The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease

Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China.


Chronic hepatitis C virus (HCV) infection is a major global health
problem. 1 Worldwide, more than 185 million people have been infected with HCV, of whom 350 000 die each year. 2 The prevalence of chronic HCV infection is estimated to be 1.5% in the United States (US) based on National Health and Nutrition Examination Survey; however, the actual prevalence is likely much higher with at least 3.5 million Americans chronically infected. 2 In China, the prevalence of chronic HCV infection is estimated at 1%-1.9%, affecting roughly 25 million people representing nearly 15% of the total HCVinfected population worldwide. 3,4 Chronic HCV infection is the leading cause of cirrhosis and HCC in the US and many western countries. In the US, HCV is estimated to account for 33.9% of HCC. 5 In China, chronic hepatitis B virus (HBV) infection had been the predominant cause of HCC; however, with the success of hepatitis B vaccination programmes, chronic HCV infection has become an increasingly important cause of HCC with recent estimates showing 5.2% of HCC is due to HCV. 6 Cirrhosis develops in roughly 20% of persons with chronic HCV infection after 20 years of infection. However, progression of HCVrelated liver disease is variable with roughly 22% of liver clinic patients and 24% of patients in post-transfusion studies but only 4%-7% of patients in community-based studies developing cirrhosis after 20 years of infection. 7,8 In a cohort of Chinese paid plasma donors, we followed up for a median of 17 years, the incidence of liver cirrhosis was 10.0%, HCC 2.9%, and overall mortality 8.2%. 9 Host (genetics, obesity, diabetes), virus (duration of HCV infection, HCV genotype, coinfection with HBV or human immunodeficiency virus [HIV]), and environmental (alcohol, smoking, coffee) factors contribute to progression of hepatitis C. 10,11 The contribution of each of these factors to cirrhosis and HCC may be different in different countries. Obesity and diabetes are more common in American patients while coinfection with HBV is more prevalent among Chinese patients. Coffee consumption which has been shown to have a protective effect on liver disease including HCC is more common in American patients. 12,13 These differences and differences in timing of the peak of HCV epidemic in the two countries may contribute to differences in disease progression and burden of HCVrelated liver disease in the US and China.
This study was designed to compare the epidemiologic and clinical characteristics, the stage of liver diseases, and the factors associated with advanced liver disease (cirrhosis or HCC) in two cohorts of adult patients with chronic HCV infection in the US and China. and alcohol, tobacco and coffee consumption were assessed using a standardised questionnaire. Total alcohol consumption over a lifetime was defined as none-minimal (<1 drink/day 9 1 year, ie, <365 total drinks), moderate (365-3650 total drinks, ie, up to 2 drinks/day 9 5 years in women and 365-5475 total drinks, ie, up to 3 drinks/day 9 5 years in men) and heavy (>3650 total drinks for women and >5475 total drinks for men). Tobacco use was defined as never smoked, <10 pack-years, 10-20 pack-years and >20 pack-years. Regular coffee consumption was defined as at least 1 cup/day.

| Assessment of advanced liver disease
Patients were categorised as having chronic hepatitis, cirrhosis or HCC. Patients meeting criteria for diagnosis of cirrhosis or HCC were considered to have advanced liver disease.
Standardised criteria for diagnosis of cirrhosis and HCC were used at both centres. Diagnosis of cirrhosis was based on histology when available. In the absence of biopsy results, diagnosis of cirrhosis was based on evidence of clinical decompensation or 2 of the following 4 criteria: radiological imaging showing features of cirrhosis (nodular liver, intra-abdominal varices or splenomegaly), platelet count <1000/lL in the absence of other explanations, liver stiffness measurement >13 kPa, and gastro-oesophageal varices on endoscopy.
HCC was diagnosed by histology wherever possible and in the absence of histology, by triple phase CT or MRI per the American Association for the Study of Liver Diseases guidelines. 14 Source documents supporting the diagnosis of cirrhosis and HCC were collected and investigators from each country audited the documents from the other country to confirm these diagnoses.

| Definition of diabetes and obesity
Diabetes was defined by medical history or use of medications for treatment of diabetes; and for those with no history of diabetes by fasting blood glucose≥126 mg/dL or random blood glucose ≥200 mg/dL. 15,16 Obesity was defined using race adjusted cutoff for body mass index (BMI) and waist circumference (WC). 17 Figure S1). Baseline characteristics of patients enrolled did not differ from those not enrolled.

| Statistical analysis
US patients were more likely to be men (61.4% vs 48.5%) and to be older, median age 57 vs 53 years ( The three groups of patients enrolled in China differed in many respects (Table 1 and Table S1). Patients in Gu'an were more likely to be obese by BMI and by waist circumference but patients in Beijing were more likely to have diabetes. Patients in Kuancheng were more likely to be current/past drinkers or smokers while patients in Beijing were more likely to regularly consume coffee. Patients in Kuancheng had the highest prevalence of anti-HBc while patients in Beijing were most likely to have received HCV treatment in the past.

| Factors associated with advanced liver disease
In both cohorts, patients with advanced liver disease were significantly older, more likely to have truncal obesity, diabetes and hypertension; and to have received prior HCV treatment, but similar use of alcohol and tobacco, compared to those without advanced liver disease ( Table 2). Patients with advanced liver disease were more likely to be anti-HBc positive (US: 34.0% vs 29.8%, China: 55.3% vs 44.3%) but the difference was significant only in the Chinese cohort.
While there were significant differences in sex, obesity by BMI and         | 735 coffee consumption between US patients with and those without advanced liver disease, these differences were not observed in the Chinese cohort.

| Multivariate analysis of predictors associated with advanced liver disease
Multivariate analyses of predictors associated with advanced liver disease were run after exclusion of patients with ascites. The analysis showed that older age, truncal obesity, diabetes and prior HCV treatment were independently associated with higher likelihood of advanced liver disease in the US cohort while regular coffee consumption was protective (Table 3). Older age, truncal obesity, diabetes and prior HCV treatment were also independently associated with increased risk of advanced liver disease in the Chinese cohort ( 19.4%, respectively (P <.001) for those with estimated duration of infection >30 years (Figure 2).

| Association of obesity and diabetes with advanced liver disease
Truncal obesity and diabetes were independent predictors of advanced liver disease in multivariate analysis of the US and Chinese cohorts in separate as well as in combined analysis. Obesity, truncal obesity and diabetes were significantly more prevalent in US than in Chinese patients. Diabetes remained more prevalent in US patients even after stratification by BMI, waist circumference, and age (except for those <45 years). However, when analysis was stratified by liver disease severity, diabetes was more common only in US patients without cirrhosis (15.7% vs 7.8%, P <.001) and not in those with cirrhosis or HCC. (Table 4 Our finding could potentially be related to under-diagnosis of cirrhosis or HCC in the Chinese cohort; however, both teams followed the same protocol and manual of procedures and underwent training together prior to the start of the study. Furthermore, criteria for diagnosis of cirrhosis and HCC were pre-defined and source documents used to support these diagnoses were audited. Our finding could also be related to differences in clinical setting in which the patients were enrolled. The US cohort was enrolled from a tertiary liver centre, which has a large liver transplant programme and a multi-disciplinary liver tumour clinic but this was also true for the Beijing site, and a statistically significant difference in proportion of patients concomitant fatty liver. Indeed, one study of 96 patients with HBVrelated cirrhosis who had maintained virus suppression after 5 years of tenofovir therapy showed that obesity and diabetes mellitus were significantly more common in patients who failed to have regression of cirrhosis on repeat liver biopsy compared to those who did. 28 Our study is unique in the use of an identical protocol, structured interviews and uniform data collection in two parallel cohorts of patients and the strict adherence to pre-defined criteria for cirrhosis and HCC. There are, however, several limitations. While this study enrolled nearly 2000 patients, the number is too small to represent all patients with chronic HCV infection in the US and in China. Furthermore, patients in the US were enrolled from only one tertiary liver centre and the findings may not be generalised to other US patients.
Indeed, we observed differences in patient characteristics and stage of liver disease in the three Chinese sites. Nonetheless, significant difference in liver disease stage was observed between the US and Beijing sites despite similarities in clinical setting.
In summary, our study found a higher per cent of US patients with chronic HCV infection had cirrhosis or HCC compared to Chinese patients even among patients with similar estimated duration of infection. We believe that a higher prevalence of concomitant fatty liver in the US patients may be a major contributor to this observed difference. Our findings if confirmed highlight that management of glycometabolic abnormalities should go hand in hand with anti-viral treatment for patients with chronic hepatitis C and concomitant obesity or diabetes.