In this study, our objective to assess the influence the effect of insulin resistance on patients with fatty liver disease. We reveal that for every unit increase of insulin resistance measured by HOMA-IR, there is a roughly 16% higher likelihood of experiencing substantial fibrosis, as determined by non-invasive scoring tests. This association remained significant regardless of the presence of diabetes or BMI status. Consequently, our findings support the value of insulin resistance is of added value in predicting fibrosis stage and implies the validity of integrating it into the diagnostic criteria for MAFLD.
Patients with MAFLD linked with metabolic dysfunction exhibit significant variability in the severity of fibrosis. Our investigation of a cohort of patients with MAFLD revealed that insulin resistance is directly linked to the extent of fibrosis, regardless of other factors. This discovery aligns with the findings of a previous study, including 361 Japanese non-diabetic patients with biopsy-confirmed MAFLD. The study demonstrated that HOMA-IR independently predicted the presence of advanced liver fibrosis17. Another longitudinal study, involving 32,606 participants and an 8-year follow-up period, found that the level of baseline insulin resistance, as measured by HOMA-IR values, was linked to the likelihood of fibrosis advancement in non-diabetic patients with MAFLD18. Metabolic score for IR, including HOMA-IR, was found to be associated with the incident advanced liver fibrosis19. Similarly, children with MAFLD who have higher HOMA-IR are more likely to have liver fibrosis20.
We found high HOMA-IR levels are considered a risk factor for significant fibrosis among MAFLD subgroups. A recent study of 1,727 adults from the National Health and Nutrition Examination Surveys showed that HOMA-IR can be used for assessing metabolic risks, early screening and monitoring disease progression in patients with MAFLD21 Similarly, a study of 1020 individuals demonstrated that a sequential algorithm incorporating AST and HOMA-IR levels improves fibrosis risk stratification among non-diabetic overweight/obese MAFLD individuals22. In a study of 2550 participants, those with advanced fibrosis were more likely to have higher HOMA-IR and advanced fibrosis was positively associated with subclinical atherosclerosis among MAFLD patients23. Interestingly, a recent study found that differences in subcutaneous adipose tissue transcript profiles in patients with vs without ≥ F2 fibrosis were explained by differences in HOMA-IR24.
The pathophysiology of hepatic fibrosis is significantly influenced by metabolic syndrome25. Metabolic syndrome-induced systemic inflammation worsens hepatic damage and speeds up extracellular matrix deposition, which eventually results in the onset and advancement of hepato-fibrosis26,27. The interplay between insulin resistance and lipid metabolism alteration influences MAFLD and MASH, which is a key precursor of fibrosis27. Our findings suggest that these pathological alterations begin to occur in the early stages of fibrosis before cirrhosis develops. Insulin resistance may contribute to the development of liver inflammation, which in turn stimulates the formation of fibrous tissue. Insulin resistance is an important component that can be modified and targeted with drugs to combat fibrosis in MAFLD28. The hyperinsulinemic clamp has traditionally been regarded as the most reliable technique for evaluating insulin resistance (IR), despite its drawbacks of being time-consuming, expensive, and challenging to use in clinical environments. The HOMA model was employed in this study as a proxy assessment of insulin resistance due to its simplicity, practicality, and affordability. These data indicate that it is important to examine insulin resistance, as measured by HOMA-IR, in individuals with MAFLD and include it in the diagnostic criteria. Notably, recent data suggest the superior utility of the MAFLD definition in identifying hepatic and extra-hepatic outcomes in adults and children29,30,31,32,33.
A significant fraction of patients with MAFLD are not obese, and this subgroup of patients appears to have distinct clinical and prognosis characteristics compared to their obese counterparts32,33,34,35. Our findings indicate that elevated insulin levels have a deleterious effect on the severity of fibrosis in both obese and non-obese patients with MAFLD. Furthermore, there was a significant correlation between HOMA-IR and the severity of fibrosis in both patients with diabetes and those without diabetes who have MAFLD.
Some limitations in our study need to be taken into account. First, we only studied Egyptian individuals. Consequently, our findings may not apply to other nations or ethnicities that exhibit distinct lifestyle trends. Fibrosis is assessed by transient elastography, which relies on inter-observer evaluation and experience, overcome by experienced technicians. All patients were recruited from tertiary hospitals, so there might be a referral bias. The utilization of a cross-sectional design hinders the ability to establish causal relationships. Furthermore, the data on lipid profile and waist circumference were not available for all cases in the cohort, so we could not compare the performance of HOMA-IR to other insulin resistance-related scores in predicting fibrosis. Finally, while our study group had sufficient statistical power to identify the primary outcome, its size was insufficient to conduct statistical tests for interaction between the different risk variables that influence the severity of liver disease.
In conclusion, insulin resistance is a reliable predictor of the severity of MAFLD, regardless of other factors. However, our research brings up the issue of whether excluding the measurement of HOMA-IR as one of the criteria in defining metabolic dysregulation in the definition of MASLD, as originally specified by the MAFLD definition, could decrease emphasis on addressing insulin resistance. Our findings suggest that metabolic factors, including insulin resistance, should be included in the clinical evaluation and diagnostic criteria for MAFLD.