Commonly used markers of the liver dysfunction such as ALT and AST levels have been implicated with the risk of cardiovascular disease (CVD) [1]. The association between liver enzyme such as ALT level and the prevalence of metabolic syndrome has been reported [2]. Endothelial dysfunction using flow-mediated vasodilation (FMD) test was demonstrated in patients with non-alcoholic fatty liver disease (NAFLD) [3-6] and type 2 diabetes mellitus (DM) [7]. The significant procedures for evaluating vascular endothelial and vascular smooth muscle cell function are flow-mediated vasodilation (FMD), an endothelium-dependent function, and nitroglycerin-mediated vasodilation (NMD), an endothelium-independent function in the brachial artery [8]. The author has reported some studies and reviews on the diseases of migraine, cardiovascular disease (CVD), chronic kidney disease (CKD), dyslipidemia, aging liver, and COVID-19 [9-20] using FMD and NMD tests. Despres [21, 22] noted that both visceral adipose tissue and liver fat are regarded as 2 key drivers of cardiometabolic risk associated with a level of total body fat. We studied whether the interrelationship among serum ALT, endothelial function, and anthropometric markers were recognized. Meanwhile, some studies have found relationships between AST level and CVD [23], between AST level and coronary heart disease (CHD) [24], and between AST level and coronary artery disease (CAD) [25]. AST level is an inflammatory and/or fibrosis marker in hepatic diseases [26, 27] and may be a plausible CVD risk marker as previously described [23]. Well, genetically, CHUK gene, related to glucose and lipid metabolism [28] and PNPLA3 gene, involved in energy metabolism and storage of adipocyte were associated with AST and ALT levels [29]. We investigated whether the relationship between AST level and FMD study was identified. Well, aspartate aminotransferase to platelet ratio index (APRI) is a useful marker for liver fibrosis in patients with hepatic-related disease [30, 31]. Recently, the association between liver fibrosis scores and the risk of mortality in patients with CAD has been described [32]. In the general population, the previous report by Unalp-Arida showed that higher liver fibrosis scores were associated with increased liver disease and overall mortality [33]. Meanwhile the study has provided that fibrosis marker such as hyaluronates could be considered as an index of aging [34], indicating that aging may be regulated by liver organ. Age-related changes in the liver, hepatic sinusoidal endothelium or pseudocapillarisation, have been described and contribute to be hepatic dysfunction [35, 36]. The survey of senescent cell markers with age in human tissues has been studied [37]. We presumed that the association between endothelial dysfunction reflecting systemic atherosclerosis condition and liver fibrosis, partially due to aging was recognized in patients without hepatic-related causes such as NAFLD and hepatic virus infection. We studied whether the relationship between endothelial function including FMD test and vWF level and APRI in patients without hepatic diseases was recognized.

Study Population

Sixty-four patients without hepatic diseases were examined in this study (42 women and 22 men) including 19 cerebral infarction, 12 migraine, 5 cervical spondylosis, and 28 not otherwise, between April 2008 and April 2014. With respect to forty-two women cases, we have previously described in our previous study [13]. This research has been studied by adding further 22 men cases to forty-two women ones [13].

Biochemical Analysis

Analyses were performed for AST and ALT levels by standard enzymatic laboratory techniques. APRI was calculated as: APRI = AST (IU/L)/ AST (the upper limit of normal, ULN) X 100/platelet count (10⁹/L) [27, 32]. Von Willebrand factor as a serum endothelial marker was examined by a platelet aggregation method.

Vascular Reactivity

FMD of the brachial artery was determined using high resolution B-mode ultrasonographic system (UNEXEF 18G, Japan) with a linear transducer midfrequency of 7.5MHz. We used the procedure as previously mentioned [8-10]. Parameters including FMD, BAD, NMD, FMD/NMD, and P-NTGD were examined as previously described [9].

Carotid Ultrasonography

The intima-media thickness (IMT) of the bilateral common carotid arteries (CCA) was measured by ultrasonography with a 10-MHz probe using an ultrasound system (Aplio SSA-700A, Toshiba Medical System, and Tochigi, Japan). Measurement of IMT were performed as previously described [9, 38].

Brachial-Ankle Pulse Wave Velocity (baPWV) Measurement

baPWV was measured using a volume-plethysmographic apparatus (form PWV/ABI; Colin, Co.,Ltd., Komaki, Japan) and ankle- brachial pressure index (ABI) is measured simultaneously by these machines in accordance with a described method [9, 39].

Numerical variables were expressed as mean±SD. Spearman’s bivariable correlation analysis was used to test the relationships between the numerical variables when appropriate. Statistical significance was defined as a p value of less than 0.05. The statistical analyses were performed using the SPSS software package (version 16.0; SPSS Inc., Chicago, IL).

Baseline characteristics of study population are summarized in Table 1. 42 women and 22 men were included in this study. Age year was 59.6±1.7 in whole subjects, 65.1±11.1 in men and 57.3±14.3 in women (mean±SD). Table 2 shows Spearman’s rank correlation coefficients of the brachial artery measures in the participants. BAD was significantly correlated with FMD% (r=-0.44, p=0.004). The significant correlation between BAD and P-NTGD (r=0.93, p<0.001) was recognized. Thus, BAD closely reflect FMD value or endothelial function. Table 3 shows Spearman’s rank correlation coefficients of the atherosclerotic parameters in the participants. Correlations between FMD and right (rt) IMT (r=-0.56, p=0.009) and between FMD and left (lt) IMT (r=-0.42, r=0.001) were significantly recognized. Interrelationship among FMD, IMT, and baPWV were demonstrated at both sites. Table 4 shows Spearman’s rank correlation coefficients for FMD, BAD, P-NTGD, NMD, and FMD/NMD with clinical and biochemical parameters in the participants. A positive correlations between ALT level and BAD (r=0.288, p=0.026) and between P-NTGD and ALT level (r=0.319, p=0.014) were recognized. Positive relations between BAD and anthropometric markers including body mass index (BMI), waist circumference, and weight were shown. There were positive correlations between ALT level and anthropometric markers (data not shown). The result shows the interrelationship among endothelial function, ALT level, and anthropometric markers. Inverse correlations between FMD and vWF (r=-0.303, p=0.021) and between AST level and FMD (r=-0.301, p=0.020) were found. A positive correlation between AST level and vWF (r=0.260, p=0.045) was recognized. Thus, relationship between AST and endothelial marker including FMD and vWF were significantly found. With respect to APRI in whole subjects, the inverse correlations between FMD and APRI (r=-0.375, p=0.003) and between FMD and age (r= -0.453, p<0.001) were found (Table 4). Table 5 shows the correlation between APRI and other parameters. A positive correlations between APRI and vWF (r=0.502, p<0.001) and between APRI and age (r=0.295, p=0.02) were shown. The inverse correlation between APRI and PLT (r=-0.610, p<0.001) was recognized. Table 6 represents the correlation between age and other parameters. Positive correlation between age and vWF (r=0.628, p<0.001) was recognized. Significant inverse correlations between FMD/NMD and vWF (r=-0.332. p=0.012), between FMD/NMD and APRI (r=-0.391, p=0.002), and between FMD/NMD and age (r=-0.265, p=0.041) were recognized (Table 4). These results may be presumed that the significant relationship between endothelial marker including FMD and vWF and APRI was recognized. Restricting to the analyses in women cases, the inverse correlations between APRI and FMD (r=-0.331, p=0.035) and between APRI and FMD/NMD (r=-0.359, p=0.021) were shown at table 4 in our previous study [13]. Table 7 shows the correlation between APRI and other parameters in women. A positive correlation between vWF and APRI (r=0.561, p<0.001) was also recognized. The association between age and APRI (r=0.305, p=0.053) tends to correlate. Table 8 represents the correlation between age and other parameters in women. A positive correlation between age and vWF (r=0.538, p<0.001) and an inverse correlation between age and FMD (r=-0.556, p<0.001) were observed. The results indicate the relationship between endothelial function including FMD and vWF and APRI in women. In men cases, as a sample size is small, statistical method has not been performed. 

Table 1: The clinical and biochemical characteristics of the participants (mean ± SD).

Table 2: Spearman’s rank correlation coefficients of the brachial artery measures in the participants (64 cases).

*p <0.001

BAD: Brachial Artery Diameter, BAD-b: BAD Baseline Diameter, BAD-m: BAD Maximal Diameter, FMD: Flow-Mediated Vasodilation, NMD: Nitroglycerin-Mediated Vasodilation, P-NTGD: Post Nitroglycerin Brachial Artery Diameter

Table 3: Spearman’s rank correlation coefficients of the atherosclerotic parameters in the participants (64 cases).

*p <0.001

Rt: Right, Lt: Left, IMT: intima-media thickness, PWV: Pulse Wave Velocity

Table 4: Spearman’s rank correlation coefficients for FMD, BAD, P-NTGD, NMD, and FMD/NMD with clinical and biochemical parameters in the participants (64 cases).

*p <0.05

Table 5: Correlation between APRI and other parameters in the participants (64 cases).

*p <0.05

Table 6: Correlation between age and other parameters in the participants (64 cases).

*p<0.05

Table 7: Correlation between APRI and other parameters in the participants (42 women-cases).

*p<0.05

Table 8: Correlation between age and other parameters in the participants (42 women-cases).

*p<0.05

Liver function markers such as ALT and AST levels have been implicated with the risk of CVD [1]. Metabolic disorders including obesity, dyslipidemia, and diabetes mellitus (DM) have been reported independently associated with mild-to moderate ALT elevation [40]. The association of higher level of within-normal-limits liver enzyme such as ALT level and the prevalence of metabolic syndrome have been recognized [2]. The inverse correlation between ALT level and FMD study in normotryglyceridaemic subjects with type 2 DM [7] and ALT-CHD association in a population-based cohort [41] have been recognized. Masoudkabir et al. also described the correlation between ALT level and premature CAD [25]. In hepatic-related causes, endothelial dysfunction using FMD procedures was demonstrated in patients with NAFLD [3-6]. Out of these studies, a few reports of the correlation between FMD study and ALT level have been provided [3, 6,7]. Underlying mechanism of endothelial dysfunction was considered as insulin resistance, and oxidative stress and inflammation [4, 6, 7]. The study showed that elevated liver enzymes such as ALT level are associated with markers of oxidative stress and several inflammatory parameters, namely CRP [42]. Elevated ALT level may be a marker of the systemic inflammation and oxidative stress irrespective of the metabolic syndrome [42]. Masoudkabir et al. [25] suggested the evidence of role of systemic inflammatory state consequences in the liver and the development of coronary atherosclerosis. While Simental-Mendia et al. described that insulin resistance is significantly associated with elevated ALT level [43]. Despres [21, 22] have reported that dysfunctional adipose tissue have caused altered free fatty acid (FFA) metabolism and/or altered release of adipokines, leading to make lipid overflow-ectopic fat. In result, altered metabolic profile develop the presence of metabolic syndrome [21, 22]. Meanwhile, they mentioned that a high liver fat content can, by itself, largely explain the hyperinsulinemic, hyperglycemic, hypertriglyceridemic, and elevated apolipoprotein B dysmetabolic state of visceral obesity without visceral adipose tissue [22]. They also suggested that both visceral adipose tissue and liver fat are regarded as 2 key drivers of cardiometabolic risk associated with a level of total body fat [22]. In this study, the interrelationship among serum ALT level, endothelial function, and adiposity markers may be presumed. It is putative that underlying mechanism of cardiometabolic profile features might be partially due to visceral adipose tissue. As some studies have been investigated to evaluate upper limit of normal (ULN) of ALT level [44], it may be useful to estimate the ULN of higher ALT for early detection and prevention of clinical and/or subclinical disease such as CVD, DM, and metabolic syndrome.

AST is mainly distributed in the myocytes, followed by hepatocytes. AST may serve as a parameter used to evaluate the extent of liver injury or myocardial injury as previously described [24]. Some researchers have found relationships between AST level and CVD [23], between AST level and CHD [24], and between AST level and CAD [25]. AST level as a liver fibrosis marker has been reported in patients with non-alcoholic steatohepatitis (NASH) [26] and chronic hepatitis with virus infection [27]. It has been described that AST level is more closely related to hepatic inflammation and may be the main biochemical abnormality in NASH leading to hepatic fibrosis [26]. Wai et al. [27] suggested that platelet count, AST level, and alkaline phosphatate (ALP) were the independent predictors for significant fibrosis in patients with chronic hepatitis C. Many studies provided the evidence of decreased platelet count and increased AST level with progression of liver fibrosis [27]. Monami et al. [23] have reported that elevated AST level is an independent predictor of CVD. As the mechanism underlying of this association of higher AST level with CVD are difficult to identify, insulin resistance, which is a relevant CV risk factor has been presumed [23]. Masoudkabir et al. [25] have reported that both AST and ALT levels would be useful biomarkers for CV risk evaluation [41]. Shen et al. [24] have suggested that high serum AST and ALT levels are biochemical markers which can be used to predict the severity of CHD and are also independent risk factors of CHD. Genetically, it is suggested that single-nucleotide polymorphism (SNP) is useful to analyze genetic elements of clinical findings [28]. In the PNPLA3 gene, rs4823173, rs2896019, and rs2281135 were associated with AST and ALT levels [29]. PNPLA3 gene, involved in energy mobilization and storage of adipocyte, has been reported to be related to both AST and ALT levels. While, CHUK gene, related to glucose and lipid metabolism, is known to be gene influencing ALT level [28]. The author previously described the reports of NAFLD/NASH-associated HCC from a current genetic perspective [45-47]. With regard to vWF value, vWF value plays a role as an endothelial marker, though it was an established marker for varices, portal hypertension, and mortality in patients with liver cirrhosis [48]. Maieron et al. have reported that vWF score is as a new marker for non-invasive assessment of liver fibrosis and cirrhosis in patients with chronic hepatitis C in comparison to other fibrosis scores assessed (APRI, FCI, FORNS, FI, Fib-4) [49]. They suggested that elevated vWF might be a key player in establishing liver fibrosis [49]. In this study, a negative correlation between FMD or the endothelium-mediated vascular reactivity study and vWF or serum endothelial marker was identified. Furthermore, a negative correlation between AST level and FMD test and a positive correlation between AST level and vWF value have been found, suggesting the relationship between endothelial indicators including FMD study and vWF value and AST level. The results indicated the correlation between endothelial function and AST level, thereby AST level as an inflammatory and fibrosis marker may also serve as a CVD biomarker. Well, if vWF value plays roles as both the endothelial and fibrosis markers, endothelial dysfunction reflecting systemic atherosclerosis condition as extrahepatic manifestation concomitantly occur in patients with liver fibrosis and/or cirrhosis. 

Concerning APRI reports, several studies of APRI have recently focused on patients with HCV, HCV/human immunodeficiency virus (HIV) co-infection, alcoholic liver disease [30], and HBV [31]. Barone [50] suggested that HCV has a proatherosclerotic activity due to both its local action on the vessel walls, representing HCV-RNA sequences within the atherosclerotic plaques and stimulation of proinflammatory substances such as interleukin-6 (IL-6) and tumor necrosis factor α(TNFα). They have indicated that an inverse correlation between endothelial function assessed by FMD study and liver fibrosis estimated by liver elastography was recognized in patients with chronic HCV infection [50]. The evidence shows that HCV advanced liver fibrosis promotes atherosclerosis by inducing endothelial dysfunction independently of common CV risk factors [50]. The role of systemic inflammation in the genesis of atherosclerosis is supported by studies on chronic infections and chronic inflammatory autoimmune disease [50-52]. Recently, Schmidt et al. described that HCV infection affects endothelial function and that new direct acting antivirus (DAA)- treatment reverses these effects and enhance endothelial function [53]. These studies provided that hepatic-related causes such as hepatic virus infectious disease can contribute to not only liver damage but also systemic atherosclerosis status. Recently, Chen et al. [32] described that higher liver function scores such as APRI are associated with increased risk of all-cause and cardiovascular mortality among patients with CAD. NAFLD are highly prevalent in patients with CAD and is associated with severity of subclinical atherosclerosis, including carotid IMT, endothelial dysfunction, arterial stiffness, and coronary calcification [32]. In the general population, Unalp-Arida et al. [33] described that higher liver fibrosis scores including APRI were attributed to a higher risk for overall and CVD mortality. In our study, negative correlations between FMD and APRI and between FMD/NMD and APRI were identified. A positive correlation between vWF value and APRI was also identified. Our data indicates that liver fibrosis marker may correlate with endothelial indicators including vascular reactivity and serum marker in patients without hepatic-related cause. In restricted to analyses in women cases, the similar result was detected as previously shown at Table 4 [13]. In our study, local liver fibrosis marker or APRI correlates systemic endothelial marker such as FMD study and vWF value in patient without hepatic disease, thereby suggesting that liver fibrosis reflect systemic atherosclerosis condition. It has been known that the presence of liver pathologies and systemic disease can contribute to liver fibrosis.

Concerning the liver-related fibrosis, Thabut et al. [54] described that intrahepatic angiogenesis and sinusoidal remodeling have been identified in chronic liver disease. Iwakiri [55] have reported that mechanism of increased intrahepatic resistance or portal hypertension were due to chronic liver damage such as virus infection, drugs, alcohol, and endotoxin. These factors induce oxidative stress, activation of Toll-like receptor 4/myeloid differentiation protein 88 (TLR4/MyD88) signaling, and gene profile changes (microRNA), leading to liver sinusoidal endothelial cell (LSEC) dysfunction. In result, defenestration was induced and develop fibrosis, angiogenesis, sinusoidal remodeling, changes in local flow patterns through the shear stress, and gene profile changes via Kruppel-like factor 2 (KLF2) [55].

With respect to age-related liver change, Eto et al. described that aging may be regulated by liver organ. The study indicated that fibrosis marker such as hyaluronates could be considered as an index of aging [34]. Age-related changes in the human hepatic sinusoidal endothelium or pseudocapillarisation, have been described and contribute to be hepatic dysfunction [35, 36]. In response to aging, it has been reported that sinusoidal endothelial cell dedifferentiate into a more regular endothelium, namely capillarisation or pseudocapillarisation, resulting in fibrosis status [35]. Koehler et al. have described that higher age is also one of the factors associated with clinically relevant liver fibrosis [56]. It has been demonstrated that in the cellular and molecular biology, aging is associated with chronic and low-grade inflammatory state characterized by increases in circulating acute phase proteins and pro-inflammatory cytokines. The age-associated pro-inflammatory arterial phenotype is downstream of increased nuclear factor κB activity (NFκB) as previously described [57]. It is suggested that the correlation between systemic atherosclerosis status and local liver fibrosis may be found in patients with NAFLD and chronic HCV infection, in especially advanced condition. Similar to the NAFLD and chronic HCV infection associated with atherosclerosis status, it is plausible that aging, this is the chronic and low grade inflammatory condition, can concomitantly contribute to the systemic atherosclerosis and liver fibrosis. Liver fibrosis status may represent an atherosclerotic manifestation of the liver in the elderly subjects without hepatic disease. With respect to the vascular change, age-related arterial dysfunction is also represented in the absence of clinical CVD and traditional CVD risk factors, indicating the concept that age-related arterial dysfunction is a primary effect of advancing age [58]. Idda et al. [37] studied the survey of senescence cell markers with age in human tissues and found increased p16-expressing cells in the liver. In the present study, the interrelationship among APRI, age, and endothelial function were recognized. The similar tendency without the statistical significance was found in women as shown in our previous study [13], thereby indicating that APRI as liver fibrosis marker may reflect systemic atherosclerosis condition, partially due to aging in patients without hepatic-related causes. In this study, as relatively elderly subjects were included, aging may be considered as one of the causal factors of the close association. Result provided that systemic atherosclerosis condition and liver fibrosis may concomitantly occur at the higher APRI of ULN in this study. It might be useful to investigate the higher APRI for the early detection and prevention of clinical and/or subclinical diseases in patients without hepatic-related causes.

In Summary

Our results indicated that APRI may reflect systemic atherosclerosis condition in a retrospective and cross-sectional study. APRI value may represent atherosclerotic status, partially due to aging. It is putative that liver fibrosis status may represent an atherosclerotic manifestation of the liver in the elderly subjects without hepatic disease. In this study, as relatively elderly subjects were included, aging may be regarded as one of the causal factors of a close correlation. In the higher APRI of upper limit of normal range, systemic atherosclerosis condition and liver fibrosis may concomitantly occur. 

Study Limitation

There were some limitations. In a cross-sectional and retrospective setting of the patients without liver disease, a strong association between APRI index and endothelial function was found. APRI index as a fibrosis marker for NAFLD and hepatic virus infection may also reflect systemic atherosclerosis condition in this setting of patients without liver-related disease. But several confounding factors related to FMD study as well as APRI index were present. The significant differences in risk factors are important to address as they are likely independently related to FMD study and APRI index. However, we did not have adjusted by confounding factors, because our sample size is relatively small numbers. Future perspective studies are warranted to elucidate more detailed conclusion.

Aspartate aminotransferase to platelet ratio index (APRI) may be a marker of the systemic atherosclerosis condition in patients without hepatic-related causes at least in women. It may be potential to investigate the higher APRI of the upper limit of normal for the early detection and prevention of clinical and/or subclinical diseases in patients without hepatic-related causes.

The author appreciates Dr. Minoru Oishi for his kind support.

Informed consent was obtained from patients in this study and the study was approved by the Ethics Committee of NIihon University School of Medicine.

The author declares that I have no conflicts of interest.

1. Kunutsor SK, Apekey TA, Khan H. Liver enzymes and risk of cardiovascular disease in the general population: a meta-analysis of prospective cohort studies. Atherosclerosis. 2014; 236: 7-17.
2. Steinvil A, Shapira I, Ben-Bassat OK, Cohen M, Vered Y, Berliner S, et al. The association of higher levels of within- normal-limits liver enzymes and the prevalence of the metabolic syndrome. Cardiovasc Diabetol. 2010; 9: 30.
3. Senturk O, Kocaman O, Hulagu S, Sahin T, Aygun C, Konduk T, et al. Endothelial dysfunction in Turkish patients with non-alcoholic fatty liver disease. Intern Med J. 2008; 38: 183-189.
4. Colak Y, Senates E, Yesil A, Yilmaz Y, Ozturk O, Doganay L, et al. Assessment of endothelial function in patient with nonalcoholic fatty liver disease. Endocrine. 2013; 43: 100-107.
5. Kucukazman M, Ata N, Yavuz B, Dal K, Sen O, Deveci OS, et al. Evaluation of early atherosclerosis markers in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2013; 25: 147-151.
6. Arinc H, Sarli B, Baktir AO, Saglam H, Demirci E, Dogan Y, et al. Serum gamma glutamyl transferase and alanine transaminase concentrations predict endothelial dysfunction in patients with non-alcoholic steatohepatitis. Ups J Med Sci. 2013; 118: 228-234.
7. Schindhelm RK, Diamant M, Bakker SJ, van Dijk RA, Scheffer PG, et al. Liver alanine aminotransferase, insulin resistance and endothelial dysfunction in normotriglyceridaemic subjects with type 2 diabetes mellitus. Eur J Clin Invest. 2005; 35: 369-374.
8. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002; 39: 257-265.
9. Fujioka K, Oishi M, Fujioka A, Nakayama T. Increased nitroglycerin-mediated vasodilation in migraineurs without aura in the interictal period. J Med Ultrason. 2018; 45: 605-610.
10. Fujioka K. Reply to: Endothelium-dependent and –independent functions in migraineurs. J Med Ultrason. 2019: 46: 169-170.
11. Fujioka K, Oishi M, Nakayama T, Fujioka A. Association of brachial artery measures with estimated GFR>60mL/min/1.73m in a cross-sectional study of the community-based women. Angiology Open Access. 2019; 7: 231
12. Fujioka K. Propensity to the vascular smooth muscle cell abnormality in migraine without aura and vasospastic angina along with a genome-wide association studies. J Carcinog Mutagen. 2019; 10: 334.
13. Fujioka K, Oishi M, Fujioka A, Nakayama T, Okada M. Interrelationship among lipid profiles, arterial stiffness, and nitroglycerin-mediated vasodilation in the community-based setting of the Japanese women. Angiology Open Access. 2019; 7: 235.
14. Fujioka K. Effect on microRNA-92a in atherosclerosis along with flow-mediated vasodilation study. J Cancer Oncol. 2020; 4: 000153.
15. Fujioka K. A novel biomarker microRNA-92a-3p as a link between cardiovascular disease and chronic kidney disease. J Carcinog Mutagen 2020; 11: 1000345
16. Fujioka K, Oishi M, Nakayama T, Fujioka A. Correlation between vascular failure (endothelial dysfunction) and fibrosis markers. Jpn J Med Ultrsonics. 2016; 43: S458.
17. Fujioka K. Association between chronic liver disease and atherosclerosis: an inflammation as common pathway. J Clin Trials. 2021; 11: 444.
18. Fujioka K. A link between endothelial dysfunction and SARS-CoV-2 infection in patients with COVID-19. CPQ Medicine. 2021; 11: 01-08.
19. Fujioka K. Cutaneous manifestation and vasculitis of COVID-19 in dermatology. Acta Sci Med Sci 2021; 5: 16-19.
20. Fujioka K. Clinical manifestation of endotheliitis in COVID-19 along with flow-mediated vasodilation study. J Clin Trials 2021; 11: 1000469.
21. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006; 444: 881-887.
22. Despres JP. Body fat distribution and risk of cardiovascular disease: an update. Circulation. 2012; 126: 1301-1313.
23. Monami M, Bardini G, Lamanna C, Pala L, Cresci B, Francesconi P, et al. Liver enzymes and risk of diabetes and cardiovascular disease: results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism. 2008; 57: 387-392.
24. Shen J, Zhang J, Wen J, Ming Q, Zhang J, Xu Y. Correlation of serum alanine aminotransferase and aspartate aminotransferase with coronary heart disease. Int J Clin Exp Med. 2015; 8: 4399-4404.
25. Masoudkabir F, Karbalai S, Vasheghani-Farahani A, Aliabadi LL, Boroumand MA, Aiatollahzade-Esfahani F, et al. The association of liver transaminase activity with presence and severity of premature coronary artery disease. Angiology. 2011; 62: 614-619.
26. Lioudaki E, Ganotakis ES, Mikhailidis DP. Liver enzymes: potential cardiovascular risk markers? Curr Pharm Des. 2011; 17: 3632-3643.
27. Wai CT, Greenson JK, Fontana RJ, Kalbtleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003; 38: 518-526.
28. Seo JY, Lee JE, Chung GE, Shin E, Kwak MS, Yang JI, et al. A genome-wide association study on liver enzymes in Korean population. PLoS One. 2020; 15: e0229374.
29. Young KA, Palmer ND, Fingerlin TE, Langefeld CD, Norris JM, Wang N, et al. Genome-wide association study identifies loci for liver enzyme concentrations in Mexican Americans: the GUARDIAN Consortium. Obesity. 2019; 27: 1331-1337.
30. Sethi S, Simonetto DA, Abdelmoneim SS, Campion MB, Kaloiani I, Clayton AC, et al. Comparison of circulating endothelial cell/platelet count ratio to aspartate transaminase/platelet ratio index for identifying patients with cirrhosis. J Clin Exp Hepatol. 2012; 2: 19-26.
31. Xiao G, Yang J, Yan L. Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis. Hepatology. 2015; 61: 292-302.
32. Chen Q, Li Q, Li D, Chen X, Liu Z, Hu G, et al. Association between liver fibrosis scores and the risk of mortality among patients with coronary artery disease. Atherosclerosis. 2020; 299: 45-52.
33. Unalp-Arida A, Ruhl CE. Liver fibrosis scores predict liver disease mortality in the United States population. Hepatology. 2017; 66: 84-95.
34. Eto N, Yoshino J, Inui K, Wakabayashi T, Okushima K, Kobayashi T, et al. Fluctuation of the fibrosis markers with aging. Jpn J Geriat. 2002; 39: 176-180.
35. Scioli MG, Bielli A, Arcuri G, Ferlosio A, Orlandi A. Aging and microvasculature. Vasc Cell. 2014; 6: 19.
36. Xu B, Broome U, Uzunel M, Nava S, Ge X, Kumagai-Braesch M, et al. Capillarization of hepatic sinusoid by liver endothelial cell-reactive autoantibodies in patients with cirrhosis and chronic hepatitis. Am J Pathol. 2003; 163: 1275-1289.
37. Idda ML, McClusky WG, Lodde V, Munk R, Abdelmohsen K, Rossi M, et al. Survey of senescent cell markers with age in human tissues. Aging. 2020; 12: 4052-4066.
38. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, et al. Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3^rd, 4^th and 5^th watching the risk symposia, at the 13^th , 15^th and 20^th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.Cerebrovasc Dis. 2012; 34: 290-296.
39. Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, et al. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res. 2002; 25: 359-364.
40. Liu Z, Que S, Xu J, Peng T. Alanine aminotransferase-old biomarker and new concept: a review. Int J Med Sci. 2014; 11: 925-935.
41. Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, et al. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis. 2007; 191: 391-396.
42. Yamada J, Tomiyama H, Yambe M, Koji Y, Motobe K, Shiina K, et al. Elevated serum levels of alanine aminotransferase and gamma glutamyltransferase are markers of inflammation and oxidative stress independent of the metabolic syndrome. Atherosclerosis. 2006; 189: 198-205.
43. Simental-Mendia LE, Rodriguez-Moran M, Gomez-Diaz R, Wacher NH, Rodriguez-Hernandez H, Guerrero-Romero F. Insulin resistance is associated with elevated transaminases and low aspartate aminotransferase/alanine aminotransferase ratio in young adults with normal weight. Eur J Gastroenterol Hepatol. 2017; 29: 435-440.
44. Cho JY, Jeong JY, Sohn W. Risk of metabolic syndrome in participants within the normal range of alanine aminotransferase: A population-based nationwide study. PLos One. 2020; 15: e0231485.
45. Fujioka K. NAFLD/NASH-related hepatocellular carcinoma: along with the role of genetics. J Cancer Oncol. 2020; 4: 000165.
46. Fujioka K. Current genetic advances in NAFLD/NASH: related hepatocellular carcinoma along with characteristic clinical manifestations. J Carcinog Mutagene. 2021; 12(S17): 1000001.
47. Fujioka K. Polygenic risk scores in NAFLD/NASH-associated hepatocellular carcinoma along with multifactorial process. J Carcinog Mutagene. 2021; 12: 1000370.
48. Ferlitsch M, Reiberger T, Hoke M, Salzl P, Schwengerer B, Ulbrich G, et al. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology. 2012; 56: 1439-1447.
49. Maieron A, Salzl P, Peck-Radosavljevic M, Trauner M, Hametner S, Schofl R, et al. Von Willebrand Factor as a new marker for non-invasive assessment of liver fibrosis and cirrhosis in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2014; 39: 331-338.
50. Barone M, Viggiani MT, Amoruso A, Schiraldi S, Zito A, Devito F, et al. Endothelial dysfunction correlates with liver fibrosis in chronic HCV infection. Gastroenterol Res Pract. 2015; 2015: 682174.
51. Voulgaris T, Sevastianos VA. Atherosclerosis as extrahepatic manifestation of chronic infection with hepatitis C virus. Hepat Res Treat. 2016; 2016: 7629318.
52. Principi M, Mastrolonardo M, Scicchitano P, Gesualdo M, Sassara M, Guida P, et al. Endothelial function and cardiovascular risk in active inflammatory bowel diseases. J Crohns Colitis. 2013; 7: 427-433.
53. Schmidt FP, Zimmermann T, Wenz T, Schnorbus B, Ostad MA, Feist C, et al. Interferon- and ribavirin-free therapy with new direct acting antivirals (DAA) for chronic hepatitis C improves vascular endothelial function. Int J Cardiol. 2018; 271: 296-300.
54. Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol. 2010; 53: 976-980.
55. Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver Int. 2012; 32: 199-213.
56. Koehler EM, Plompen EPC, Schouten JNL, Hansen BE, Murad SD, Taimr P, et al. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: the Rotterdam Study. Hepatology. 2016; 63: 138-147.
57. Donato AJ, Morgan RG, Walker AE, Lesniewski LA. Cellular and molecular biology of aging endothelial cells. J Mol Cell Cardiol. 2015; 89: 122-135.
58. Donato AJ, Machin DR, Lesniewski LA. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res. 2018; 123: 825-848.