Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in western countries [1, 2]. The prevalence of NAFLD is increasing and varies significantly with ethnicity; from 24% in black and 33% in white, to 45% in Hispanic people [3]. An increasing prevalence of NAFLD is associated with the increasing incidence of obesity and in 2007, about a third of the population in the United States of America aged from 40 to 79 years was obese [2, 4]. The mortality rate of patients with NAFLD in the community was found to be higher than that in the general population in the United States [5]. During an average 8.4 years of follow up of patients with NAFLD, death occurred in about 10%. Cardiovascular disease and coronary heart disease (CHD) were the most common cause of death, followed by malignancy, and liver related causes [6]. The survival outcome of patients with nonalcoholic steatohepatitis (NASH) was reduced significantly and they more often died from CHD (
Patients with NASH showed progression of fibrosis in about 5%-32% during a 4.3-to-6 year follow-up period [9,10,11]. Several simple noninvasive scoring systems for assessment of liver fibrosis have been proposed for use in general clinical practice. NAFLD Fibrosis Score (NFS), which is a composite score of age, hyperglycemia, body mass index, platelet count, albumin, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio [12]. These factors were found to be independent indicators of separating NAFLD patients with and without advanced fibrosis at the initial diagnosis of NAFLD. The BARD score is a simple clinical score based on
The study was approved by the Institutional Review Board (IRB) of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (IRB Nos. 248/50 and 249/54).
All patients included provided their written informed consent to participate in the present study. We prospectively included 139 consecutive patients with liver biopsy-proven NAFLD patients in King Chulalongkorn Memorial Hospital (KCMH) from January 2009 to October 2012. The inclusion criteria included patients at least 18 years old with NAFLD was diagnosed by liver biopsy with standard criteria. Exclusion criteria were incomplete data needed for the 4 noninvasive scoring system calculations. Patients who met the inclusion criteria were admitted for liver biopsy using standard procedures with ultrasonography guidance. Data of all patients were recorded, including demographic data, anthropometric data and biochemical tests on the day of liver biopsy or within 2 weeks of the procedure. All patients were followed-up with the results of liver histological findings within the following 2 weeks. We used the histological findings of liver fibrosis as the criterion standard or index diagnosis.
The diagnosis of NAFLD was based on the following criteria: (1) liver biopsy showing steatosis in at least 5% of hepatocytes, or (2) fatty infiltration of the liver confirmed on imaging studies (ultrasound, computed tomography, or magnetic resonance imaging), and (3) exclusion of liver disease from other etiologies including alcohol-induced (history of excessive alcohol consumption defined as >20 gm/ day), drug-induced liver disease, autoimmune or viral hepatitis, and cholestatic or metabolic/genetic liver disease [17]. The staging of liver inflammation and fibrosis in patients with NAFLD was based on that proposed by Kleiner et al. [18]. The presence of metabolic syndrome (Mets) was defined by using the 2001 National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) criteria and the new definition, which required the presence of at least 3 of the 5 features [19], BMI was calculated as weight divided by height squared (kg/m2). Because waist circumference (WC) measurements were not taken from the majority of patients, we defined obesity using BMI >30 kg/m2 in accordance with the World Health Organization (WHO) definition of insulin resistance syndrome [20, 21]. The histological liver fibrosis stages 1–2 (F1–F2) were classified as “mild liver fibrosis” and those with histological fibrosis stages 3–4 (F3–F4) were classified as “advanced liver fibrosis” according to standard criteria [18]. Baseline NAFLD Fibrosis Scores, BARD, and FIB-4 calculations were used to distinguish NAFLD patients with and without advanced liver fibrosis, for which the cutoff NFS at >–1.455 (web-based calculation;
Thai NAFLD patients were categorized by the severity or staging of liver fibrosis into 2 groups of the mild and advanced liver fibrosis based on histological diagnosis. Continuous outcomes are presented as mean (standard deviation, SD) and categorical data are presented as numbers (percentage). Differences between groups were tested by independent
The analyses in this study were performed using SPSS for Windows (version 15.0.1.1; SPSS Inc, Chicago, IL, USA).
We included 139 Thai patients with liver biopsy-proven NAFLD with mean age of 40.95 (13.3) years, and 47% were male. There were 75 (54%) patients with impaired fasting glucose or diabetes mellitus and 73% of Thai NAFLD patients had a BMI >28 kg/m2. Baseline characteristics are shown in Table 1.
Baseline characteristics of 139 Thai patients with nonalcoholic fatty liver disease Student median Student median Mann-Whitney median Student Mann-Whitney Mann-Whitney Mann-Whitney Mann-Whitney Mann-Whitney Mann-Whitney Student Student Student Student Student Variable Total (n=139) No/mild fibrosis Advanced fibrosis (F0-F2)(n=139) Advanced fibrosis (F3-F4)(n=9) P Age (years) 40.9 (13.3) 40.3 (13.0) 48.8 (15.5) 0.07 Male sex (%) 65 (47%) 61 (47%) 4 (44%) 1.00t BMI (kg/m2) 36.1 (14.7) 40.6 (14.8) 29.4 (8.6) 0.01 BMI >28 (kg/m2) 102 (73%) 97 (75%) 5 (56%) 0.23t Diabetes mellitus (DM) 53 (38%) 47 (36%) 6 (67%) 0.08t IFG/DM 75 (54%) 67 (52%) 8 (89%) 0.04t AST (IU/L) 38.0 (39.4) 38.0 (34.6) 39 (81.2) 0.24 ALT (IU/L) 56.0 (47.2) 56.0 (47.7) 59.0 (40.7) 0.29* Albumin (g/L) 4.4 (0.4) 4.4 (0.4) 4.4 (0.3) 0.84 Platelet (×109/L) 267 (64.2) 270 (64.3) 222 (43.7) 0.02 Total cholesterol (mg/dL) 198 (46.6) 197 (45.5) 214 (60.8) 0.44 Triglyceride (mg/dL) 146 (60.8) 145 (60.9) 164 (59.6) 0.31 HDL (mg/dL) 45.6 (12.1) 45.5 (12.4) 46.8 (8.1) 0.53 LDL (mg/dL) 125 (42.1) 125 (41.1) 135 (56.2) 0.61 FPG (mg/dL) 112 (33.2) 109 (30.9) 142 (49.2) 0.01 HbA1C (%) 7.38 (8.7) 7.36 (9.0) 7.59 (1.7) 0.08 AST/ALT ratio 0.78 (0.37) 0.78 (0.38) 0.85 (0.38) 0.59 BARD score 0.48 0 10 (7%) 10 (8%) 0 (0) 1 45 (32%) 43 (33%) 2 (22%) 2 41 (30%) 37 (29%) 4 (44%) 3 26 (19%) 24 (19%) 2 (22%) 4 17 (12%) 16 (12%) 1 (11%) FIB-4 score 0.98 (0.79) 0.91 (0.61) 1.9 (1.9) 0.17 NAFLD Fibrosis Score -1.37 (1.70) -1.418 (1.748) -0.772 (0.668) 0.03
Advanced fibrosis (F3–F4) was found histologically in 9 patients (6%). Using the baseline AST/ALT ratio with a cutoff >0.8, NFS with a cutoff ≥–1.455, BARD with a cutoff ≥2, and FIB-4 calculation with a cutoff >1.3, the prevalence of patients with a high risk of advanced liver fibrosis were 36%, 54.5%, 61.2%, and 19.1%, respectively.
The sensitivity, specificity, positive-predictive values (PPV), and negative-predictive values (NPV) of the 4 noninvasive scoring systems were calculated. NFS with a cutoff ≥ –1.455 was found to be the best scoring system with highest sensitivity for identifying patients with advanced fibrosis, followed by BARD score ≥2, FIB-4 >1.45, and AST/ALT ratio >0.8, respectively (Table 2).
Comparison of the 4 noninvasive scoring systems for the diagnosis of advanced fibrosis in 139 Thai patients with nonalcoholic fatty liver diseaseNon-invasive scoring system Cutoff ≥ Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy Patients avoiding liver biopsy False negative result AST/ALT 0.8 44.4 64.6 8.0 94.4 63 89 (64%) 5 (4%) BARD score 2.0 77.8 40.0 8.2 96.3 42 54 (39%) 2 (1%) FIB-4 score 1.3 55.6 83.5 19.2 96.4 79 110 (81%) 4 (3%) NAFLD –1.455 88.9 48.0 11.0 98.4 48 61 (46%) 1 (1%) Fibrosis Score
Patients with advanced fibrosis were significantly older and had higher blood glucose level than those with mild liver fibrosis. Using the area under the ROC curve of four noninvasive scoring systems at baseline, FIB–4 and NFS showed the highest AUROC in Thai NAFLD patients for predicting the advance liver fibrosis (Figure 1). By using these 4 noninvasive scoring systems, liver biopsy could potentially be avoided in at least 38% of patients with BARD score, 45% with NFS, 64% with AST/ALT ratio, and 80% with FIB–4.
We demonstrate that the NAFLD Fibrosis Score (NFS) with a cutoff ≥ –1.455 is the best scoring system with the highest sensitivity for identifying Thai patients with advanced fibrosis and a low PPV of 21%, whereas NFS <1.5 had high NPV of 91%, and can be used to exclude Thai patients with NAFLD and advanced fibrosis. The low prevalence (6%) of advanced liver fibrosis in Thai patients with NAFLD is critically associated with the drop-off in diagnostic ability of these 4 noninvasive scoring systems. The prevalence of advanced fibrosis in other studies of patients with Asian ethnicity ranged from 4% to 11% in China [22, 23], and together with 6% found in Thais in the present study was lower than that reported in studies conducted in western countries, which ranged from 23% to 27% as shown in
Comparison of the diagnostic ability of the 4 noninvasive scoring systems for advanced fibrosis between 2 studiesShah et al. [16] Present study Baseline characteristics Impaired fasting glucose or DM 19.4% 54% Body mass index (mean; kg/m2) 34 (6.3) 36 (14.7) %F3-F4 54% 6% AST/ALT 0.74 0.57 BARD score 0.70 0.58 FIB-4 score 0.80 0.74 NAFLD Fibrosis Score 0.77 0.66
However, we can use the NFS or FIB-4 for excluding the advanced liver fibrosis because of its high AUROC (0.66–0.74) and high NPV of 96.4%–98.4%. This can reduce unnecessary liver biopsy in 67% of patients. With the limited sensitivity, specificity, and accuracy of these 4 scoring system for Thai patients with NAFLD, additional testing, for example, serum cytokeratin-18 fragments, liver stiffness measurement, or other biomarkers [24] may be used to add to the diagnostic yield for liver fibrosis assessment in these patients.
Our study has some limitations. First, we were only able to include a relatively small number of patients with NAFLD and advanced liver fibrosis (6%) within the time available for this prospective cohort study, which may affect the diagnostic ability. Second, we had limited information of long-term follow up and the serial liver biopsy, which may add new information on the natural history of liver histology and the change in scoring systems during the follow up period.
Liver fibrosis in patients with NAFLD progresses slowly over time, and the changes of aminotransferase did not parallel changes in fibrosis stage [25]. This information was supported by a study of the natural history of histological changes, which was performed in 103 of the patients with NAFLD who had no effective treatment with mean interval between serial liver biopsies of 3.2 years (range 0.7–21.3) [25]. Fibrosis stage progressed in 37%, remained stable in 34%, and regressed in 29% [25]. The rate of fibrosis change ranged from –2.1 to 1.7 stages per year. Diabetes (
Advanced fibrosis was prevalent in 6% of our Thai patients with NAFLD. NFS had the highest negative predictive value for excluding patients with advanced fibrosis. At least 38% of patients with NAFLD could avoid liver biopsy by using the BARD scoring system.