NAFLD is a part of multisystem disease,and was considered as the hepatic manifestation of metabolic syndrome.The advanced form of NAFLD is NASH,which is strongly linked to obesity and metabolic disorders [20].Approximately 30% of patients with DM have NASH.The strong association between NASH and DM might not establish causality,but does demonstrate the impact of diabetes on liver.NASH is now among the top causes of HCC [21-22].Approximately 15% of NAFLD patients have significant liver fibrosis,and they are more likely to progress to adverse liver-related events.The gold standard technique for the diagnosis of NASH still established on liver biopsy.New techniques like genetic testing are still not recommended in the clinical realm for the management of patients with NASH [1-2].With the expansion of prevention and treatment measures for hepatitis B and C, NASH is expected to overtake them soon as the leading cause of cirrhosis [2].
The indications for antiviral of hepatitis B and C have been extended to patients with normal ALT,as inflammation or fibrosis could also be observed pathologically in patients with normal ALT [9].However,there are potentials for delay in the diagnosis of NASH or significant fibrosis in those NAFLD patients with normal ALT levels.
Under the Background that the diagnosis of NASH or significant fibrosis in NAFLD patients with normal ALT is always missed,Lomonaco R et al. [23] assessed the prevalence of NAFLD and of liver fibrosis associated with NASH in patients with DM,in which elevated ALT≥40 U/L was present in a minority of patients with liver fibrosis.They found that ALT alone is insufficient as initial screening.Verma S et al. [24] aimed to determine ALT value that might accurately predict NASH or significant fibrosis.Using 35 U/L as normal upper limits,they found no optimal ALT level to predict NASH or significant fibrosis.These studies had’t taken the confounding bias of the difference in the upper limit of ALT between male and female into account.
In this study,liver biopsies of those with elevated ALT demonstrated NASH or significant fibrosis in a higher rate compared to NAFLD patients with ALT under frequently-used upper limit (ALT<50 U/L for men and 40 U/L for women).But 24.7% patients with normal ALT levels had evidence of NASH or significant fibrosis,which could have been missed diagnosed.Using lower ALT upper limit (30 U/L for male and 19 U/L for female) with the Sensitivity of 93.7% and the Specificity of 20.9%,will miss diagnosis 6.3% of patients.Although lower ALT value might reduce missed diagnosis,to create an “easy-to-use” standard,we still used this ALT upper limit (30 U/L for male and 19 U/L for female) as it has been recommended by guidelines or expert opinions for multiple liver diseases [2,10].
Lower ALT upper limit could be used to assess the risk of NASH or significant fibrosis in NAFLD patients.But due to the low specificity of ALT on the prediction of NASH or significant fibrosis,patients still needs further examination.Studies have focused on non-invasive serological markers to assess disease severity.The haematological components of the systemic inflammatory response,including WBC [25],HB,RDW,MPV [26],NLR,PLR,and MLR have emerged as efficient prognostic indicators in patients with inflammatory disease,representing promising tools for risk stratification among patients with inflammatory diseases [13-14,27-28].But they could not effectively predict (P≥0.05) the risk of NASH or significant fibrosis in NAFLD patients.Studies reported the link between IL-6 and liver injury [7].But IL-6 couldn’t effectively predict (AUC=0.512) the risk of NASH or significant fibrosis in NAFLD patients.Our team aimed to explore the association between sensitivity to thyroid hormones and significant fibrosis in NAFLD patients.In euthyroid NAFLD patients, higher TFQI value was strongly associated with an increased incidence of advanced liver fibrosis [29].We also aimed to investigate the association between variables associated with iron metabolism and advanced liver fibrosis among untreated patients with AIH.Higher serum ferritin was independently associated with advanced liver fibrosis among patients with treatment-naive AIH [30].In this study,Ferritin couldn’t effectively predict (AUC=0.685) the risk of NASH or significant fibrosis in NAFLD patients.CHI3L1 is linked to inflammation and fibrosis [31].But it is not suitable for the predicting (P≥0.05) of NASH or significant fibrosis.NAFLD patients with ALT higher than this upper limit (30 U/L for male and 19 U/L for female) still needs further assessment including liver biopsy.
This study has several limitations.Firstly,most of the NAFLD patients who accepted liver biopsy in this study came only after the ALT elevation was found in physical examination.Further study on community population is needed.Second,the number of patients is relatively small because of the low acceptance of liver biopsy.Although ample size determination through statistical analysis is important in the validation of study findings,the protocol of this study did not formally determine the sample size through statistical analysis,as the sample size was determined by the availability of existing data.Third,as a cross-sectional study,it could not demonstrate a causal link between variables and the risk of NASH or significant fibrosis.Besides,the retrospective nature of the study raises the possibility of bias.
Serum ALT level might be the most commonly used,easy to obtain,and inexpensive marker for hepatocellular injury.This study showed the using of lower ALT upper limit (30 U/L for male and 19 U/L for female) could significantly reduce the missed diagnosis of NASH and significant fibrosis in patients with NAFLD.Patients with ALT higher than this upper limit should receive further assessment,which might include liver biopsy.