Association between serum uric acid level and non-alcoholic fatty liver disease in Koreans
, , , et | 28 févr. 2022
Article Category: Original article
Publié en ligne: 28 févr. 2022
Pages: 15 - 22
DOI: https://doi.org/10.2478/abm-2022-0003
Mots clés
© 2022 Huiyul Park et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.
Non-alcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver from causes other than alcohol. As the number of patients with obesity and metabolic diseases increases, the prevalence of NAFLD, considered to be a major cause of chronic liver disease worldwide [1, 2], has increased to 28% of the Korean population [3, 4].
NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). While NAFL may be associated with increased cardiovascular disease and malignancy, it is considered benign with a good prognosis from a hepatological perspective. By contrast, NASH is progressive and causes NAFLD-related cirrhosis and hepatocellular carcinoma. As NAFLD has a substantially different prognosis, it is clinically important to confirm the presence or progression of hepatic fibrosis in patients with NAFLD [3, 4]. However, there are some reports of association between serum uric acid (SUA) levels and NAFLD without consideration of the severity of NAFLD, such as the presence of NASH or hepatic fibrosis [5, 6].
Uric acid (UA), a major product of purine metabolism involved in gouty arthritis, is closely related to metabolic disorders and insulin resistance, which are the major features of NAFLD [7]. Previous studies have shown that hyperuricemia is an independent risk factor for NAFLD [8]. However, some studies suggest that NAFLD may cause hyperuricemia [9]. Although it is difficult to determine a causal relationship because of their complex interactions, it is clear that there is a strong association between NAFLD and hyperuricemia.
Similarly, when evaluating a usefulness of biomarker for NAFLD, it is crucial to confirm whether it simply indicates just the amount of fat in the liver or includes information regarding liver damage and degree of fibrosis. There have been several reports that SUA level is associated with not only hepatic steatosis, but also liver damage [10] or histological changes in the liver [11]. However, there are few studies directly comparing the relation of hyperuricemia with the amount of fat in the liver or the degree of liver fibrosis. Moreover, there is inconsistency in the association between SUA level and significant liver fibrosis [10, 12].
In the present study, we compared the associations of SUA level with the presence of NAFLD defined by abdominal ultrasound and hepatic fibrosis estimated by liver fibrosis formulas in an average risk Korean population to clarify the association of SUA level with NAFLD.
We conducted a retrospective cross-sectional study. The medical records of patients who had undergone a health checkup at Hanyang University Medical Center were reviewed for analysis. The Institutional Review Board (IRB) of Hanyang University Medical Center approved this study protocol (IRB file No. HYUH 2020-02-010-001, approval date 2020 Oct 20) in accordance with ICH Good Clinical Practice (GCP) Guidelines, the principles outlined in the contemporary revision of the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013), the study complies with domestic and international related laws, such as the enforcement ordinance of the Bioethics and Safety Act. Informed consent was specifically waived because of the retrospective nature of our study. Reporting is in accordance with STROBE statement [13].
In the present study, the medical records of a total of 2,025 of adult patients who had undergone health check-up at Hanyang University Medical Center between March 2019 and June 2019 were initially reviewed. We excluded data of non-Koreans (n = 339) and patients with missing data for their medical history (n = 58), abdominal ultrasonography (n = 48), or alcohol consumption (n = 28). We further excluded data of patients with a high risk of liver disease, who had the positive serological markers for hepatitis B virus (HBV) or hepatitis C virus (HCV) or who self-reported as being an HBV carrier (n = 65), as well as patients whose weekly alcohol consumption was >210 g for men or >140 g for women (n = 160). Ultimately, data of 1,343 patients were included in this study (
Figure 1
Study flow diagram. HbsAg, surface antigen hepatitis B virus; HCV, hepatitis C virus; NAFLD, non-alcoholic fatty liver disease.
Fatty Liver Index (FLI) was calculated from descriptive statistical analysis by using the equation:
(ey/(1 + ey) × 100, where y = 0.953 × ln(Tg [mg/dL]) + 0.139 × BMI [kg/m2] + 0.718 × ln(GGT [U/L]) + 0.053 × WC [cm] − 15.745 [14],
where Tg is triglycerides, BMI is body mass index, GGT is γ-glutamyl transferase, and WC is waist circumference.
NAFLD fibrosis score (NFS) was calculated according to Hagström et al. [15]. NFS grades were divided into grade 0 (low risk), 1 (intermediate risk), and 2 (high risk) by using a cut-offs at −1.455 and 0.675. When age of patients was >65 years, a cut-off at 0.12 was used as the low cut-off instead of −1.455 [16].
NAFLD was diagnosed by ultrasonography of Korean patients without excessive alcohol consumption or viral or genetic liver disease. The degree of fatty liver was graded as normal, mild, moderate, or severe on the degree of fat infiltration [17]. The degree of fat infiltration was evaluated by the following ultrasound parameters, such as liver echotexture, liver attenuation, and visualization of intrahepatic vessel borders or diaphragm.
Abnormal alanine transferase (ALT) was defined as having a serum ALT level ≥40 IU/L. Hyperuricemia was defined as having an SUA level of >7.0 mg/dL in men and >5.7 mg/dL in women.
Continuous and categorical variables are presented as mean (standard deviation, (SD)) and number (percent), respectively. To compare the mean values between the groups, a Student
We included data of 1,343 patients for analysis, but not that of 952 patients with risk factors for chronic liver disease or insufficient data (
Baseline characteristics, demographic data, and hyperuricemia and metabolic disease prevalence of patients according to presence of NAFLD
| Age (years) | 44.1 (13.0) | 48.9 (10.7) | 48.7 (11.2) | 49.5 (10.0) | 46.8 (10.0) | <0.001 | <0.001 |
| Male sex, n (%) | 265 (44.5) | 509 (68.1) | 261 (60.0) | 196 (79.0) | 52 (81.3) | <0.001 | <0.001 |
| Normal weight (BMI <23) | 425 (71.3) | 183 (24.5) | 151 (34.7) | 30 (12.1) | 2 (3.1) | ||
| Overweight (BMI ≥23, <25) | 119 (20.0) | 236 (31.6) | 155 (35.6) | 75 (30.2) | 6 (9.4) | <0.001 | <0.001 |
| Obese (BMI ≥25) | 52 (8.7) | 328 (43.9) | 129 (29.7) | 143 (57.7) | 56 (87.5) | ||
| Body weight (kg) | 59 (10) | 70 (11) | 66 (10) | 73 (10) | 82 (13) | <0.001 | <0.001 |
| Height (cm) | 165 (8) | 167 (8) | 166 (8) | 168 (7) | 170 (9) | <0.001 | <0.001 |
| SBP (mmHg) | 115 (15) | 123 (17) | 120 (16) | 126 (16) | 132 (20) | <0.001 | <0.001 |
| WC (cm) | 73 (7) | 82 (8) | 79 (7) | 85 (6) | 93 (9) | <0.001 | <0.001 |
| Platelet count (×104/mL) | 240 (47) | 244 (51) | 243 (52) | 244 (50) | 250 (51) | 0.17 | 0.38 |
| Fasting glucose (mg/dL) | 91 (9) | 101 (17) | 98 (14) | 103 (17) | 112 (26) | <0.001 | <0.001 |
| Triglyceride (mg/dL) | 85 (39) | 144 (97) | 118 (66) | 174 (120) | 203 (119) | <0.001 | <0.001 |
| AST (IU/L) | 24 (9) | 27 (13) | 25 (11) | 30 (13) | 38 (18) | <0.001 | <0.001 |
| ALT (IU/L) | 19 (9) | 29 (23) | 22 (15) | 35 (27) | 54 (28) | <0.001 | <0.001 |
| Total cholesterol (mg/dL) | 190 (33) | 199 (37) | 196 (35) | 203 (38) | 206 (38) | <0.001 | <0.001 |
| HDL cholesterol (mg/dL) | 60 (12) | 52 (10) | 54 (10) | 49 (9) | 47 (8) | <0.001 | <0.001 |
| LDL cholesterol (mg/dL) | 111 (24) | 122 (27) | 118 (26) | 126 (29) | 128 (29) | <0.001 | <0.001 |
| SUA (mg/dL) | 5.03 (1.29) | 5.75 (1.38) | 5.46 (1.32) | 6.09 (1.32) | 6.43 (1.51) | <0.001 | <0.001 |
| NFS | –2.44 (1.12) | –2.00 (1.15) | –2.01 (1.14) | –2.01 (1.17) | –1.86 (1.17) | <0.001 | <0.001 |
| Prevalence of hyperuricemia and metabolic disease n (%) | |||||||
| Hyperuricemia (19.1) | 76 (12.8) | 181 (24.2) | 71 (16.3) | 80 (32.3) | 30 (46.9) | <0.001 | <0.001 |
| HTN (22.9) | 72 (12.1) | 235 (31.5) | 113 (26.0) | 90 (36.3) | 32 (50.0) | <0.001 | <0.001 |
| Low LDL or statin medication(24.3) | 93 (15.6) | 234 (31.3) | 114 (26.2) | 99 (39.9) | 21 (32.8) | <0.001 | <0.001 |
| DM (6.4) | 15 (2.5) | 71 (9.5) | 25 (5.7) | 33 (13.3) | 13 (20.3) | <0.001 | <0.001 |
Data are presented as mean (SD) or number (percent).
Between normal patients and patients with NAFLD. A Student
ALT, alanine aminotransferase; ANOVA, analysis of variance; AST, aspartate aminotransferase; BMI, body mass index; MetS, metabolic syndrome; DBP, diastolic blood pressure; DM, diabetic mellitus; HDL, high density lipoprotein; HTN, hypertension; LDL, low-density lipoprotein; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score; SBP, systolic blood pressure; SUA, serum uric acid; WC, waist circumference.
The mean value of SUA level (5.03 vs. 5.75 mg/dL;
Prevalence of hyperuricemia according to underlying disease
| NAFLD (−) | 76 (12.8) | <0.001 |
| NAFLD (+) | 181 (24.2) | |
| ALT abnormality (−) | 200 (17) | <0.001 |
| ALT abnormality (+) | 57 (34.5) | |
| HTN (−) | 176 (17) | <0.001 |
| HTN (+) | 81 (26.4) | |
| Liver fibrosis (NFS grade £ 1) | 254 (19.1) | 0.82 |
| Liver fibrosis (NFS grade =2) | 3 (21.4) | |
| Diabetes mellitus (−) | 243 (19.3) | 0.49 |
| Diabetes mellitus (+) | 14 (16.3) |
Data are presented as number (percent). χ
Pearson correlation analysis showed that SUA level was positively correlated with the FLI (
Figure 2
Scatter plots for SUA level versus FLI
To evaluate the independent association between liver fibrosis (NFS grade) and SUA level, logistic regression analysis was conducted (
Multivariate risk factor analysis for patients with elevated NFS grade by logistic regression
| Age (year) | 44.7 (12) | 54.3 (8.9) | 1.08 | 1.06–1.09 | <0.001 |
| Male sex | 572 (54.4) | 202 (69.2) | 1.59 | 1.15–2.20 | 0.005 |
| BMI (kg/m2) | 22.9 (3.1) | 25.2 (3.2) | 1.27 | 1.20–1.34 | <0.001 |
| HTN | 205 (19.5) | 102 (34.9) | 0.73 | 0.51–1.04 | 0.085 |
| Diabetes mellitus | 36 (3.4) | 50 (17.1) | 2.82 | 1.70–4.69 | <0.001 |
| NAFLD | 538 (51.2) | 209 (71.6) | 0.97 | 0.68–1.39 | 0.88 |
| Abnormal ALT | 115 (10.9) | 50 (17.1) | 0.68 | 0.43–1.05 | 0.082 |
| Hyperuricemia | 198 (18.8) | 59 (20.2) | 0.94 | 0.65–1.37 | 0.75 |
Data are presented as mean (SD) or number (percent).
ALT, alanine aminotransferase; BMI, body mass index; HTN, hypertension; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score.
To identify the association of SUA with NAFLD distinctly, we compared the associations between SUA and the presence of NAFLD, abnormal ALT, and the degree of liver fibrosis. We observed a strong association with the presence of NAFLD. However, we found no association with degree of hepatic fibrosis.
Notably, there was no significant difference in SUA and prevalence of hyperuricemia between non-DM and DM groups in our cohort, unlike the difference found by others [18]. There is a possibility of hidden medication for hyperuricemia as medication history was completely determined through self-reported questionnaires. Just 2 of 1,343 patients said they took medication for hyperuricemia, which can be omitted more easily, than medication for hypertension, diabetes, or dyslipidemia. In addition, there is a possibility that patients with DM took a statin to lower the SUA. Patients with DM showed the worse metabolic profiles such as higher blood pressure, BMI, and serum triglyceride level than patients without DM. However, total cholesterol (196 ± 34 mg/dL in non-DM vs. 171 ± 40 mg/dL in DM,
Recent guidelines for NAFLD management established by the American Association for the Study of Liver Diseases (AASLD) and the Korean Association for the Study of the Liver (KASL) recommend estimating the degree of hepatic fibrosis in high-risk NAFLD patients by using liver fibrosis formulas, transient/magnetic resonance elastography, or liver biopsy because progressive hepatic fibrosis is an important surrogate for advanced liver disease. They also report that estimating fat in the liver would not be helpful for discriminating NASH from NAFLD because the quantity of fat in the liver does not match liver damage or fibrosis in NAFLD patients [19, 20]. Although SUA levels showed a mild correlation with ALT, Pearson correlation analysis showed a stronger relationship with the FLI (
A study that included biopsy-proven NAFLD patients (n = 634) found higher levels of SUA were independently associated with hepatocellular steatosis and NASH. However, there was no association with liver fibrosis (stage F2 to F4) [21]. Recent meta-analyses by Jaruvongvanich et al. [22, 23] also found that SUA level was not associated with severity of advanced liver fibrosis (≥ F3), but liver histologic severity as determined by NAFLD activity score (NAS) in patients with NAFLD. In addition, some studies that included patients with severe liver fibrosis (liver cirrhosis) found an inverse correlation between SUA level and the degree of fibrosis because of reduced hepatic production of uric acid [24]. Our present results are consistent with previous reports suggesting that SUA is correlated not with liver fibrosis, but with the quantity of fat in the liver or abnormal ALT. The reason for not observing inverse correlation may be that our patients were otherwise generally healthy.
Hyperuricemia and NAFLD have common characteristics that include insulin resistance and oxidative stress [25]. In particular, the quantity of free fatty acids in portal venous blood is considered to drive the development of NAFLD [26]. Uric acid could drive free fatty acid to shunt into the liver and accelerate lipogenesis de novo by upregulating lipogenic enzymes or activating genes involved in lipogenesis through endoplasmic reticulum stress directly or by indirect means such as weight gain and insulin resistance [27,28,29]. Through these mechanisms, hepatic fat accumulation is stimulated by uric acid, and our finding of its high association with quantity of fat supports these explanations.
The present study has several limitations. First, the hepatic steatosis found were evaluated not by criterion standard methods such as magnetic resonance imaging (MRI) or liver biopsy, but by ultrasonography and an estimated fibrosis formula (NFS). If the data from MRI or liver biopsy was used, the results would be considered more reliable. However, routine MRI and liver biopsy measurement for diagnosing fatty liver and liver fibrosis are not possible in general health check-ups due to their high cost and invasiveness. In health check-ups ultrasonography is generally used for diagnosing fatty liver and liver biopsy is recommended to patients with a high fibrosis burden. Nevertheless, further study using data from MRI or liver biopsy will be needed to know clearly the relationship between the degree of fatty liver or fibrosis and SUA. Second, there is a possibility that data about medical and medication history might be inaccurate, because they were completely determined through self-reported questionnaires. Third, dietary information, which is highly related to NAFLD, was not considered. Fourth, the causal relationship between SUA and the main variables such as hepatic steatosis, abnormal liver enzymes, and hepatic fibrosis can not be assessed because of the observational study design. Moreover, the degree of correlation in Pearson correlation analysis was not sufficiently high to conclude clinical importance. Large-scale longitudinal studies using criterion standard methods to evaluate liver fibrosis and include clinical outcomes would be needed to provide causal evidence. The present findings for our Korean patients may not be applicable to other populations with different ancestry.
Nevertheless, a study using a biopsy-proven NAFLD cohort [15] and review article [30] to evaluate the use of noninvasive assessment for NAFLD reported NFS showed not only reasonable diagnostic performance for liver fibrosis (negative predictive value [NPV] = 88%–95% for grade 0, positive predictive value [PPV] = 75%–90% for grade 2), but also good correlation with disease severity, and the American Association for the Study of Liver Diseases (AASLD) recommends using fibrosis formulas, such as NFS or FIB-4 for patients with NAFLD at high risk to evaluate their liver fibrosis burden. Moreover, the present study was focused not on showing the diagnostic performance of SUA level for significant or advanced liver fibrosis, but what variables SUA levels correlates with. When data were reanalyzed using the FIB-4 to compensate for our limitations, similar results were obtained (data not shown). Taken all together, we consider that NFS reflects well the tendency to hepatic fibrosis in our otherwise healthy Korean patients.
The strongest association of SUA levels in generally healthy Korean patients was observed with the presence of NAFLD, and there was no association with the degree of hepatic fibrosis in multivariable logistic regression. We consider that SUA level is more closely associated with the hepatic steatosis than abnormal LFT or hepatic fibrosis.