**5. Monitoring disease progression**

A recent meta-analysis of 11 studies that evaluated the progression of NAFLD through the use of paired liver biopsies revealed that patients with NAFL and NASH presented a progression of fibrosis of 33.6% and an improvement of it of 22.3%, the rate of fibrosis progression being greater in patients with NASH than with NAFL (progression in a stage of 7.1 years compared to 14.3 years, respectively) [5]. However, there is a lack of homogenization in the speed of fibrosis progression in all these studies with paired biopsy, which is mostly due to the presence of characteristics of the metabolic syndrome in the patients [5–7, 62, 65, 138–144]. For this reason, due to the lack of studies that provide complete data about the differential progression of the disease in patients with different stages of NAFLD, there is no guide on the frequency of follow-up of these patients or on the means available to monitor the progression. Nevertheless, once the diagnosis of NAFLD is made, the follow-up will depend on the presence of metabolic risk factors and the severity of the hepatic disease, which will be determined by the presence of NASH and, especially, the stage of fibrosis.

The principal metabolic factor of the risk of NAFLD progression is DM2 [1, 19, 145]. Patients with DM2 have a more severe grade of NAFLD than the patients without DM2, with rates of NASH up to 80% and of advanced fibrosis of 30–40% [146, 147]. These data confirm the need for closer monitoring in these patients. Bazick et al. [147] developed a clinical model to detect NASH and advanced fibrosis in patients with NAFLD and DM2 with a sensitivity and specificity of 57 and 90%, respectively. This model includes easily accessible parameters such as BMI, circumference at the waist, HbA1c, insulin resistance, ALT, AST, albumin and ferritin, for NASH; and age, BMI, waist/hip ratio, arterial hypertension, ALT/AST ratio, alkaline phosphatase, bilirubin, globulin, albumin, serum insulin, hematocrit, INR and platelets, to predict advanced fibrosis. However, further studies are still necessary to externally validate this model. Other metabolic factors described with more evidence for the disease progression are central obesity, arterial hypertension and high levels of LDL cholesterol [7, 148–150]. No study shows cost-efficacy in the monitoring of the progression in these at-risk patients, but we recommend carrying out NFS and/or FIB-4 every 2 or 3 years in these patients with nonsignificant fibrosis, and if NASH and/or significant fibrosis is presented in the initial diagnosis, the follow-up will not differ from the rest of the patients.

The other factor having the greatest effect on the disease progression is liver fibrosis [151]. In general, in a period of 15 years, 13% of the patients with stage F2 and 25% of those presenting with F3 will develop cirrhosis [6, 7, 62]. These patients with significant fibrosis should be considered for pharmacological treatment, besides lifestyle modifications (diet and exercise). Moreover, NAFLD patients may develop HCC even in the absence of cirrhosis [152], given that it is the continuous hepatocyte injury that leads to a compensatory proliferation, key driver of the development of HCC [153]. Therefore, patients with NASH and significant fibrosis, which is indicative of important cellular damage, are also at risk of developing this liver tumor.

With all this information, we recommend recalculating NFS and/or FIB-4 every 4–5 years for patients with NAFL without risk factors or if the patient develops DM2; in patients with NASH without significant fibrosis, we recommend an annual follow-up with a calculation of NFS and/or FIB-4 and carrying out TE and ultrasound, and in patients with significant fibrosis, a 6-monthly follow-up is recommended with special interest in screening for HCC. The management and follow-up of the patients with advanced fibrosis/cirrhosis due to NASH does not differ from the rest of etiologies [25].

Another important question is the evaluation of the response to the therapy provided. The non-invasive methods available currently have not been reliable or have not been validated to document efficacy of the treatments, so liver biopsy is still necessary to determine this efficacy, especially in a clinical trial setting.
