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Keywords:

  • blood tests;
  • non-alcoholic fatty liver disease;
  • risk factors;
  • physical measurements;
  • predictive factors

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhosis, liver failure, and complicated hepatocellular carcinoma. In addition, NAFLD is a risk factor for the development of other serious diseases, such as diabetes or cardiovascular disease. Therefore, the detection of early-stage NAFLD is important. Many studies have described the factors that predict the presence of NAFLD and its onset, and several markers have been identified. These markers have enabled the identification of high-risk patients and have improved routine medical practice. To prevent advanced disease, clinicians need to have simple markers that predict the onset of NAFLD so that interventions can be started at much earlier stages of disease. This review summarizes the current state of knowledge regarding independent factors, as reported in large studies, that predict the presence of NAFLD and its onset, especially markers that can be used in daily medical practice, such as physical measurements and blood tests.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is a manifestation of metabolic syndrome in the liver.[1, 2] Pathologically, NAFLD represents a wide spectrum of liver conditions from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH may progress to cirrhosis, liver failure, or hepatocellular carcinoma[1-5] and thus requires periodic follow-up. NAFLD is also an independent risk factor for the onset of cardiovascular disease (CVD)[6] and diabetes,[7] making the prevention of NAFLD as important as the management of the condition.

In contrast, NAFLD has not been shown to be associated with an increased risk of death from all causes, CVD, cancer, or liver disease.[8] In large studies, approximately 5% of patients showing evidence of NAFLD are ultimately diagnosed with advanced NASH,[9] which is associated with a mortality rate similar to that of advanced liver fibrosis due to hepatitis C virus infection.[10] Considering the financial burden of the increasing number of individuals with metabolic syndrome, the identification of simple markers that can identify patients with NAFLD or those who might progress to NAFLD is desired. In this regard, this review provides an overview of the independent factors that predict NAFLD onset in individuals who do not have any other known liver disease, as previously reported in large studies.

Body mass index

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A risk factor for the presence of NAFLD

Body mass index (BMI) is a simple marker that reveals an individual's degree of obesity. In Japan, a BMI of 22 is used to indicate the ideal body weight, and obesity-related diseases are associated with higher BMIs.[11] Previously, we reported a community-based, cross-sectional study involving the records of 6370 Japanese subjects, and confirmed that BMI was an independent marker for the presence of NAFLD (men: odds ratio [OR] 1.257; 95% confidence interval [CI] 1.20–1.319; P < 0.001; women: OR 1.291; 95% CI 1.245–1.340; P < 0.001)[12, 13] (Table 1). The BMI cut-off levels for identifying the presence of NAFLD were identified in men and women using the area under the receiver operating characteristic (ROC) curve (AUC) (95% CI). Using these techniques, the AUC (95% CI) (men, 0.809 [0.791–0.825]; women, 0.831 [0.82–0.843]), cut-off level (men, 24.1 kg/m2; women, 22.5 kg/m2), sensitivity (men, 71.6%; women, 77.9%), specificity (men, 76.5%; women, 75.4%), positive predictive value (PPV; men, 66.3%; women, 31.2%), negative predictive value (NPV; men, 80.6%; women, 96%), and diagnostic accuracy (men, 74.6%; women, 75.7%) for predicting NAFLD were identified (Table 1).[13] Eguchi et al. also carried out a large, multicenter, retrospective study examining 5075 subjects who underwent health checkups at three health centers, and identified BMI as a useful marker for determining the presence of NAFLD. They showed that BMI (> 25 kg/m2) was an independent risk factor for NAFLD (men: OR 3.81; 95% CI 3.11–4.67; P < 0.01; women: OR 7.23; 95% CI 5.5–9.5; P < 0.01) by multiple regression analysis, and the prevalence of NAFLD showed a linear increase with increasing BMI (BMI < 23 kg/m2, 10.5%; 23 ≤ BMI < 25 kg/m2, 37.9%; 25 ≤ BMI < 28 kg/m2, 58.4%; BMI ≥ 28 kg/m2, 84.2%)[14] (Table 1).

Table 1. Risk factors predicting the presence of NAFLD
FactorAuthorCountryPopulationOthers (OR, cut-off level)
  1. ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; HbA1c, hemoglobin A1c; HDL-c, high-density lipoprotein-cholesterol; IR, insulin resistance; NAFLD, non-alcoholic fatty liver disease; OR, odds ratio; TG, triglyceride; UA, uric acid.

BMIMiyake et al.[12]Japan6370 (health checkup, community-based)

Men: OR 1.257; 95% CI 1.20–1.319

Women: OR 1.291; 95% CI 1.245–1.340

Cut-off level: 24.1 kg/m2 for men, 22.5 kg/m2 for women

Eguchi et al.[14]Japan5075 (health checkup, in three health centers)

BMI > 25 kg/m2

Men: OR 3.81; 95% CI 3.11–4.67

Women: OR 7.23; 95% CI 5.5–9.5

ALTMiyake et al.[12]Japan6370 (health checkup, community-based)

Men: OR 1.096; 95% CI 1.078–1.114

Women: OR 1.062; 95% CI 1.049–1.076

Cut-off level: 25 IU/L for men, 17 IU/L for women

Total bilirubinKwak et al.[15]Korea17 348 (health checkup, health-care centers)OR 0.88; 95% CI 0.80–0.97
Uric acidLi et al.[16]China8925 (health checkup, company employees)OR 1.291; 95% CI 1.067–1.564
Sirota et al.[17]United States10 732 (non-diabetic adults who participated in the National Health and Nutrition Examination Survey 1988–1994)

Highest quartile versus lowest quartile

OR 1.43; 95% CI 1.16–1.76

Hwang et al.[18]Korea9019 with normal UA levels (health checkup)

Highest quartile versus lowest quartile

Men: OR 1.46; 95% CI 1.17–1.82

Women: OR 2.13; 95% CI 1.42–3.18

Kuo et al.[19]Taiwan54 325 (health checkup, subjects with or without gout received a health-screen at a hospital)

versus lowest quartile without gout

2nd quartile: OR 2.16; 95% CI 1.94–2.41

3rd quartile: OR 3.98; 95% CI 3.55–4.46

Highest quartile: OR 5.99; 95% CI 5.19–6.90

versus lowest quartile without gout

1st quartile with gout: OR 2.61; 95% CI 1.39–4.91

2nd quartile with gout: OR 2.87; 95% CI 2.04–4.04

3rd quartile with gout: OR 4.53; 95% CI 3.70–5.56

Highest quartile with gout: OR 6.31; 95% CI 5.12–7.77

HbA1cMa et al.[20]China949 (retired elderly employees)OR 1.547; 95% CI 1.054–2,27
IRSesti et al.[21]Italy473 (subjects who participated in the Catanzaro metabolic risk factors study)

Highest quartile versus lowest quartile

Liver IR index: OR 5.61; 95% CI 2.23–13.12

Hepatic IR index: OR 2.09; 95% CI 1.27–6.63

White blood cellLee et al.[22]Korea3681 (health checkup, healthy subjects received a medical examination at a hospital)

Men versus lowest quartile

2nd quartile: OR 1.48; 95% CI 1.10–1.98

3rd quartile: OR 1.59; 95% CI 1.18–2.14

Highest quartile: OR 1.84; 95% CI 1.35–2.51

Women versus lowest quartile

2nd quartile: OR 1.15; 95% CI 0.67–1.96

3rd quartile: OR 1.88; 95% CI 1.13–3.11

Highest quartile: OR 2.74; 95% CI 1.68–4.46

IndexMiyake et al.[12]Japan6 370 (health checkup, community-based)

Men: −10.48 + 0.232 × BMI (kg/m2) + 0.064 × ALT (U/L) + 0.004 × TG (mg/dL) − 0.022 × HDL-c (mg/dL) + 0.164 × UA (mg/dL) + 0.439 × HbA1c (%)

Women: −13.815 + 0.256 × BMI (kg/m2) + 0.06 × ALT (U/L) + 0.006 × TG (mg/dL) − 0.016 × HDL-c (mg/dL) + 0.3 × UA (mg/dL) + 0.784 × HbA1c (%)

Cut-off level: 0.871 for men, −1.976 for women.

A predictive factor for the onset of NAFLD

A previous community-based, longitudinal study was conducted to identify those factors that predict the onset of NAFLD. The study enrolled 3215 subjects (882 men and 2333 women) and analyzed the individuals after an observation period of 1208 days.[23] Multivariate analyses confirmed that BMI, at baseline, was the most useful factor for predicting NAFLD onset in both sexes (men: OR 1.223; 95% CI 1.138–1.318; P < 0.001; women: OR 1.331; 95% CI 1.263–1.404; P < 0.001) (Table 2). For men, the BMI cut-off level for NAFLD onset, according to ROC analysis, was estimated to be 23 kg/m2, with an AUC (95% CI) of 0.705 (0.674–0.735) and a sensitivity, specificity, PPV, NPV, and accuracy of 64.4%, 68.3%, 36.4%, 87.2%, and 67.4%, respectively. For women, the BMI cut-off level for NAFLD onset was estimated to be 22.2 kg/m2, with an AUC (95% CI) of 0.749 (0.731–0.767) and a sensitivity, specificity, PPV, NPV, and accuracy of 63.1%, 77.1%, 21.1%, 95.6%, and 75.8%, respectively (Table 2). These cut-off levels were similar to those recommended by the World Health Organization for preventing the development of metabolic disease.[31] Taken together, these results indicate that BMI is a good surrogate marker for identifying the presence and onset of NAFLD.

Table 2. Factors predicting the onset of NAFLD
FactorAuthorCountryPopulationOthers (OR, cutoff level)
  1. ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; GGT, γ-glutamyl transpeptidase; HR, hazard ratio; NAFLD, non-alcoholic fatty liver disease; OR, odds ratio.

BMIMiyake et al.[13]Japan3215 (health checkup, community-based)

Men: OR, 1.223; 95% CI, 1.138–1.318

Women: OR 1.331; 95% CI, 1.263–1.404

Cut-off level: 23 kg/m2 for men, 22.2 kg/m2 for women

ALTChang et al.[24]Korea5237 healthy men without increases in ALT or GGT (health checkup, company employees)HR (95% CI): 1.53 (1.18–1.98), 1.66 (1.29–2.13), 1.62 (1.26–2.08), 2.21 (1.73–2.81) for ALT concentrations of 16–18, 19–21, 22–25, and 26–34 U/L, respectively
Direct bilirubinChang et al.[25]Korea5900 men (health checkup, company employees)

Highest quartile versus lowest quartile

HR, 0.86, 95% CI 0.76–0.98

Uric acidXu et al.[26]China6890 (health checkup, company employees)

versus lowest quintile

2nd quintile: HR 1.18; 95% CI 0.91–1.54

3rd quintile: HR 1.32; 95% CI 1.03–1.70

4th quintile: HR 1.39; 95% CI 1.09–1.78

Highest quintile: HR 1.50; 95% CI 1.18–1.92

Lee et al.[27]Korea4954 (health checkup, healthy subjects participating in a health-screening program)

versus lowest quartile

2nd quartile: OR 1.53; 95% CI 1.09–2.16

3rd quartile: OR 1.69; 95% CI 1.17–2.44

Highest quartile: OR 1.84; 95% CI 1.25–2.71

Metabolic syndromeHamaguchi et al.[28]Japan3147 (health checkup, healthy subject received a medical health checkup in a general hospital

Men: OR 4; 95% CI 2.63–6.08

Women: OR 11.2; 95% CI 4.85–25.87

HemoglobinYu et al.[29]China6944 (health checkup, company employees)

versus lowest quintile

2nd quintile: HR 1.36; 95% CI 1.02–1.81

3rd quintile: HR 1.66; 95% CI 1.23–2.25

4th quintile: HR 1.76; 95% CI 1.28–2.41

Highest quintile: HR 1.83; 95% CI 1.33–2.53

FerritinKim et al.[30]Korea2410 men (health checkup, company employees)

Highest quartile versus lowest quartile

HR 1.33; 95% CI 1.02–1.75

Liver enzymes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A risk factor for the presence of NAFLD

Liver enzymes have long been regarded as reliable and sensitive markers of liver disease. Several large studies have proposed cut-off values, or normal ranges, for transaminases and γ-glutamyl transpeptidase (GGT) for liver disease. Alanine aminotransferase (ALT) is one of the most popular markers used to screen for liver disease. In one of the earlier-mentioned studies involving Japanese subjects (n = 6370), ALT levels were shown to be independent predictors of NAFLD in multivariate analysis (men: OR 1.096; 95% CI 1.078–1.114; P < 0.001; women: OR 1.062; 95% CI 1.049–1.076; P < 0.001) (Table 1).[12] The ROC analysis-derived cut-off level of ALT required to diagnose NAFLD was estimated to be 25 U/L for men and 17 U/L for women. The OR of 1.096 in men means that the risk of having NAFLD is 1.096 times higher with a 1-U/L increase in ALT levels. Therefore, this risk is 1.58, 2.50, 3.96, 6.25, and 9.89 times higher in men with ALT levels of 30, 35, 40, 45, and 50 U/L, respectively, than in those with ALT levels of 25 U/L. These results showed that lower ALT cut-off values were associated with the prevention of the progression of several diseases associated with NAFLD.

Other reports have also proposed a revision of the ALT cut-off level that defines a healthy range of values for this enzyme.[32-34] Prati et al. previously conducted a study among 3927 European hospital-based blood donors and proposed that the normal, upper (95th percentile) limits for serum ALT levels should be 30 U/L for men and 19 U/L for women.[32] Lee et al. studied 1105 hospital-based Asian individuals who were proven to have normal liver biopsies, prior to liver donation, and proposed that the serum ALT thresholds at the 97.5th percentile should be 35 U/L for men and 26 U/L for women (29 U/L in men and 22 U/L in women at the 95th percentile).[33] Whereas these studies investigated special populations, Kim et al. carried out a population-based study in Korea that enrolled approximately 4 600 000 government and private school employees and their dependents; the etiologies of the liver diseases in this study were unknown. The study's primary end-point was mortality, and it showed that the best cut-off values for identifying men at risk of death from liver disease were 31 IU/L for aspartate aminotransferase (AST) and 30 IU/L for ALT in men, but it failed to identify the cut-off value for women.[34]

A predictive factor for the onset of NAFLD

Chang et al. studied the onset of NAFLD by enrolling 5237 healthy Korean men who had either ALT or GGT levels below the upper reference range.[24] They reported that the hazard ratios (HRs) (95% CI) were 1.53 (1.18–1.98), 1.66 (1.29–2.13), 1.62 (1.26–2.08), and 2.21 (1.73–2.81) for ALT concentrations of 16–18, 19–21, 22–25, and 26–34 U/L, respectively, compared with an ALT concentration of < 16 U/L, after adjusting for age, weight change, BMI, blood glucose level, blood pressure (BP), triglyceride (TG) level, high-density lipoprotein-cholesterol (HDL-c) level, smoking, alcohol consumption, regular exercise, homeostasis model assessment of insulin resistance (HOMA-IR), C-reactive protein (CRP) level, and incident diabetes (Table 2). They showed that an increased serum ALT concentration, even if it was below the normal upper limit, was an independent predictor of NAFLD. Linear increases in ALT levels were shown to be associated with the presence and onset of NAFLD. Increased ALT levels are one of the most popular markers for the diagnosis of NAFLD in clinical practice. Thus, clinicians should be more aware of this evidence.

Bilirubin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A risk factor for the presence of NAFLD

Bilirubin is a product of heme catabolism that may have potent antioxidant and cytoprotective properties.[35, 36] Some studies have shown that higher bilirubin levels are inversely associated with HOMA-IR and insulin levels,[37] and with the prevalence of CVD[38, 39] and diabetes.[40] In this regard, Kwak et al. conducted a hospital-based retrospective study of 17 348 Korean people undergoing health checkups to examine the relationship between total bilirubin levels and NAFLD.[15] They conducted a multivariate regression analysis, adjusted for age, gender, BMI, waist circumference (WC), smoking, total cholesterol (TC) level, hypertension, and diabetes, and showed that the total bilirubin level was inversely associated with the prevalence of NAFLD (OR 0.88; 95% CI 0.80–0.97). Furthermore, they found an inverse, dose-dependent association between NAFLD and total bilirubin levels (OR 0.83, 95% CI 0.75–0.93 in the third quartile and OR 0.80, 95% CI 0.71–0.90 in the fourth quartile versus the lowest quartile; the P-value for this trend was < 0.001) (Table 1).

A predictive factor for the onset of NAFLD

In terms of the prospective association between serum bilirubin concentrations (total, direct, and indirect) and the risk of NAFLD onset, a cohort study was conducted among 5900 Korean men, without evidence of liver disease or major risk factors for liver disease.[25] The study demonstrated that increasing serum levels of direct bilirubin, at baseline, were progressively associated with a decreasing incidence of NAFLD during 28 100 person-years of follow-up, and this association persisted after adjusting for age, BMI, current smoking status, alcohol intake, exercise, diabetes mellitus, history of CVD, history of malignancy, HDL-c level, TG level, glucose level, insulin level, and uric acid (UA) level (HR, comparing the highest to the lowest quartiles, 0.86; 95% CI 0.76–0.98; P value for the trend = 0.039) (Table 2). This study clearly indicated that higher serum levels of direct bilirubin are significantly associated with a lower risk of developing NAFLD. Nevertheless, application of these results to the general population of either sex remains controversial because NASH was associated with a significantly decreased prevalence of unconjugated hyperbilirubinemia,[41] and this Korean study was limited to men.

UA

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A risk factor for the presence of NAFLD

UA is the final oxidation product of purine catabolism, and hyperuricemia is considered a metabolic disease; many studies have also reported a relationship between hyperuricemia and NAFLD. Li et al. examined the relationship between UA levels and NAFLD in a cross-sectional study among 8925 company employees (6008 men) and showed that hyperuricemia, as well as male gender, age, BMI, WC, GGT level, TG level, HDL-c level, low-density lipoprotein-cholesterol level, and fasting plasma glucose (FPG), was an independent risk factor for NAFLD (OR 1.291; 95% CI 1.067–1.567; P < 0.001) in multiple regression analysis (Table 1).[16] Sirota et al. conducted a cross-sectional analysis of 10 732 non-diabetic adults who participated in the National Health and Nutrition Examination Survey 1988–1994 in the United States.[17] They defined sex-specific UA quartiles (≤ 5.2, 5.3–6.0, 6.1–6.9, and > 6.9 mg/dL for men and ≤ 3.7, 3.8–4.5, 4.6–5.3, and > 5.3 mg/dL for women) and revealed that the OR for the highest quartile was 1.43 (95% CI 1.16–1.76, P < 0.001) compared with the lowest quartile after adjusting for demographic data, hypertension, WC, TG level, HDL-c level, HOMA-IR, estimated glomerular filtration rate (eGFR), and AST level (Table 1). In addition, Hwang et al. studied 9019 Korean individuals who visited a health checkup center and had UA levels within the normal range. These patients were categorized into four groups according to UA quartiles for both sexes, and the relationship between the UA level and the presence of NAFLD was examined.[18] After adjusting for age, smoking status, regular exercise, BMI, BP, FPG, TC level, TG level, HDL-c level, AST level, ALT level, and GGT level, the adjusted ORs (95% CIs) for the presence of NAFLD in the subjects with the highest UA level was 1.46 (1.17–1.82) for men and 2.13 (1.42–3.18) for women as compared with the subjects with the lowest UA level (Table 1). These authors suggested that increased UA concentrations, even those within the normal range, were independently associated with the presence of NAFLD.

Another study, which was hospital-based, enrolled 54 325 Taiwanese subjects who underwent a health-screening program, and these individuals were classified into eight groups according to their UA level and gout status (≤ 4.9, 5.0–6.9, 7.0–8.9, and ≥ 9.0 mg/dL, with and without gout) to examine the association between gout and NAFLD.[19] The prevalence of NAFLD was significantly higher in subjects with gout (23.1%, n = 445) than in those without gout (10.9%, n = 5724, P < 0.001). Gout remained associated with an increased risk for NAFLD (OR 1.42; 95% CI 1.25–1.60; P < 0.001) after adjusting for age, gender, presence of metabolic syndrome, and low eGFR. The results showed an independent association between gout and the risk of NAFLD and a dose–response relationship between UA levels and the presence of NAFLD in subjects with and without gout, with UA ≤ 4.9 mg/dL in the absence of gout as a reference: OR (95% CI) 2.16 (1.94–2.41)–5.99 (5.19–6.90) without gout and 2.61 (1.39–4.91)–6.31 (5.12–7.77) with gout (Table 1).

A predictive factor for the onset of NAFLD

An investigation was conducted to examine whether elevated levels of serum UA play a causal role in NAFLD. This investigation was a population-based prospective study among the employees of a Chinese company.[26] The study investigators followed a total of 6890 initially NAFLD-free subjects for 3 years and showed that UA levels were independently and positively associated with a risk for the onset of NAFLD through the use of Cox proportional hazards regression analyses; the age-, gender-, and metabolic syndrome-adjusted HR (95% CI) for the subjects in quintiles 2, 3, 4, and 5 versus quintile 1 were 1.18 (0.91–1.54), 1.32 (1.03–1.70), 1.39 (1.09–1.78), and 1.50 (1.18–1.92), respectively (Table 2). Another study examined the incidence of NAFLD in 4954 apparently healthy subjects who participated in a health-screening program. The incidence of NAFLD over a 5-year period was assessed according to the individuals' baseline UA levels, categorized into quartiles.[27] Multiple logistic regression analysis showed that hyperuricemia was associated with the development of NAFLD. When compared with subjects in quartile 1, the ORs for the incidence of NAFLD in subjects in quartiles 2, 3, and 4 were 1.53 (95% CI 1.09–2.16; P = 0.014), 1.69 (95% CI 1.17–2.44; P = 0.005), and 1.84 (95% CI 1.25–2.71; P = 0.002), respectively (Table 2). On the basis of the findings from many of these large studies, more attention should be paid to UA levels than was previously appreciated. Further studies examining the mechanism of this association are desired.

Metabolic syndrome

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A predictive factor for the onset of NAFLD

Subjects with metabolic syndrome often develop NAFLD, and this has led to an examination into the influence of metabolic syndrome on the onset of NAFLD. A prospective, observational study involving 3147 healthy Japanese men and women who underwent a medical health checkup at a general hospital was conducted to evaluate the association between metabolic syndrome and the incidence of NAFLD.[28] In the multivariate model, adjusted for age, light drinking, and weight gain, the presence of metabolic syndrome at baseline was independently associated with the onset of NAFLD during the follow-up period of 414 ± 128 days (men: OR 4.0; 95% CI 2.63–6.08; P < 0.001; women: OR 11.2; 95% CI 4.85–25.87; P < 0.001) (Table 2). Moreover, several studies have examined metabolic factors such as TG, FPG, and hemoglobin A1c (HbA1c) levels and their relationship with NAFLD. Chen et al. also conducted a cross-sectional, community-based study in Taiwan to determine the risk factors for NAFLD.[42] Their multivariate logistic regression analyses of a general population of 2520 showed that the risk factors for the presence of NAFLD included metabolic factors, such as obesity (OR 7.21; 95% CI 5.29–9.84), FPG ≥ 126 mg/dL (OR 2.08; 95% CI 1.41–3.05), TC level ≥ 240 mg/dL (OR 1.50; 95% CI 1.06–2.13), TG level ≥ 150 mg/dL (OR 1.76; 95% CI 1.32–2.35), and hyperuricemia (OR 1.53; 95% CI 1.16–2.01), as well as male gender (OR 1.44; 95% CI 1.09–1.90), elevated ALT level (OR 5.66; 95% CI 3.99–8.01), and age ≥ 65 years (OR 0.53; 95% CI 0.36–0.77).

Ma et al. examined the relationship between HbA1c and NAFLD among 949 elderly, retired employees undergoing health checkups.[20] Their cross-sectional study confirmed that HbA1c, as well as age, gender, BMI, WC, GGT, TG, HDL-c, FPG, and UA, was an independent marker for the presence of NAFLD (OR 1.547; 95% CI 1.054–2,27) (Table 1). With regard to the onset of NAFLD, a cohort of 2589 Korean workers without fatty livers, as noted during a baseline abdominal ultrasound examination, were observed for 4.4 years to identify factors associated with incident NAFLD.[43] The obtained data were analyzed by multivariate logistic regression, which revealed that an increase in the TG level (per mmol/L increase) (OR 1.378; 95% CI 1.179–1.611; P < 0.0001), glucose level (per mmol/L increase) (OR 1.215; 95% CI 1.042–1.416; P = 0.013), and WC (per cm increase) (OR 1.078; 95% CI 1.057–1.099; P < 0.001), in addition to an increase in the ALT levels (per IU/L increase) (OR 1.009; 95% CI 1.002–1.017; P = 0.016) and platelet counts (per 1 × 109/L increase) (OR 1.004; 95% CI 1.001–1.006; P = 0.001), were variables that were independently associated with incident NAFLD.

Insulin resistance

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A risk factor for the presence of NAFLD

NAFLD, a component of metabolic syndrome, was reported to be associated with insulin resistance (IR), as well as other metabolic diseases such as diabetes and dyslipidemia.[2] Peripheral IR increases lipolysis in adipose tissue and the delivery of free fatty acids to the liver, thereby predisposing the liver to the development of fatty disease. Hepatic IR is also tightly linked to NAFLD. Hepatic IR enhances lipogenesis and eventually results in increased synthesis of fatty acids and TGs.[44] Therefore, IR is thought to be a core component of NAFLD.[2] However, there were few reports, with more than 1000 subjects, on IR as a risk factor for the presence of or a predictive factor for the onset of NAFLD. Although involving a comparatively small number of subjects, Sesti et al.[21] conducted a cross-sectional study among 473 subjects, who participated in a study on metabolic risk factors, to examine the relationship between IR and NAFLD (Table 1). The subjects were divided into quartiles according to the three hepatic IR indexes (HOMA index: fasting insulin [mU/mL] × fasting glucose [mg/dL] / 405; hepatic IR index: glucose0–30 AUC × insulin0–30; and liver IR index: −0.091 + [log insulin AUC 0–120 min × 0.400] + [log fat mass% × 0.346] − [log HDL cholesterol × 0.408] + [log BMI × 0.435]). In a logistic regression model, adjusted for age and gender, subjects in the highest quartile of the liver IR index had a 9.85-fold higher risk of having NAFLD than those in the lowest quartile (OR 9.85; 95% CI 5.33–18.20). Subjects in the highest quartile of the HOMA index had a 5.12-fold higher risk of having NAFLD than those in the lowest quartile (OR 5.12; 95% CI 2.19–9.31). Further, subjects in the highest quartile of the glucose0–30 (AUC) × insulin0–30 (AUC) index had a 3.99-fold higher risk of having NAFLD than those in the lowest quartile (OR 3.99; 95% CI 2.30–6.92). After additional adjustment for a wide range of potential confounders, including WC, ALT level, AST level, GGT level, alkaline phosphatase level, high-sensitivity CRP level, insulin-like growth factor 1 level, and glucose tolerance status, subjects in both the highest quartile of the liver IR index and in the highest quartile of the hepatic IR index continued to have an increased risk of NAFLD as compared with those in the lowest quartile (OR 5.61, 95% CI 2.23–13.12 and OR 2.09, 95% CI 1.27–6.63, respectively), although the HOMA index was associated with a non-significant risk.

White blood cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A risk factor for the presence of NAFLD

White blood cell (WBC) count is a simple clinical marker of inflammation. Recently, elevated WBC levels have become useful predictors of CVD, diabetes, and metabolic syndrome.[22, 45] A cross-sectional study was conducted on 3681 healthy subjects (2066 men and 1615 women) undergoing medical checkups to determine the relationship between WBC counts and the presence of NAFLD.[46] After adjusting for age, smoking status, regular exercise, BMI, BP, FPG, TG, and HDL-c, multivariate logistic regression analysis showed that the ORs (95% CI) for NAFLD, according to WBC quartiles, were 1.00, 1.48 (1.10–1.98), 1.59 (1.18–2.14), and 1.84 (1.35–2.51) for men and 1.00, 1.15 (0.67–1.96), 1.88 (1.13–3.11), and 2.74 (1.68–4.46) for women (Table 1). These results show that WBC counts were independently associated with the presence of NAFLD regardless of the presence of classical cardiovascular risk factors or other components of metabolic syndrome.

Hemoglobin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A predictive factor for the onset of NAFLD

Proteomic methods were used to analyze 70 serum samples to identify potential new biomarkers for NAFLD.[29] The results suggested that serum hemoglobin was a biomarker, and this observation led to a prospective study to evaluate the predictive value of hemoglobin for NAFLD. The prospective study enrolled 6944 subjects who were followed up for 3 years[29] and showed that a higher baseline hemoglobin level was associated with a higher incidence of NAFLD. Cox proportional hazards regression analyses showed that the age-, gender-, and BMI-adjusted HRs (95% CI) for subjects with baseline hemoglobin levels in quintiles 2, 3, 4, and 5 versus quintile 1 were 1.36 (1.02–1.81), 1.66 (1.23–2.25), 1.76 (1.28–2.41), and 1.83 (1.33–2.53), respectively (Table 2). This study indicated that serum hemoglobin levels may be significant predictive factors for NAFLD.

Ferritin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A predictive factor for the onset of NAFLD

Hyperferritinemia is associated with mild iron deposition in the liver and is commonly observed in NAFLD patients.[47] Kim et al. conducted a study on 2410 healthy male Korean workers to examine whether serum ferritin levels predict incidental NAFLD.[30] They showed that the HR (95% CI) for incidental NAFLD, comparing the highest quartile of serum ferritin levels with the lowest quartile, was 1.33 (1.02–1.75) after adjusting for age, BMI, smoking, alcohol intake, exercise, HDL-c level, TG level, glucose level, systolic BP, HOMA-IR, UA level, and CRP level during 7500 person-years of follow-up (Table 2). In this study, serum ferritin levels were identified as independent predictors of incident NAFLD.

Index and score

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

A risk factor for the presence of NAFLD

To improve the diagnostic accuracy of NAFLD, a NAFLD index was created as part of a community-based study (Table 1).[12] Evaluation of this index showed a high sensitivity, specificity, NPV, and diagnostic accuracy for both genders, as well as a high PPV for men, compared with evaluation of ALT levels alone. Previously, screening for fatty liver disease, including for NAFLD, using standard laboratory tests and anthropometric parameters among a large population of individuals had also been reported.[48, 49] One of these reports, involving Italian subjects, showed that the fatty liver index (FLI) can rule out fatty liver if the FLI is < 30 and can detect fatty liver if the FLI is ≥ 60.[48] However, the FLI showed inconsistent results in an Asian population because the BMIs and WCs were substantially lower than those for Caucasians,[49] and this index could not classify subjects with 30 ≤ FLI < 60. Another group proposed a hepatic steatosis index (HSI) for a Korean population. This index could rule out fatty liver if the HSI was < 30 and could detect fatty liver if the HSI was > 36.[49] However, this index was also unable to distinguish subjects with fatty liver from those with non-fatty liver when 30 ≤ HSI ≤ 36. Thus, although useful in some specific contexts, these complicated indexes are not broadly applicable and are therefore not useful as a general clinical tool.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

To prevent the progression of NAFLD and its associated complications, many researchers have tried to diagnose NAFLD at an early stage and to predict the onset of NAFLD. In these attempts, several variables and risk factors have been identified. Many studies, mainly from Asian countries, have shown that metabolic factors associated with NAFLD and factors affecting the metabolism of glucose and lipids are good surrogate markers. BMI, in particular, may be an ideal marker for predicting the presence and/or onset of NAFLD because the measurement of BMI does not require any specific tests and involves only the use of physical measurements. NAFLD is the most common form of chronic liver disease worldwide and its prevalence is expected to continue to increase in the future. Thus, these types of simple markers may help identify NAFLD at an early stage.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References

This work was supported in part by a grant-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (KAKENHI no. 23700907), and a research grant from Ehime University.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Body mass index
  5. Liver enzymes
  6. Bilirubin
  7. UA
  8. Metabolic syndrome
  9. Insulin resistance
  10. White blood cells
  11. Hemoglobin
  12. Ferritin
  13. Index and score
  14. Conclusion
  15. Acknowledgments
  16. References
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