Nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), constitutes a global nightmare, since it affects up to one-fourth of people worldwide, representing a major cause of cirrhosis and hepatocellular carcinoma.1 Besides the fact that NAFLD is usually thought to be closely related to obesity, almost 40% of affected individuals are classified as nonobese and 20% as lean, all of whom consequently suffer from excessive morbidity and mortality as well.2 NAFLD is interconnected with significant comorbidities, namely atherosclerotic cardiovascular disease (although it is still a controversial area of knowledge), chronic kidney disease, type 2 diabetes mellitus (T2DM), atrial fibrillation, and obstructive sleep apnea.3–8 Therefore, there is an urgent need for biomarkers that could contribute to the identification and risk stratification of subjects with NAFLD, especially those with or at high risk for major comorbidities, and their response to therapeutic management.
Recently, another disease profile has been proposed to replace the existing one for NAFLD, termed as “metabolic dysfunction-associated fatty liver disease” (MAFLD) with diagnosis being based upon histological criteria (liver biopsy), imaging or circulating biomarker evidence of fat accumulation in the liver (hepatic steatosis) in addition to one of the following three criteria, namely overweight/obesity, presence of T2DM, or evidence of metabolic dysregulation.9 This definition, despite initial doubts, may be of better clinical utility, as demonstrated in recent cohort studies.10
In the present issue of Journal of Clinical and Translational Hepatology, Han and colleagues11 performed a thorough and methodologically rigorous meta-analysis assessing the potential applicability of serum resistin, a pro-inflammatory adipokine, as a biomarker of NAFLD at its entire spectrum. The authors initially demonstrated that subjects with NAFLD have significantly higher serum resistin levels compared to controls [standardized mean difference (SMD) = 0.522, 95% confidence interval (CI): 0.004 to 1.040, I2=95.9%] and subjects with NASH have lower serum resistin levels than the healthy controls (SMD = −0.44, 95% CI: −0.83 to −0.55, I2=74.5%), while no significant difference was identified for patients with NAFL compared to controls and patients with NAFL compared to those with NASH. Based on the contradictory results, Han et al.11 performed a meticulous sensitivity analysis, documenting that patients with NASH have lower resistin levels compared to healthy controls, whereas no significant difference between NAFL patients versus controls and NAFL versus NASH patients exists. Additionally, their thorough meta-regression analysis failed to identify any significant source of the high observed heterogeneity for the generated results. The high number of included studies and the extensive subgroup, sensitivity and meta-regression analyses attribute further power to the generated results, despite the significant heterogeneity.
As the authors state, in interpreting the retrieved results, “resistin levels seem to rise with the progression of NAFLD, from healthy to NAFL, but decline when NAFL progresses to NASH”. The question that arises is then “who and when should be monitored”? According to these results, it seems that resistin may be inadequate to serve as a marker for the distinguishment of a patient with NAFLD from the general population but may be useful for fibrosis risk stratification of a patient with an established diagnosis of NAFLD, since lower levels might indicate more severe disease. Its association with liver tumorigenesis (as shown in hepatitis C virus-infected patients with liver cirrhosis) could enhance this diagnostic strategy, although further data is required.12 In addition, circulating resistin might be useful for the early identification of patients with some form of NAFLD at high risk for developing other co-morbidities, such as cardiovascular disease and renal impairment.13,14
To sum up, the meta-analysis by Han et al.11 provides new, significant insights into the role of circulating resistin as a biomarker in NAFLD. According to current knowledge, it seems that this adipokine could be useful for monitoring of liver fibrosis among NAFLD patients, while it might have a role in the early detection of NAFLD-related comorbidities. However, it seems that further research in the field is still required to determine its exact role in risk stratification of affected individuals. Cost-effectiveness analyses are required, in order to establish resistin as a biomarker of choice in NAFLD.
Abbreviations
- CI:
confidence interval
- MAFLD:
metabolic dysfunction-associated fatty liver disease
- NAFL:
nonalcoholic fatty liver
- NAFLD:
nonalcoholic fatty liver disease
- NASH:
nonalcoholic steatohepatitis
- SDM:
standardized mean difference
- T2DM:
type 2 diabetes mellitus
Declarations
Funding
None to declare.
Conflict of interest
The authors have no conflict of interests related to this publication.