquired hemochromatosis may result in hepatic iron overload. NAFLD is frequently associated with elevated serum iron indices when hepatic iron in the absence of hemochromatosis. Epidemiologic data on the association between serum iron markers and risk of HCC are sparse. The aim of the study was to examine the association of iron related serum markers with risk of HCC in NAFLD patients. We hypothesized that elevated serum iron levels, which reflects hepatic iron, are associated with increased risk of HCC among NAFLD patients. Methods: 48,328 patients with NAFLD were identified in the electronic health records (EHR) of the University of Pittsburgh Medical Center (UPMC) between 1/1/2004 to 12/31/2018. Among them, 19,908 had at least one measurement of serum iron, transferrin saturation, total iron binding capacity (TIBC) and serum ferritin. After an average 4.47 years of follow-up, 363 patients with NAFLD were diagnosed with HCC at least 30 days after measurement of iron markers. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and the 95% confidence intervals (CIs) for HCC incidence associated with elevated levels of the four iron markers adjusted for age, sex, race, body mass index, history of diabetes and tobacco smoking. Results: Serum iron and transferrin saturation were significantly elevated in NAFLD patients who developed HCC compared to others who remained free of HCC during the study. The HR of HCC for elevated serum iron &amp;gt;175 mcg/dl was 3.41 (95% CI 1.48 - 7.85) compared to its normal range at 75-175 mcg/dl. Similarly, the HR for HCC associated with elevated transferrin saturation &amp;gt;35% was 2.56 (95% CI 1.49-4.39) relative to the normal range at 25-35%. The associations were not statistically significant for TIBC and serum ferritin with HCC risk. Conclusions: Elevated serum iron and transferrin saturation levels, but not TIBC or serum ferritin, were significantly associated with increased risk of developing HCC in NAFLD patients. These findings support future studies evaluating serum iron level in risk stratification of NAFLD patients at risk of HCC and potential links to pathogenesis of HCC. Citation Format: Yi-Chuan Yu, Renwei Wang, Jaideep Behari, Ada Youk, Nancy W. Glynn, Jian-Min Yuan. Serum iron markers in relation to hepatocellular carcinoma risk among patients with non-alcoholic fatty liver disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 754.

FIB-4 Is a Potential Tool for Hepatocellular Carcinoma Risk Stratification in Ethnically Diverse Chronic Hepatitis B Patients When Using Specific Cutoff Values

Background: In a previous publication, a FIB-4 cutoff value of ≥ 1.25, which had been determined in an Asian population, did not allow reliable prediction of the development of hepatocellular carcinoma (HCC) in a patient collective with chronic hepatitis B (CHB) of predominantly non-Asian descent. Objectives: Here, we aimed to validate the modified FIB-4 cutoff values as a means of stratifying the HCC risk in a non-Asian cohort seen at an outpatient university hospital liver unit in Germany. Methods: We retrospectively analyzed 350 adult patients with CHB infection. We recorded demographics, laboratory parameters, results from liver imaging, serological hepatitis B markers, antiviral treatment, and histology. We separated patients into two groups based on individual FIB-4 levels. We, then, analyzed the patients’ hazard ratios for HCC and adjusted it for sex, age, antiviral medication, duration of CHB infection, body mass index, alcohol consumption, and type 2 diabetes. An additional sub-analysis was performed by including only non-cirrhotic patients to determine the validity of the proposed cutoffs in that cohort. Results: The median duration of follow-up was 8.9 years with a range of 1 - 21.3 years. Our patients were 65% males. In comparison with patients that had a low FIB-4 (< 0.3635), those with elevated FIB-4 (≥ 0.3635) had an HCC incidence hazard ratio of 11.67 (95% confidence interval (CI): 2.73 - 49.96; P = 0.001) and an adjusted hazard ratio of 7.90 (95% CI: 1.58 - 39.39; P = 0.012). Elevated FIB-4 non-cirrhotic patients had a hazard ratio (HR) of 15.88 (95% CI: 2.04 - 123.20) for HCC incidence (P < 0.0001) and an adjusted HR of 11.99 (95% CI: 1.36 - 105.72) (P = 0.001). Conclusions: A FIB-4 value of < 0.3635 appears to be a clinical indicator for a low likelihood of HCC incidence in non-Asian patients with CHB with or without cirrhosis. Further studies in patients of diverse descent are necessary to prove its utility as a clinical tool in this setting.

Meat intake and risk of hepatocellular carcinoma in two large US prospective cohorts of women and men.

Epidemiological evidence on the associations between meat intake and risk of hepatocellular carcinoma (HCC) was limited and inconsistent. We prospectively examined the association between consumption of meats and meat mutagens with HCC risk using data from the Nurses' Health Study and the Health Professionals Follow-up Study. Cox proportional-hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for known liver-cancer risk factors. During up to 32 years of follow-up, we documented 163 incident HCC cases. The HRs of HCC for the highest vs the lowest tertile intake levels were 1.84 (95% CI: 1.16-2.92, Ptrend = 0.04) for processed red meats and 0.61 (95% CI: 0.40-0.91, Ptrend = 0.02) for total white meats. There was a null association between unprocessed red meats and HCC risk (HR = 1.06, 95% CI: 0.68-1.63, Ptrend = 0.85). We found both poultry (HR = 0.60, 95% CI: 0.40-0.90, Ptrend = 0.01) and fish (HR = 0.70, 95% CI: 0.47-1.05, Ptrend = 0.10) were inversely associated with HCC risk. The HR for HCC risk was 0.79 (95% CI: 0.61-1.02) when 1standard deviation of processed red meats was substituted with an equivalent amount of poultry or fish intake. We also found a suggestive positive association of intake of meat-derived mutagenicity or heterocyclic amines with risk of HCC. Processed red meat intake might be associated with higher, whereas poultry or possibly fish intake might be associated with lower, risk of HCC. Replacing processed red meat with poultry or fish might be associated with reduced HCC risk.

Association between physical activity and risk of hepatobiliary cancers: A multinational cohort study

To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. We examined this association in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC). We identified 275 hepatocellular carcinoma (HCC) cases, 93 intrahepatic bile duct cancers (IHBCs), and 164 non-gallbladder extrahepatic bile duct cancers (NGBCs) among 467,336 EPIC participants (median follow-up 14.9 years). We estimated cause-specific hazard ratios (HRs) for total physical activity and vigorous physical activity and performed mediation analysis and secondary analyses to assess robustness to confounding (e.g. due to hepatitis virus infection). In the EPIC cohort, the multivariable-adjusted HR of HCC was 0.55 (95% CI 0.38-0.80) comparing active and inactive individuals. Regarding vigorous physical activity, for those reporting >2 hours/week compared to those with no vigorous activity, the HR for HCC was 0.50 (95% CI 0.33-0.76). Estimates were similar in sensitivity analyses for confounding. Total and vigorous physical activity were unrelated to IHBC and NGBC. In mediation analysis, waist circumference explained about 40% and body mass index 30% of the overall association of total physical activity and HCC. These findings suggest an inverse association between physical activity and risk of HCC, which is potentially mediated by obesity. In a pan-European study of 467,336 men and women, we found that physical activity is associated with a reduced risk of developing liver cancers over the next decade. This risk was independent of other liver cancer risk factors, and did not vary by age, gender, smoking status, body weight, and alcohol consumption.

Association Between Aspirin Use and Risk of Hepatocellular Carcinoma

Prospective data on the risk of hepatocellular carcinoma (HCC) according to dose and duration of aspirin therapy are limited. To examine the potential benefits of aspirin use for primary HCC prevention at a range of doses and durations of use within 2 prospective, nationwide populations. Pooled analysis of 2 prospective US cohort studies: the Nurses' Health Study and the Health Professionals Follow-up Study. Data were accessed from November 1, 2017, through March 7, 2018. A total of 133 371 health care professionals who reported data on aspirin use, frequency, dosage, and duration of use biennially since 1980 in women and 1986 in men were included. Individuals with a cancer diagnosis at baseline (except nonmelanoma skin cancer) were excluded. Cox proportional hazards regression models were used to calculate multivariable adjusted hazard ratios (HRs) and 95% CIs for HCC. Of the 133 371 participants, 87 507 were women and 45 864 were men; in 1996, the median time of follow-up, the mean (SD) age was 62 (8) years for women and 64 (8) years for men. Over more than 26 years of follow-up encompassing 4 232 188 person-years, 108 incident HCC cases (65 women, 43 men) were documented. Compared with nonregular use, regular aspirin use (≥2 standard-dose [325-mg] tablets per week) was associated with reduced HCC risk (adjusted HR, 0.51; 95% CI, 0.34-0.77). This benefit appeared to be dose related: compared with nonuse, the multivariable-adjusted HR for HCC was 0.87 (95% CI, 0.51-1.48) for up to 1.5 standard-dose tablets per week, 0.51 (95% CI, 0.30-0.86) for more than 1.5 to 5 tablets per week, and 0.49 (95% CI, 0.28-0.96) for more than 5 tablets per week (P for trend = .006). Significantly lower HCC risk was observed with increasing duration (P for trend = .03); this decrease was apparent with use of 1.5 or more standard-dose aspirin tablets per week for 5 or more years (adjusted HR, 0.41; 95% CI, 0.21-0.77). In contrast, use of nonaspirin nonsteroidal anti-inflammatory drugs was not significantly associated with HCC risk (adjusted HR, 1.09; 95% CI, 0.78-1.51). This study suggests that regular, long-term aspirin use is associated with a dose-dependent reduction in HCC risk, which is apparent after 5 or more years of use. Similar associations were not found with nonaspirin NSAIDs. Further research appears to be needed to clarify whether aspirin use represents a feasible strategy for primary prevention against HCC.

Incidence and Survival Trends of Hepatocellular Carcinoma in Non-Cirrhotics With Ishak Fibrosis Score of 0-4 Between 2005-2014: A SEER Analysis

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the leading causes of cancer related deaths. Although HCC occurs most commonly in cirrhotic livers, there is growing concern about HCC in non-cirrhotics, especially those with metabolic syndrome and NAFLD. However, there are limited data regarding HCC incidence and survival among non-cirrhotic patients in the United States. Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was utilized to obtain data for HCC in non-cirrhotic patients with Ishak fibrosis scores of 0-4 from 2005-2014. Results: Overall incidence from 2005-2014 was 0.30 cases per 100,000 persons per year, with higher incidence in males (0.49, 95% CI: 0.47-0.51) compared to females (0.13, 95% CI: 0.12-0.14). For race, incidence was greatest among Asian or Pacific Islanders (APIs) (0.83, 95% CI: 0.77-0.90), but annual percent change (APC) was highest among whites (APC 3.29) and blacks (APC 6.53) (figure 1). APC in APIs has been stable (0.56)(table 1). Incidence analysis by HCC stage (localized, regional, and distant) shows that localized disease has the greatest incidence (0.18, 95% CI: 0.17-0.18) and localized and regional disease have the highest APC (3.24 and 6.51, respectively). Survival analysis showed that females had a higher five-year survival (42.8%, 95% CI: 37.2%-48.2%) than males (36.6%, 95%CI: 33.6%-39.5%). For race, APIs had the highest five-year survival (46.5%, 95% CI: 41.5%-51.2%) and blacks had the lowest (25.3%, 95% CI: 17.9%-33.3%) (figure 2). For stage and AFP levels, survival was highest for localized disease (51.7%, 95%CI: 48.2%- 55.1%) and negative/normal AFP levels (54.06%, 95%CI: 48.44%-59.34%), respectively. Conclusion: The incidence of HCC in non-cirrhotic patients in the US with Ishak fibrosis scores of 0-4 is increasing. Moreover, our findings correlate well with obesity trends in the US, where lower rates of obesity are observed among non-Hispanic Asians (11.7%) than among non-Hispanic white (34.5%), Hispanic (42.5%), and non-Hispanic black (48.1%)[1]. Survival is influenced by gender, race, AFP level, and stage of disease. These findings may help to identify at-risk populations as well as risk factors for improving surveillance for HCC in non-cirrhotics.832_A Figure 1. Incidence Rate, Race 2005-2014; decimal place indicates number of months in year832_B Figure 2. Count, Annual Percent Change and Hazard Ratios for HCC In Non-Cirrhotics with Ishak Fibrosis 0-4832_C Figure 3. Survival Based on Race

Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: Results from two prospective cohort studies.

T2D is independently associated with increased risk for HCC in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC. (Hepatology 2018;67:1797-1806).

Predictability of Liver-Related Seromarkers for the Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Patients

BackgroundHepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is a major global health problem. A few risk calculators have been developed using mainly HBV seromarkers as predictors. However, serum HBV DNA level, HBV genotype, and mutants are not routinely checked in regular health examinations. This study aimed to assess the predictability of HCC risk in chronic hepatitis B patients, using a combination of liver-related seromarkers combined with or without HBV seromarkers.MethodsA prospective cohort of 1,822 anti-HCV-seronegative chronic HBV carriers was included in this study. Liver-related seromarkers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alpha-fetoprotein (AFP), gamma-glutamyltransferase (GGT), total bilirubin, total protein, albumin, serum globulins, apolipoprotein A1, and apolipoprotein B were examined. Hazard ratios of HCC with 95% confidence intervals were estimated using Cox proportional hazards regression models. Regression coefficients of seromarkers significantly associated with HCC risk in multivariate analyses were used to create integer risk scores. The predictability of various risk models were assessed by area under receiver operating characteristic curves (AUROCs).ResultsDuring a median follow-up of 5.9 years, 48 newly-developed HCC cases were ascertained. Elevated serum levels of ALT (≥28 U/L), AFP (≥5 ng/mL), and GGT (≥41 U/L), an increased AST/ALT ratio (AAR, ≥1), and lowered serum levels of albumin (≤4.1 g/dL) and alpha-1 globulin (≤0.2 g/dL) were significantly associated with an increased HCC risk (P<0.05) in multivariate analysis. The risk model incorporating age, gender, AAR, and serum levels of ALT, AFP, GGT, albumin, and alpha-1 globulin had an AUROC of 0.89 for predicting 6-year HCC incidence. The AUROC was 0.91 after the addition of HBV seromarkers into the model, and 0.83 for the model without liver-related seromarkers, with the exception of ALT.ConclusionLiver-related seromarkers may be combined into useful risk models for predicting HBV-related HCC risk.

111 THE COMBINATION OF GENETIC VARIANTS IN PRO-INFLAMMATORY CYTOKINES PREDICTS THE RISKS OF DEATH AND HEPATOCELLULAR CARCINOMA OCCURRENCE IN PATIENTS WITH HCV-RELATED CIRRHOSIS

Background and Aim: The prevalence of childhood overweight has reached epidemic proportions around the globe. In parallel with the obesity epidemic, non-alcoholic fatty liver disease has increased, and has now become the most common cause of liver disease in children. The epidemic of childhood overweight is of great concern because, in addition to these adverse effects on the liver in childhood, overweight in childhood may also affect the risk of liver disease in adulthood. Therefore we investigated if childhood body size from the ages of 7 to 13 years was associated with the risk of hepatocellular carcinoma (HCC) in adulthood. Methods: Individuals were 165,540 men and 160,883 women born between 1930 and 1989 from the Copenhagen School Health Records Register. Information on HCC was obtained by linkage to the Danish Cancer Registry. Anthropometry was measured by school doctors or nurses, and body mass index (BMI) z-scores were calculated from internal ageand sex-specific references. Hazard ratios (HR) (95% confidence intervals) of HCC were calculated from Cox proportional hazard models. Results: During follow-up, there were 252 cases of HCC. At 7 years of age, the HR of HCC in adulthood was 1.12 (0.97, 1.29) per 1-unit increase in BMI z-score. By age 13 years, the HR of HCC was 1.25 (1.09, 1.44) per 1-unit increase in BMI z-score. Associations were similar in boys and girls, consistent across year of birth and essentially unchanged by exclusion of individuals with hepatitis B and C, alcoholic conditions and biliary diseases. Conclusion: Childhood BMI is positively associated with the risk of HCC in adulthood. The risk is present in both boys and girls, and increase slightly with increasing age of the children. The epidemic of childhood overweight is alarming because, in addition to the many adverse metabolic effects in childhood, the epidemic may also translate into a large number of adverse health effects in adulthood, such as cardiovascular disease and liver cancer. Acknowledgement: This work is funded by and carried out as a part of FLIP (fatty liver inhibition of progression) under the Seventh Framework Programme (FP7/2007–2013, grant agreement no. Health-F2–2009–241762.

Clinical Scoring System to Predict Hepatocellular Carcinoma in Chronic Hepatitis B Carriers

Hepatitis B virus (HBV) infection is an important etiology for hepatocellular carcinoma (HCC). We aim to develop a simple clinical score in predicting the risk of HCC among HBV carriers. We first evaluated 1,005 patients and found that the following five factors independently predicted HCC development: age, albumin, bilirubin, HBV DNA, and cirrhosis. These variables were used to construct a prediction score ranging from 0 to 44.5. The score was validated in another prospective cohort of 424 patients. During a median follow-up of 10 years, 105 patients (10.%) in the training cohort and 45 patients (10.6%) in the validation cohort developed HCC. Cutoff values of 5 and 20 best discriminated HCC risk. By applying the cutoff value of 5, the score excluded future HCC development with high accuracy (negative predictive value = 97.8% and 97.3% in the training and validation cohorts, respectively). In the validation cohort, the 5-year HCC-free survival rates were 98.3%, 90.5%, and 78.9% in the low-, medium-, and high-risk groups, respectively. The hazard ratios for HCC in the medium- and high-risk groups were 12.8 and 14.6, respectively. A simple prediction score constructed from routine clinical and laboratory parameters is accurate in predicting HCC development in HBV carriers. Future prospective validation is warranted.

Cirrhosis and Hepatocellular Carcinoma in HIV-Infected Veterans With and Without the Hepatitis C Virus

Because they develop slowly and infrequently, the incidence and relative risk of cirrhosis and hepatocellular carcinoma (HCC) in patients with the human immunodeficiency virus (HIV) only and in patients coinfected with the hepatitis C virus (HCV) are not known. By using national Veterans Health Administration administrative databases, we conducted a retrospective cohort study. Excluding patients with preexisting liver disease, 11,678 HIV-only and 4761 coinfected patients hospitalized between October 1, 1991, and September 30, 2000, were included. Incidence rates and adjusted hazard ratios (HRs) for nonalcoholic cirrhosis and HCC after discharge were calculated through September 30, 2001. The incidence rates of cirrhosis in the HIV-only and coinfected groups were 1.47 and 15.88 per 1000 person-years, respectively. In a Cox multivariate proportional hazards regression model, coinfected patients had an adjusted HR for cirrhosis of 9.24 compared with HIV-only patients (95% confidence interval, 6.92-12.33; P<.001). The incidence rates of HCC in the HIV-only and coinfected groups were 0.20 and 1.32 per 1000 person-years, respectively. In a Cox multivariate proportional hazards regression model, coinfected patients had an adjusted HR for HCC of 5.35 compared with HIV-only patients (95% confidence interval, 2.34-12.20; P<.001). Among patients identified during the highly active antiretroviral therapy era, the HR for cirrhosis was 19.06 (95% confidence interval, 10.14-35.85; P<.001), while the HR for HCC was 5.07 (95% confidence interval, 1.72-14.99; P = .003). To our knowledge, this study is the largest longitudinal study to examine the incidence of nonalcoholic cirrhosis and HCC in HIV-only and HCV-coinfected patients. Hepatitis C virus coinfection dramatically promotes the development of HCC (5-fold) and of cirrhosis (10- to 20-fold), and is especially associated with cirrhosis in the highly active antiretroviral therapy era. Treatment of HCV in HIV-infected patients, while often unsuccessful, should be considered.

Risk of death due to hepatocellular carcinoma among drinkers and ex-drinkers. Univariate analysis of JACC study data.

Hazard ratios (HR) of death due to hepatocellular carcinoma (HCC) were analyzed by gender and age strata (40-59 and 60-79) among drinkers and ex-drinkers in 66,974 eligible subjects from a a large cohort of male and female subjects aged 40-79 years, based on information about several drinking related characteristics. The HR of dying from HCC for ex-drinkers was 4 to 8 times higher than for those who had never consumed alcohol at the baseline survey. When the subjects were restricted to those without history of liver disease (LD), the HR was still high for ex-drinkers among younger males, though the difference was not statistically significant. It appeared that the earlier drinking habits were established, the higher the HR, especially for younger males without LD. Among total current drinkers, the amount ingested per occasion and the cumulative amount ingested at the baseline did not show significantly increased HRs. Among subjects without LD, larger amounts ingested per occasion and larger cumulative amount seemed to have higher HRs in older male current drinkers. Frequent drinking and later age (50 to 79) at cessation of drinking were associated with higher HRs among both genders and both age strata. After restricting the analysis to subjects without LD, many of these increased HRs remained among males. The results suggested that the association between alcohol drinking history and HR of HCC differs depending on the presence of LD. Major confounders other than age and gender associated with both drinking and HCC, e.g. smoking, hepatitis virus infection, or history of diabetes, were not considered in this analysis, and the observed associations might be confounded by any of these factors. To clarify the net association between alcohol drinking and HCC, further analysis is needed to control potential confounders, including past history of liver disease, and to consider probable effect modifiers.