Letter to the Editor: Filling the gaps in non-invasive assessment of liver fibrosis in metabolic dysfunction-associated steatotic liver disease

Abstract

In this letter to the editor, we discuss the strengths and weaknesses of the paper from Joseph et al. We take to opportunity to review the clinical importance of screening metabolic dysfunction associated steatotic liver disease patients for significant fibrosis. The use of a first line blood test is crucial for cost and availability, although this may overestimate and underestimate in patients with normal liver enzymes. Liver stiffness as a second line test, decreases the number of false positives, although it may be influenced by operator experience, cost and patients’ body habitus. Future studies are required to explore the application of further technologies in the screening. Nevertheless, for the time being, a 2 tier-system still represents the best option to screen a large number of patients and to optimise resources.

Key Words: Metabolic dysfunction associated steatotic liver disease; Liver fibrosis; Screening; Non-invasive assessment; Liver function tests

Core Tip: Non-invasive assessment of liver fibrosis remains challenging in patients suffering from metabolic dysfunction associated steatotic liver disease. A two-tier system including blood tests and elastography still remains the most sensible and practical approach to address this unmet need.

TO THE EDITOR

We were delighted to read the article from Joseph et al[1] on the potential role of blood markers vs transient elastography for liver stiffness and steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD). This article aims to fill an important gap in clinical practice regarding screening significant liver disease in patients suffering from MASLD[2].

In this paper, 300 patients with a clinical diagnosis of MASLD underwent transient elastography with liver stiffness measurements (LSM) and controlled attenuation parameter (CAP) score for further characterization[1]. A wide range of blood-based markers, such as aspartate transaminase to platelet ratio index (APRI), neutrophil-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and neutrophil percentage-to-albumin ratio (NPAR) were compared against LSM and CAP score. Despite an extensive literature on the application of fibrosis-4 index (FIB-4) in patients with MASLD, only little is known so far about the potential application of APRI, NLR and NPAR in this cohort of patients[3].

Identifying patients at high-risk of significant liver disease is of primary importance when managing MASLD patients[3,4]. Screening high-risk groups (i.e., those with type-2 diabetes mellitus and or other features of metabolic syndrome) is strongly recommended by current international guidelines. The recent approval of a liver-targeted medication (resmetirom) has emphasized the importance of identifying those with moderate-advanced fibrosis (F2 or F3) from MASLD, who could benefit from treatment[5]. Moreover, several studies have shown that potentially any patient with MASLD could benefit from screening, as changes in lifestyle and weight loss with optimisation of metabolic risk factors, lead to better outcomes regardless of the severity of liver disease[6].

In this study, on a diagnostic performance analysis, FIB-4 exhibited the highest diagnostic performance for differentiating advanced fibrosis (F3 and F4) from lower stages (F0-F2), with an area under the curve of 0.806 (P < 0.001), sensitivity of 69.2%, and specificity of 80.4%. Most recent guidelines have suggested the implementation of a 2-step approach including a first line FIB-4, followed by LSM as this strategy has proved to maximise false negatives in high-risk groups of patients and to be cost-effective[6]. This study confirms that FIB-4, combined with LSM, is accurate at selecting those with significant liver disease. However, liver histology still represents the gold standard for diagnosing steatohepatitis as well as for staging fibrosis, therefore non-invasive markers performance should ideally be validated against liver biopsy rather than LSM directly[3]. Furthermore, a large-scale application of LSM may present some specific challenges, such as cost and availability. Moreover, despite a good reproducibility, experience may still have an impact on how exams are performed, especially in patients with challenging body habitus such as patients with visceral obesity. Other technologies based on elastography could potentially mitigate these limitations, such as ultrasound-based share wave elastography or magnetic resonance elastography, although these should better be applied in the a smaller setting of clinical trials. All these factors should be considered when setting up policies for large scale use of non-invasive markers including LSM.

Recent evidence has shown that many patients with advanced fibrosis secondary to MASLD may present with normal liver function tests, especially diabetics[6,7]. Conversely to what happened to other chronic liver diseases, liver function tests should not be used to assess the severity of fibrosis in MASLD. This poses a significant clinical challenge, as still many colleagues rely on transaminases when evaluating these patients. This is likely the reason why blood tests, such as APRI, which were developed from cohorts of biopsied patients with elevated liver function tests, perform worse in predicting severe liver disease in MASLD. Similarly, changes in white blood cells as well as in platelets may occur quite late in the natural history of the disease, making NLR and PLR not accurate for early diagnosis in this cohort. On the other hand, the application of blood-based, non-invasive markers which do not rely on liver function tests, such as enhanced liver fibrosis (ELF), could mitigate the effect of normal liver enzymes on screening detection rates. It would be interesting to see future studies analysing the performance of ELF in a specific cohort of patients with normal transaminases.

CONCLUSION

Identifying patients at high risk of significant liver disease from MASLD represents an important challenge in clinical practice. The use of non-invasive markers is recommended to increase the accessibility to screening outside of specialist care. FIB-4 proves to be a good predictor of fibrosis severity, while APRI, NLR and PLR may be impacted negatively by a long proportion of patients having completely normal blood tests. Algorithms including FIB-4 as first step for testing, should be implemented in accordance with resources and local availability.