A New Marker for Steatohepatitis and Fibrosis in NAFLD
A New Marker for Steatohepatitis and Fibrosis in NAFLD
The main clinical and laboratory data of our patient population are summarized in Table 1. The mean patient age was (49.5 ± 10.8 years) and the mean BMI was 31.4 kg/m ± 4.9. Fifty-two per cent of patients were men and 87% were Caucasian. Features of the metabolic syndrome were commonly present. Twenty-seven per cent of the patients had clinical diabetes, 39% had hypertension and 50% had dyslipidemia. Sixty-four per cent of patients in this study never smoked, 30% were ex-smokers (defined as giving up smoking more than 1 year prior to the biopsy date) and only 6% were current smokers. The mean white cell count was 7.1 × 10/L ± 2.1 with a mean neutrophil count of 4.1 × 10/L ± 1.4 and a mean lymphocyte count of 2.2 × 10/L ± 0.9.
Histological features of liver biopsy are summarized in Table 2. Fifty patients (49.5%) were diagnosed with NASH according to Brunt's criteria, and 51 patients (50.5%) were included in the 'not NASH' group (simple steatosis and normal biopsy). Moderate to severe inflammation was present in 34% of patients, ballooning was identified in 55% and 48% had some degree of liver fibrosis on biopsy. Five patients (5%) had cirrhosis (stage 4, fibrosis). Interface hepatitis or other features suggestive of autoimmune hepatitis were not present in any of the cases.
The median N/L ratio in patients with NASH was 2.5 (Q25–Q75 = 1.9, 3.3), which was significantly higher than the N/L ratio in patients without NASH [1.6 (Q25-Q75 = 1.2, 2.0)] (P < 0.001)] (Fig. 1). The same observation was noted for patients with advanced fibrosis (stage 3–4) compared with patients with mild-to-moderate fibrosis (stage 1–2) [N/L ratio of 2.9 (2.0, 3.9) vs. 1.8 (1.2, 2.2) respectively] (P < 0.001) (Fig. 1). The ROC analysis suggested that a cut-off value of 1.9 has the highest sensitivity (72%) and specificity (70%) for detecting patients with NASH (Fig. 2) with an area under the curve (AUC) of 0.77 (95% confidence interval: 0.68–0.87). The AUC for N/L was found to be higher than the AUCs of both serum AST (0.69, 95% confidence interval 0.56–0.81) and alanine aminotransferase (ALT; 0.56, confidence interval 0.43–0.70). The positive predictive value (PPV) for this cut-off was 69% and the negative predictive value (NPV) was 71%. Similarly, a cut-off value of 2.3 for N/L ratio gave a sensitivity of 73% and a specificity of 77% for detecting the presence of fibrosis (Fig. 3). The PPV and NPV were 47% and 91% respectively.
(Enlarge Image)
Figure 1.
Neutrophil to lymphocyte (N/L) ratio in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis. The box represents the interquartile range (25th and 75th percentiles) from the median (the horizontal line), the bars represent the 95% confidence interval.
(Enlarge Image)
Figure 2.
ROC curve of neutrophil to lymphocyte (N/L) ratio for the identification of patients with nonalcoholic steatohepatitis (NASH). A cut-off value of 1.9 had the highest sensitivity and specificity to identify patients with NASH.
(Enlarge Image)
Figure 3.
ROC curve of neutrophil to lymphocyte (N/L) ratio for the identification of patients with fibrosis. A cut-off value of 2.3 had the highest sensitivity and specificity to identify patients with nonalcoholic steatohepatitis.
In a univariable analysis, high N/L ratio was significantly associated with necroinflammatory activity, steatosis, ballooning and high NAS and fibrosis scores (P < 0.001) ( Table 3 ). These results suggest that N/L ratio may increase with disease progression with the highest values found in patients with NASH and advanced fibrosis.
After adjusting for multiple confounders including age, gender, race, BMI, ALT, smoking status and the presence of diabetes, the association between N/L ratio and inflammation, fibrosis and the presence of NASH remained statistically significant (P < 0.05) in the multivariable analysis ( Table 4 ). For each one-unit increase in N/L ratio, the likelihood of having NASH increases by 70% and the likelihood of having fibrosis increases by 50%.
Results
Patient Characteristics and Liver Histology
The main clinical and laboratory data of our patient population are summarized in Table 1. The mean patient age was (49.5 ± 10.8 years) and the mean BMI was 31.4 kg/m ± 4.9. Fifty-two per cent of patients were men and 87% were Caucasian. Features of the metabolic syndrome were commonly present. Twenty-seven per cent of the patients had clinical diabetes, 39% had hypertension and 50% had dyslipidemia. Sixty-four per cent of patients in this study never smoked, 30% were ex-smokers (defined as giving up smoking more than 1 year prior to the biopsy date) and only 6% were current smokers. The mean white cell count was 7.1 × 10/L ± 2.1 with a mean neutrophil count of 4.1 × 10/L ± 1.4 and a mean lymphocyte count of 2.2 × 10/L ± 0.9.
Histological features of liver biopsy are summarized in Table 2. Fifty patients (49.5%) were diagnosed with NASH according to Brunt's criteria, and 51 patients (50.5%) were included in the 'not NASH' group (simple steatosis and normal biopsy). Moderate to severe inflammation was present in 34% of patients, ballooning was identified in 55% and 48% had some degree of liver fibrosis on biopsy. Five patients (5%) had cirrhosis (stage 4, fibrosis). Interface hepatitis or other features suggestive of autoimmune hepatitis were not present in any of the cases.
Association Between N/L Ratio and the Presence of NASH and Fibrosis
The median N/L ratio in patients with NASH was 2.5 (Q25–Q75 = 1.9, 3.3), which was significantly higher than the N/L ratio in patients without NASH [1.6 (Q25-Q75 = 1.2, 2.0)] (P < 0.001)] (Fig. 1). The same observation was noted for patients with advanced fibrosis (stage 3–4) compared with patients with mild-to-moderate fibrosis (stage 1–2) [N/L ratio of 2.9 (2.0, 3.9) vs. 1.8 (1.2, 2.2) respectively] (P < 0.001) (Fig. 1). The ROC analysis suggested that a cut-off value of 1.9 has the highest sensitivity (72%) and specificity (70%) for detecting patients with NASH (Fig. 2) with an area under the curve (AUC) of 0.77 (95% confidence interval: 0.68–0.87). The AUC for N/L was found to be higher than the AUCs of both serum AST (0.69, 95% confidence interval 0.56–0.81) and alanine aminotransferase (ALT; 0.56, confidence interval 0.43–0.70). The positive predictive value (PPV) for this cut-off was 69% and the negative predictive value (NPV) was 71%. Similarly, a cut-off value of 2.3 for N/L ratio gave a sensitivity of 73% and a specificity of 77% for detecting the presence of fibrosis (Fig. 3). The PPV and NPV were 47% and 91% respectively.
(Enlarge Image)
Figure 1.
Neutrophil to lymphocyte (N/L) ratio in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis. The box represents the interquartile range (25th and 75th percentiles) from the median (the horizontal line), the bars represent the 95% confidence interval.
(Enlarge Image)
Figure 2.
ROC curve of neutrophil to lymphocyte (N/L) ratio for the identification of patients with nonalcoholic steatohepatitis (NASH). A cut-off value of 1.9 had the highest sensitivity and specificity to identify patients with NASH.
(Enlarge Image)
Figure 3.
ROC curve of neutrophil to lymphocyte (N/L) ratio for the identification of patients with fibrosis. A cut-off value of 2.3 had the highest sensitivity and specificity to identify patients with nonalcoholic steatohepatitis.
Correlation Between N/L Ratio and Histological Features of NASH
In a univariable analysis, high N/L ratio was significantly associated with necroinflammatory activity, steatosis, ballooning and high NAS and fibrosis scores (P < 0.001) ( Table 3 ). These results suggest that N/L ratio may increase with disease progression with the highest values found in patients with NASH and advanced fibrosis.
After adjusting for multiple confounders including age, gender, race, BMI, ALT, smoking status and the presence of diabetes, the association between N/L ratio and inflammation, fibrosis and the presence of NASH remained statistically significant (P < 0.05) in the multivariable analysis ( Table 4 ). For each one-unit increase in N/L ratio, the likelihood of having NASH increases by 70% and the likelihood of having fibrosis increases by 50%.
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