Vitamin C and Liver Health
Association of Serum Vitamin C with NAFLD and MAFLD Among Adults in the United States
Non-alcoholic fatty liver disease (NAFLD) is a public health problem affecting approximately a quarter of the global population and has been the fastest-growing cause of liver cancer in the United States. Despite remarkable progress, this condition remains poorly improved, and effective therapeutic strategies remain elusive. According to the recent consensus, international experts redefined NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) to establish more clear diagnostic criteria. Compared with NAFLD, MAFLD is a broader disease entity that requires the presence of metabolic abnormalities, including obesity and diabetes. The proposed new term from NAFLD to MAFLD is not simply a change to a more appropriate name but also a shift in the populations who meet the criteria for one but not the other. This change highlights the unmet clinical need to investigate the association between promising treatments with those only meeting criteria for MAFLD but not the traditional NAFLD. Accordingly, determining the association of potential treatment strategies with both NAFLD and MAFLD may help to deepen our understanding and application of this new concept.
Non-alcoholic fatty liver disease encompasses a continuum of liver disorders, ranging from hepatic steatosis to steatohepatitis (NASH), liver fibrosis (LF), and liver cirrhosis (LC).
It is estimated that ~37% of NASH will develop fibrosis, and subsequently, 10–20% of them will develop cirrhosis. Within 5–7 years, 40–60% of cirrhosis can develop into liver failure, and 2.4–12% of cirrhosis eventually progresses into hepatocellular carcinoma (HCC) within 3–7 years. Although the prognosis is poor, recent studies have shown that mild to moderate LF is reversible, developing after years of NASH with hepatic inflammation. Furthermore, it is generally assumed that the transition from steatosis to NASH is crucial for disease progression, leading to cirrhosis and HCC. For this reason, researchers have focused on steatohepatitis to develop new preventing and reversing strategies. Mechanically, progression from steatosis to NASH and hepatic fibrosis is driven by a series of liver damage resulting from lipid deposition, reactive oxidative species (ROS), nitrogen oxides overload, endoplasmic reticulum stress, and inflammation, which ultimately lead to the activation of hepatic stellate cells, fibrogenesis, and extracellular matrix deposition.
In view of the antioxidant function of vitamin C (VC), it could be beneficial in NASH. Previous studies have demonstrated a vicious cycle of deficient balance between oxidant generation and antioxidant defense, leading to liver dysfunctions.
Recent studies reported that free fatty acids typically overload in steatosis, resulting in continuous adaptation and further remodeling of structure, mitochondrial bioenergetics, and energy metabolism. Furthermore, the fatty liver tends to be vulnerable to injury, especially when challenged by oxidative stress and lipid peroxidation. The dysfunctional mitochondria in NAFLD are concurrent to incomplete lipid oxidation, leading to the accumulation of lipotoxic lipids, which further activates inflammation, promoting the transition from steatosis to NASH. Therefore, ROS and inflammation are critical factors in the stepwise progression from simple steatosis to LF and LC. Thus, VC potentially contributes to the alleviation of ROS imbalance and its concomitant pro-inflammatory actions postulated to initiate NASH or cirrhosis.
However, it is difficult for clinicians to recommend the use of antioxidative substances due to the paucity of data on clinically confirmed or definitive physical benefits of VC supplements among patients with MAFLD. Moreover, based on the National Health and Nutrition Examination Survey (NHANES) III data, a recent study found that MAFLD had a greater risk for all-cause mortality, while NAFLD showed no association. Hence, assessing the serum VC levels associated with different categories of NAFLD and the proposed term MAFLD may illuminate the potential utility of antioxidative substances between the two entities.
The European Association for the Study of the Liver lifestyle recommended modifications toward a healthy diet and regular exercise for people with NAFLD, while suggested pharmacotherapy should be reserved for people with NASH. However, biological complexity and incomplete understanding of NAFLD and MAFLD complicated evidence-based clinical recommendations for VC administration. The present study found that serum VC concentrations were statistically associated with reduced risks of NAFLD, MAFLD, LF, and LC after adjusting for the corresponding risk factors and sensitivity analysis. Of note, the serum concentration of VC inversely associated with LF and LC was lower than the serum VC level associated with NAFLD and MAFLD. Given that the newly proposed MAFLD terminology identified a cohort of individuals with a wider range of metabolic traits, our finding that participants from the Q3 group experienced a slightly lower risk of MAFLD than the risk of NAFLD has major clinical implications.
Our finding that the female sex is associated with a lower prevalence of NAFLD, MAFLD, LF, and LC is of particular interest. Given that the baseline level of VC may impact the benefits of VC administration, sensitivity analysis and gender stratification were conducted. Subsequent analysis revealed that the sex predominant might be partly due to the higher dietary VC supplement among women. Interestingly, a step-like change in the VC concentration associated with LF and LC when stratified by age, suggesting dose adjustment according to age. Another important finding in our study was that participants with obesity and diabetes tended to have lower serum VC levels, which is relevant, as prior studies have shown that NAFLD is particularly common among people with obesity and diabetes. The most striking novel finding is the potential hepatoprotective effects of VC, especially for BMI ≥ 30 subjects against NAFLD, MAFLD, and significant fibrosis. These findings are highly important as the epidemic trend of NAFLD has been rising rapidly in recent decades and is increasing in parallel with obesity and diabetes worldwide. With a higher burden of metabolic dysregulation, such as obesity and diabetes, it is not surprising that our study found that participants with higher serum Vitamin C (VC) status had a lower risk of developing MAFLD compared with NAFLD.
It has been reported that the optimum plasma level is about the concentration of saturation (70 μmol/L), which is consistent with our findings that serum VC concentration of 50.5–67.0 μmol/L was associated with decreased risks of NAFLD, MAFLD, LF, and LC. Surprisingly, no correlation was found between the highest quartile of VC and the risk of NAFLD. Additionally, participants in the highest quartile of VC had a slightly higher risk of MAFLD, LF, and LC than those in the 3rd quartile of VC. These data may be partly due to the dual action of Vitamin C (VC), which tends to function as a pro-oxidant and contributes to tissue damage at higher concentrations. Moreover, several studies have reported that only high doses of VC are associated with liver injury during chronic stress conditions in animal models.
Our findings of the inverse association between serum VC levels and a spectrum of liver diseases ranging from MAFLD to LF and LC are in line with prior studies. A recent experimental study has shown that VC treatment decreased high-fat diet-induced NAFLD in mice and had hepatocellular protective effects evidenced by significant weight loss, ballooned hepatocytes, lobular inflammation, and ameliorative liver steatosis. To date, research in serum VC levels and NAFLD or MAFLD is scarce, and only two prior studies have found similar associations between VC intake and NAFLD. Dana et al. demonstrated that dietary VC intake is inversely associated with lower risks of NAFLD and NASH among 789 subjects. However, this analysis might be limited due to the inadequate sample size and inaccurately ultrasonography detection of NAFLD. Furthermore, these findings of dietary VC intake based on recall questionnaires are less reliable due to the absorption obstacles in the gastrointestinal tract, which limited its promising application as a therapeutic agent. Compared with oral VC administration, studies with serum VC levels are often of high quality because circulating VC levels were rarely determined, and therefore, bioavailability and clinical practice could be verified. Notably, we further analyzed the association of serum VC concentrations with the newly proposed MAFLD.
Our novel finding is consistent with previous study findings that VC alleviates inflammation. The subsequent inflammatory environment is a vital contribution to severe NAFLD progression. Several previous studies averred that VC inhibits inflammatory responses mediated by tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). In addition, studies have indicated that VC potentially reduces inflammatory status through alleviation of CRP and IL-6. Consistent with previous studies, findings of the current study indicated an inverse association between serum VC levels with CRP concentration. Interestingly, Seoung-Woo Lee et al. proposed dual roles of VC in early stages of NAFLD and inflammatory steatohepatitis, and findings indicated that VC deficiency significantly inhibited progression of NAFLD by impairing de novo lipogenesis, whereas VC supplementation attenuated inflammatory injuries, including ballooning and lobular inflammation. Therefore, targeted modulation of antifibrotic activity aimed to alleviate the inflammatory environment is a potential therapeutic and preventive strategy against NASH.
Merits of the current study include serum measurement of VC (compared with dietary recall questionnaires) along with representative US civilian data in NHANES. Moreover, this relatively large sample of adults with the TE examination provided opportunities for the study of weak associations. The novelty of the present study includes the application of more accurately defined NAFLD using TE compared with an examination of NAFLD using non-invasive algorithms reported in previous studies. The current study undertook a detailed stratified analysis, sensitivity analysis, and adjusted for major potential interactions between VC and NAFLD. However, the current study has some limitations. Since the current study adopted a cross-sectional design, temporality cannot be fully clear, which limited the inferences on causes and effects. However, the indicated inverse association between VC with NAFLD is having a reasonable agreement with previous studies on the relationship of VC with fatty liver disease, metabolic syndrome, and inflammation. Another limitation of the current study was the use of TE for the diagnosis of NAFLD. Although TE examination is probably the most validated non-invasive method to evaluate liver stiffness, the current study lacked histological confirmation. However, TE is considerably an accurate technique, which has been recommended by the World Federation for Ultrasound in Medicine and Biology to distinguish between non-significant and significant fibrosis.
In conclusion, the findings of the current study indicated that increased serum VC concentrations are associated with reduced risks of NAFLD, MAFLD, significant LF, and LC. This implies that individuals with MAFLD may benefit from VC supplements. Further studies, including prospective cohort studies, are recommended to identify the clinical significance of VC treatment and prevention of MAFLD.
Background and Aims: Despite the remarkable progress of the metabolic dysfunction-associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease (NAFLD), the disease remains poorly improved. Since increased oxidative stress and inflammation contribute to the initiation and progression of fatty liver disorders, vitamin C (VC), an antioxidant agent, might be a suitable treatment option for MAFLD. However, the lack of clinically confirmed benefits makes clinicians challenging to recommend antioxidant supplements for MAFLD individuals.
Methods: Herein, the nationally representative National Health and Nutrition Examination Survey 2017–2018 data were collected to evaluate the potential association between the serum VC levels with the risk of different categories of NALFD and the newly proposed MAFLD terminology. Hepatic steatosis was defined as controlled attenuated parameter scores ≥ 263 dB/m, whereas liver fibrosis (LF) status was defined as F0–F4, with the cutoff values of median liver stiffness being 6.3, 8.3, 10.5, and 12.5 (KPa), respectively. A cross-sectional analysis was performed to calculate the odds rate and determine the potential beneficial effects of VC.
Results: A total of 4,494 participants aged more than 18 years and conducted transient elastography examinations were included. Our findings demonstrated that participants with increased serum VC status were more likely to be female predominant, more educated, and moderate drinkers. Interestingly, female participants tended to have a lower prevalence of NAFLD, MAFLD, LF, and liver cirrhosis (LC) after stratification by gender. Moreover, our results revealed that participants from the quartile three group (quartile 3: 50.5–67.0 μmol/L) experienced a slightly lower risk of MAFLD than the risk of NAFLD. Of note, the serum concentration of VC (quartile 2: 30.9–50.5 μmol/L) inversely associated with LF and LC was lower than the serum VC level (quartile 3) associated with NAFLD and MAFLD. Notably, individuals from the quartile 3 group experienced a statistically significant 32.5, 42.0, 45.7, and 71% decrease in risk of NAFLD, MAFLD, LF, and LC, respectively.
Conclusion: In summary, our findings suggested an inverse association between serum VC levels and NAFLD, MAFLD, LF, or LC. Additionally, adjustment of VC supplementation according to age, gender, and ethnicity may be a promising candidate for these diseases.
ORIGINAL RESEARCH article: Front. Nutr., 04 February 2022 | https://doi.org/10.3389/fnut.2021.795391 Association of Serum Vitamin C With NAFLD and MAFLD Among Adults in the United States
Publicly available datasets were analyzed in this study. This data can be found here: https://wwwn.cdc.gov/nchs/nhanes/.