Letter to the Editor: Re: Noninvasive Tests in Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Critical Insights from STELLAR Trials
Authors: Saumya Pandey
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: The recently published article by Anstee et al.1 provides key insights into the complex etiopathogenesis of nonalcoholic steatohepatitis (NASH)–mediated advanced fibrosis.2 STELLAR trials’ baseline data strongly emphasized the predictive‐value(s)/reliability of noninvasive tests (NITs) for bias‐free, accurate assessment of liver fibrosis, thereby warranting future public health research for significantly diminishing the increasing burden of hepatic malignancies in susceptible populations worldwide.3 The well‐designed STELLAR trials reported statistically sound, error‐free baseline data sets. The data were derived from two phase 3 trials of selonsertib for assessing the ability of NITs to discriminate advanced fibrosis in patients with bridging fibrosis and compensated cirrhosis staged according to Clinical Research Network (CRN) classification (screened patients n = 4,404, evaluable‐biopsy‐data n = 3,202, F0‐F2 fibrosis n = 940, F3‐F4 fibrosis n = 2,262). These data sets highlighted the essence of sensitivity, specificity, average turnaround time, diagnostic accuracy, simplicity, reproducibility, and cost‐effectiveness in developing patient‐friendly, safe, clinically validated, and predictable NITs for stage‐specific fibrosis. Major study strengths included large sample size, accurate CRN staging of fibrosis, and robust evaluations of NIT performance using well‐characterized area under the receiver operating characteristic curves (0.75‐0.80), with 5‐fold cross‐validations repeated 100 times. The findings demonstrated reliable associations between fibrosis stage and NITs, including nonalcoholic fatty liver disease fibrosis score (NFS), Fibrosis‐4 (FIB‐4) index, enhanced liver fibrosis (ELF) test, and liver stiffness by vibration‐controlled transient elastography (VCTE). The promising data demonstrated significant differences (P < 0.001) between the median values of NITs for patients with F0‐F2 versus F3‐F4 fibrosis (NFS −0.972 versus 0.318, FIB‐4 1.18 versus 2.20, ELF 9.22 versus 10.39, liver stiffness by VCTE 8.8 versus 16.5 kPa). Interestingly, the overall acceptability of NIT performance was relatively high, with lower rates of ambiguous/indeterminate results and false positives; FIB‐4 followed by liver stiffness by VCTE or ELF test in those with indeterminate values (FIB‐4, 1.3‐2.67). Multicentric gene epidemiology studies/association analyses with considerable statistical power (≥80%) using NASH‐mediated advanced fibrosis cases of varying ethnicities, dietary patterns, and lifestyles, as well as healthy/disease‐free, age‐matched controls from random populations, are warranted for developing a global public health–oriented research model by justified allocation of health care resources and funds for significant reduction of advanced fibrosis/NASH‐related morbidities and mortalities in genetically susceptible populations. Moreover, the predictive value of NITs for generalized large‐scale screening would certainly require confirmation of STELLAR baseline data in real‐world population subsets with relevant statistical adjustments of clinical covariates/confounders, including multiple corrections for drawing definitive conclusions and successfully screening/stratifying asymptomatic, borderline, and symptomatic patients, thereby reducing the time, efforts, and costs involved in liver biopsies and subsequent patient follow‐ups. I strongly feel there is an urgent need for a global health policy/universal protocol with rigorous international standards for successfully implementing shared decision‐making. Prospective pharmacogenetics and genomics studies evaluating the association of NITs with fibrosis staging coupled with metabolomics, lipidomics, and radiodiagnostic imaging modalities in specific populations with subgroup stratifications of patients (male versus female) with concomitant usage of antibiotics and other drugs subjected to polypharmacy would prove beneficial in the design of predictive biomarkers and antifibrotic therapies.