Dietary intake and serum levels of copper and zinc and risk of hepatocellular carcinoma: A matched case-control study.

BACKGROUND: Copper and zinc are involved in the development of multiple malignancies; yet, epidemiological evidence on hepatocellular carcinoma (HCC) is limited. This study aimed to investigate the association between dietary intake and serum levels of copper and zinc with the risk of HCC. METHODS: A total of 434 case-control pairs matched for sex and age (±1 year) were included in this study. Cases with newly diagnosed HCC were from the Guangdong Liver Cancer Cohort (GLCC) study, and healthy controls were from the Guangzhou Nutrition and Health Study (GNHS). A semi-quantitative 79-item food frequency questionnaire (FFQ) was used to assess habitual dietary intakes of copper and zinc. Serum levels of copper and zinc were measured by using inductively coupled plasma mass spectrometry. The copper (Cu)/ zinc (Zn) ratio was computed by dividing copper levels by zinc levels. Conditional logistic regression models were performed to calculate the odds ratio (OR) and 95% confidence intervals (CI) for per 1 standard deviation increase (per-SD increase) in copper and zinc levels. RESULTS: Higher dietary intake (OR per-SD increase = 0.65, 95% CI: 0.44, 0.96, Ptrend = 0.029) and serum levels of zinc (OR per-SD increase = 0.11, 95% CI: 0.04, 0.30, Ptrend <0.001) were both associated with a lower risk of HCC. Subgroup analyses showed that the inverse association was only pronounced in men but not in women ( Pinteraction = 0.041 for dietary zinc intake and 0.010 for serum zinc levels). Serum copper levels (OR per-SD increase = 2.05, 95% CI: 1.39, 3.03, Ptrend = 0.020) and serum Cu/Zn ratio (OR per-SD increase = 6.53, 95% CI: 2.52, 16.92, Ptrend <0.001) were positively associated with HCC risk, while dietary copper intake and dietary Cu/Zn ratio were not associated with HCC risk. CONCLUSION: Zinc may be a protective factor for HCC, especially among men, but the effects of copper on HCC risk are not clear.

Dietary intake of one-carbon metabolism-related nutrients and hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort.

Dietary intake of one-carbon metabolism-related nutrients has been linked to cancer-related outcomes, but their effects on hepatocellular carcinoma (HCC) mortality are still unknown. The objective was to assess whether pre-diagnostic dietary intakes of methionine, folate, Vitamin B6, Vitamin B12, riboflavin and niacin are associated with HCC survival in this prospective cohort study. In total, 905 newly diagnosed HCC patients were recruited in the Guangdong Liver Cancer Cohort study between September 2013 and April 2017. Dietary intake was assessed using a validated 79-item food frequency questionnaire. Cox proportional hazard regression models were utilized to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the overall and HCC-specific mortality. During a median of 791 days of follow-up, we documented 395 deaths, 353 (89%) of which resulted from HCC. The multivariate-adjusted HRs in the highest vs. the lowest quartile of methionine intake were 0.59 (95% CI: 0.42-0.80; P for trend = 0.001) for overall mortality and 0.68 (95% CI: 0.49-0.93; P for trend = 0.027) for HCC-specific mortality. However, no significant association of other micronutrients involved in one-carbon metabolism with HCC survival was observed. Our research suggests that a high level of methionine intake, but no other one-carbon metabolism-related nutrients, may improve survival in patients with newly diagnosed HCC.

High serum fibroblast growth factor 21 is associated with inferior hepatocellular carcinoma survival: A prospective cohort study.

BACKGROUND & AIMS: Epidemiological evidence linking fibroblast growth factor 21 (FGF21) with hepatocellular carcinoma (HCC) prognosis lacked. We aimed to evaluate the associations between serum FGF21 levels and HCC survival in a large prospective cohort. METHODS: 825 newly diagnosed, previously untreated HCC patients from the Guangdong Liver Cancer Cohort were enrolled between September 2013 and April 2017. Serum FGF21 levels were measured by ELISA. Liver cancer-specific survival (LCSS) and overall survival (OS) were calculated. Multivariable Cox proportional hazards models were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Compared with patients in the lowest tertile of serum FGF21 levels, patients in the highest tertile had inferior survival outcomes. HRs in the fully adjusted models were 1.44 (95% CI: 1.07, 1.94; P-trend  = .014) and 1.48 (95% CI: 1.12, 1.97; P-trend  = .002) for LCSS and OS, respectively. The associations were not significantly modified by selected metabolic disorder diseases or state such as arterial hypertension, diabetes, dyslipidemia, fatty liver, cirrhosis, and body mass index ≥25.0 kg/m2 , except for that stronger associations were observed in patients co-occurred more than three metabolic disorder diseases (P-interaction  = .046 for OS and .151 for LCSS), with an HR of 2.01 (95% CI: 1.04, 3.85; P-trend  = .009) for OS and 1.51 (95% CI: 0.73, 3.10; P-trend  = .195) for LCSS. CONCLUSIONS: Higher serum FGF21 levels were associated with worse survival in HCC patients, suggesting that serum FGF21 may be used as a novel metabolism-related prognostic biomarker for HCC.

Dietary protein and prognosis of hepatocellular carcinoma: a prospective cohort study.

Dietary protein has been linked with all-cause and cancer mortality. However, the relationship between dietary protein and the prognosis of hepatocellular carcinoma (HCC) is still unknown. The purpose of this study was to investigate whether dietary protein intake was related to HCC mortality using data from the Guangdong Liver Cancer Cohort (GLCC), a prospective cohort study of HCC survivors established at the Sun Yat-sen University Cancer Center. Dietary information one year before the diagnosis of HCC was obtained through a 79-item semi-quantitative food frequency questionnaire (FFQ). A total of 883 patients with newly diagnosed HCC who were recruited between September 2013 and April 2017 were included in this study. The hazard ratio (HR) and 95% confidence intervals (95% CIs) were estimated by Cox proportional hazard models. The multivariate-adjusted HRs in the highest vs. the lowest tertile of total protein intake were 0.68 (95% CI: 0.52-0.91, P-trend = 0.007) for all-cause mortality and 0.74 (95% CI: 0.55-0.99, P-trend = 0.040) for HCC-specific mortality. However, the associations of animal protein intake, plant protein intake, and animal-to-plant protein ratio with all-cause and HCC-specific mortality were not significant (all P-trend >0.05). Our research suggests that higher prediagnostic dietary intake of total protein was associated with reduced all-cause and HCC-specific mortality.

Betaine Delayed Muscle Loss by Attenuating Samtor Complex Inhibition for mTORC1 Signaling Via Increasing SAM Level.

SCOPE: The muscle loss during aging results from the blunt of protein synthesis and poses threat to the elderly health. This study aims to investigate whether betaine affects muscle loss by improving protein synthesis. METHODS AND RESULTS: Male C57BL/6J mice are raised from age 12 or 15 months. Mice are fed with AIN-93M diet without or with 2% w/v betaine in distilled water as control group or betaine intervention group (Bet), respectively. Betaine supplementation to mice demonstrates better body composition, grip strength, and motor function. Muscle morphology upregulates expression of myogenic regulate factors, and elevates myosin heavy chain and also improves in Bet group. Betaine promotes muscle protein synthesis via tethering mammalian target of rapamycin complex1 protein kinase (mTORC1) on the lysosomal membrane thereby activating mTORC1 signaling. All these effects aforementioned are time-dependent (p < 0.05). Ultrahigh-performance liquid chromatography results show that betaine increases S-adenosyl-l-methionine (SAM) via methionine cycle. SAM sensor-Samtor-overexpression in C2C12 cells could displace mTORC1 from lysosome thereby inhibiting the mTORC1 signaling. Addition of betaine attenuates this inhibition by increasing SAM level and then disrupting interaction of Samtor complex. CONCLUSIONS: These observations indicate that betaine could promisingly promote protein synthesis to delay age-related muscle loss.

Profiling of phospholipid molecular species in human breast milk of Chinese mothers and comprehensive analysis of phospholipidomic characteristics at different lactation stages.

Phospholipids are critical for milk digestion and infant development. But the profile of phospholipid molecular species in human milk and its dynamic changes during the lactation period have never been reported. The present study elucidated precise qualitative and quantitative analysis of 258 phospholipid molecular species in 486 human milk samples. Phosphatidylcholine is the most abundant class, followed by phosphatidylserine, phosphatidylethanolamine and sphingomyelin as the second abundant class in different lactation period. The plasmalogens declined along the lactation period, and the polyunsaturated-phospholipids decreased after 10-15 days. The decrease of phosphatidylcholines and phosphatidylglycerols, and the increase of lysophosphatidylethanolamines and lysophosphatidylcholines are critical changes from 0 to 5 days to 10-15 days; increase of phosphatidylinositols, phosphatidylserines, lysophosphatidylethanolamines and lysophosphatidylcholines is the key changes from 10-15 days to 40-45 days; the decrease of most phospholipid molecular species is the characteristic change from 40-45 days to 200-240 days; and the phospholipid profile achieved stability after 200 days.

Dietary betaine intake is associated with skeletal muscle mass change over 3 years in middle-aged adults: the Guangzhou Nutrition and Health Study.

A higher dietary intake or serum concentration of betaine has been associated with greater lean body mass in middle-aged and older adults. However, it remains unknown whether betaine intake is associated with age-related loss of skeletal muscle mass (SMM). We assessed the association between dietary betaine intake and relative changes in SMM after 3 years in middle-aged adults. A total of 1242 participants aged 41-60 years from the Guangzhou Nutrition and Health Study 2011-2013 and 2014-2017 with body composition measurements by dual-energy X-ray absorptiometry were included. A face-to-face questionnaire was used to collect general baseline information. After adjustment for potential confounders, multiple linear regression found that energy-adjusted dietary betaine intake was significantly and positively associated with relative changes (i.e. percentage loss or increase) in SMM of legs, limbs and appendicular skeletal mass index (ASMI) over 3 years of follow-up (ß 0·322 (se 0·157), 0·309 (se 0·142) and 0·303 (se 0·145), respectively; P < 0·05). The ANCOVA models revealed that participants in the highest betaine tertile had significantly less loss in SMM of limbs and ASMI and more increase in SMM of legs over 3 years of follow-up, compared with those in the bottom betaine tertile (all Ptrend < 0·05). In conclusion, our findings suggest that elevated higher dietary betaine intake may be associated with less loss of SMM of legs, limbs and ASMI in middle-aged adults.

Dietary choline, rather than betaine intake, is associated with hepatocellular carcinoma mortality.

The dietary intakes of choline and betaine have been related to the mortality of some neoplasms, but their effects on hepatocellular carcinoma (HCC) mortality are still unknown. We examined the associations between dietary choline, five choline-containing compounds, different choline forms, betaine intake and HCC mortality. In total, 905 newly diagnosed HCC patients were enrolled in the Guangdong Liver Cancer Cohort study. Dietary intake was assessed by a valid food frequency questionnaire. Liver cancer-specific mortality (LCSM) and all-cause mortality (ACM) were calculated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox proportional hazards models. It was found that a higher total choline intake was associated with lower ACM, Q4 vs. Q1: HR = 0.72, 95% CI: 0.53-0.97, Ptrend = 0.012 in the fully adjusted model. The associations between total choline intake and LCSM were not significant. Similar associations were found between water-soluble choline intake and HCC mortality, where the fully adjusted HR for ACM was 0.72, 95% CI: 0.53-0.98, Ptrend = 0.017. However, null associations were found between neither phosphatidylcholine (the most abundant lipid-soluble choline) nor total lipid-soluble choline intake and HCC mortality. These results implied that the favorable associations between the total choline intake and ACM were more attributed to water-soluble choline. Furthermore, no significant associations were observed between betaine intake and HCC mortality. Future human intervention trials regarding choline supplementation and liver disease recovery should take the forms into consideration rather than just the total amount alone.

Association between dietary patterns and prognosis of hepatocellular carcinoma in the Guangdong liver cancer cohort study.

AIM: Adherence to dietary recommendations has been linked to a reduced risk of developing hepatocellular carcinoma (HCC) and dying of chronic liver disease. However, its role in the prognosis of HCC is still unclear. We prospectively investigated the association of two dietary quality indices, the Chinese Healthy Eating Index (CHEI) and the Healthy Eating Index-2015 (HEI-2015), with all-cause and HCC-specific mortality in a large prospective cohort of HCC survivors. METHODS: We included 887 patients with newly diagnosed, previously untreated HCC enrolled in the Guangdong Liver Cancer Cohort (GLCC) between September 2013 and April 2017 in the analysis. CHEI and HEI-2015 scores were calculated based on the dietary intake in the year before diagnosis of HCC. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for each index. RESULTS: During a median follow-up of 797 days, 389 deaths were identified, including 347 from HCC. Higher CHEI scores, reflecting favorable adherence to the 2016 Dietary Guidelines for Chinese, were associated with a lower risk of all-cause mortality (T3 vs. T1 : HR = 0.75, 95% CI: 0.58-0.98) and HCC-specific mortality (T3 vs. T1 : HR = 0.74, 95% CI: 0.56-0.98). Non-significant, inverse associations of HEI-2015 score with all-cause mortality (T3 vs. T1 : HR = 0.86, 95% CI: 0.67-1.11) and HCC-specific mortality (T3 vs. T1 : HR = 0.93, 95% CI: 0.71-1.21) were suggested. CONCLUSIONS: Our findings suggest that better adherence to the 2016 Dietary Guidelines for Chinese may reduce the risk of all-cause and HCC-specific mortality in patients with HCC.

Serum choline is associated with hepatocellular carcinoma survival: a prospective cohort study.

BACKGROUND: Higher choline and betaine levels have been linked to lower risk of liver cancer, whereas existing data in relation to hepatocellular carcinoma (HCC) prognosis are scarce. Our objective was to examine the associations of the serum choline and betaine with HCC survival. METHODS: 866 newly diagnosed HCC patients were enrolled in the Guangdong Liver Cancer Cohort. Serum choline and betaine were assessed using high-performance liquid chromatography with online electro-spray ionization tandem mass spectrometry. Liver cancer-specific survival (LCSS) and overall survival (OS) were calculated. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Serum choline levels were associated with better LCSS (T3 vs. T1: HR = 0.69, 95% CI: 0.51-0.94; P -trend < 0.05) and OS (T3 vs. T1: HR = 0.73, 95% CI: 0.54-0.99; P -trend < 0.05). The associations were significantly modified by C-reactive protein (CRP) levels but not by other selected prognostic factors including sex, age, etc. The favorable associations between serum choline and LCSS and OS were only existed among patients with CRP ≥3.0 mg/L. No significant associations were found between serum betaine levels and either LCSS or OS. CONCLUSIONS: This study revealed that higher serum choline levels were associated with better HCC survival, especially in HCC patients with systemic inflammation status. No significant associations were found between serum betaine and HCC survival. Our findings suggest the benefits of choline on HCC survival. TRIAL REGISTRATION: The Guangdong Liver Cancer Cohort was registered at clinicaltrials.gov as NCT03297255.

Prediagnostic dietary intakes of vitamin A and ß-carotene are associated with hepatocellular-carcinoma survival.

Vitamin A and its precursor (ß-carotene) have been linked with cancer incidence and mortality. However, the relationship between vitamin A and the prognosis of hepatocellular-carcinoma (HCC) is still unknown. Therefore, we investigated whether dietary intakes of vitamin A, retinol, and ß-carotene were associated with survival in patients with HCC who participated in the Guangdong Liver Cancer Cohort (GLCC) study. Patients aged 18-80 years with a diagnosis of incident Primary Liver Cancer (PLC) were enrolled within one month of diagnosis prior to cancer treatment at the Sun Yat-sen University Cancer Center. Dietary information one year before diagnosis of HCC was obtained using a 79-item, validated semiquantitative food frequency questionnaire (FFQ). We restricted the present analysis to 877 HCC patients enrolled in the GLCC between September, 2013 and April, 2017 who had completed FFQ. Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for overall and HCC-specific survival. After a median follow-up of 797 days, 384 deaths were documented, 343 of which died from HCC. The multivariable-adjusted HRs (95% CI) of overall and HCC-specific survival for the highest versus the lowest quartile were 0.70 (0.53-0.94) and 0.68 (0.50-0.92) for vitamin A, and 0.72 (0.54-0.96) and 0.69 (0.51-0.94) for ß-carotene, respectively. However, no significant association of dietary retinol intakes with survival outcomes was observed. Our observations suggest that higher prediagnostic dietary intakes of vitamin A and ß-carotene were associated with improved overall and HCC-specific survival.

Association between serum choline and betaine concentrations and longitudinal changes of body composition in community-dwelling middle-aged and older Chinese adults.

Previous studies suggest that betaine and choline may be beneficial for body composition. However, no longitudinal study has been conducted to illustrate if choline and betaine have long-term effects on changes in body composition. This study aimed to prospectively investigate the association between serum choline and betaine concentrations and 3-year changes in body composition in community-dwelling Chinese adults. This present analysis used data from 1384 women and 554 men aged 40-75 years. Serum concentrations of betaine and choline at baseline were assessed using high-performance liquid chromatography-tandem mass spectrometry. Body composition parameters, i.e., muscle mass (MM), fat mass (FM), and body fat percentage (FM%) were measured using dual-energy X-ray absorptiometry at the first and the second follow-ups. After adjustment for potential cofounders, higher serum choline concentrations were associated with a lower decrease in MM in men (ß = 0.022, P = 0.025) and a lower increase in FM and FM% in women with baseline choline concentrations below 21.5 µmol/L (all P for nonlinearity = 0.007); higher serum betaine concentrations were associated with a lower decline in MM and a lower increase in FM and FM% among men whose betaine concentrations were lower than 55 µmol/L (all P for nonlinearity < 0.05). These findings suggest that higher concentrations of serum choline and betaine may be associated with favorable changes in body composition profiles among men and women who have relatively low concentrations, especially in men. Novelty Higher concentrations of serum choline and betaine were associated with favorable changes in body composition. Such favorable associations were more pronounced in men.