Correspondence on Letter regarding “Prognosis of biopsy-confirmed MASLD: A sub-analysis of the CLIONE study”
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Dear Editor,
We thank Joo Hyun Oh and Dae Won Jun for commenting on our recent publication [1]. Their Letter comprehensively describes our analysis of liver biopsy–confirmed nonalcoholic fatty liver disease (NAFLD) patients in the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) cohort [2] divided into metabolic dysfunction-associated steatotic liver disease (MASLD) and non-MASLD groups based on the presence or absence of cardiometabolic criteria (CM) [3]. We would like to focus our response on the following three issues raised by the authors:
Is there an increased incidence of cardiovascular disease (CVD) and/or mortality in individuals with MASLD compared to the general population?
The Suita study is a prospective cohort study of 6,475 patients aged 30–84 years in Japan. During a median observation period of 16.6 years, 590 patients developed CVD, 346 of whom had stroke events and 244 who had coronary heart disease [4]. Within this cohort, female MASLD patients (Fatty Liver Index ≥60) had an elevated risk of CVD and stroke, with hazard ratios and 95% confidence intervals of 1.69 (1.16, 2.46) and 2.06 (1.31, 3.24), respectively [4]. No corresponding associations were detected in men. Leung et al. [5] reported the incidence of CVD in an Asian cohort of 307 liver biopsy–confirmed MASLD patients. These individuals were observed for a median of 49 months, with CVD noted in 23 cases and stroke occurring in eight patients. Most recently, Le et al. performed a meta-analysis of 79 articles and analyzed clinical events in 1,377,466 adult patients with NAFLD (MASLD) [6]. They found that the incidence rate per 1,000 person–years for CVD-related mortality and incidence of CVD were 4.53 and 24.77, respectively. Importantly, significantly higher rates of both CVD events and mortality were observed in North America and Europe than in Western Pacific/Southeast Asia. However, as the authors point out [3], it was not possible to determine whether MASLD patients had a clearly higher incidence or fatality rate of CVD than non-MASLD patients. Moreover, although a sub-analysis of the Le et al. [6] paper showed no sex-associated differences in the incidence of CVD or mortality, it is true that there are conflicting data, such as the Suita study. Thus, we cannot answer the question definitively, and future studies with larger cohorts in Asia are needed to resolve this issue.
What are the differences in clinical background between Western and Eastern liver biopsy–confirmed MASLD patients?
The Nonalcoholic Steatohepatitis Clinical Research Network (NASH–CRN) cohort is a prospective study of 1,773 liver biopsy–confirmed MASLD patients followed up for a median of 4 years [7]. In contrast, the CLIONE is a retrospective observation study, representing a major difference between the two studies. Comparing the two cohorts, we note that age was similar for participants of NASH–CRN and CLIONE (mean: 52 vs. 54.5 years) [2], although the proportion of women was slightly higher in NASH–CRN (64% vs. 54%). Participants in CLIONE were 100% Asian, whereas those in NASH–CRN were 85% White and 12% Hispanic. The prevalence of both diabetes (42% vs. 36%) and hypertension (61% vs. 42%) was higher in NASH–CRN than in CLIONE. Histologically, the prevalence of advanced fibrosis (stages 3 and 4) was higher in the NASH–CRN than in the CLIONE (30% vs. 16%) cohort. Similarly, the prevalence of cirrhosis (stage 4) was also higher in NASH–CRN (9% vs. 2%). When limiting the comparison of patient background to those with stage 4 disease, age (57 vs. 62 years) and percentage of women (74% vs. 81%) were lower in NASH–CRN than in CLIONE. In contrast, platelet count and body mass index (BMI) were higher in participants of NASH–CRN than those in CLIONE (platelet count, 154,000 vs. 123,000 μL; BMI, 35 vs. 30 kg/m2). We believe that the reason stage 4 platelet count was lower in CLIONE than in NASH–CRN participants is because the diagnosis of stage 4 disease was made more rigorously in CLIONE. Focusing on cardiovascular events, the incidence of cardiac and vascular events was higher in NASH–CRN than in CLIONE (cardiovascular disease, 0.83 vs. 0.57; cerebrovascular disease, 0.40 vs. 0.27). Thus, as we can see, the NASH–CRN and CLIONE cohorts have different clinical backgrounds. One reason for these discrepancies may be that liver biopsy is still the gold standard for diagnosis in Japanese guidelines [8], whereas Western guidelines do not require this method [9].
What is the most important combination of CM in MASLD?
In the CLIONE cohort, we have found that steatotic liver disease (SLD) without the presence of CM is a mild condition, and no severe outcomes, such as carcinogenesis or cardiovascular events, occurred in this patient group during the observation period [1]. However, the answer to the question of which specific CM most affect outcomes is more unclear. In our analysis, CM had no effect on long-term prognosis, including mortality or the incidence of liver-related events, when the cumulative number of risk factors was divided into low (0–2) and high (3–5) groups [1]. However, each of the CM is quite broad, including a range of severities, and it is unclear whether meeting the criteria really has an impact on severe outcomes of SLD. Additionally, we understand that the reason why CM do not include Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) or high-sensitivity C-reactive protein (Hs-CRP) is to facilitate the identification of SLD for more clinicians around the world. However, given that there is currently no universally accepted biomarker of chronic inflammation in SLD, further research on the usefulness of indicators, including HOMA-IR and Hs-CRP, for diagnosis of MASLD pathophysiology is needed.
Recent studies have demonstrated the usefulness of the diabetes mellitus drugs sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) for treatment of MASLD. Thus, their potential as therapeutic agents is expanding [10-12], and in actual clinical practice, there are many MASH/MASLD patients already taking SGLT-2i and GLP-1RA. In addition, the United States Food and Drug Administration recently approved the first oral thyroid hormone receptor-beta selective agonist [13] for MASH/MASLD treatment. The world is therefore entering an era in which we will likely see a cure for MASH/MASLD. Moreover, with continuing advances in noninvasive diagnostic methods, we expect the need for liver biopsy to decrease in the future. In this historical context, the importance of the liver biopsy cohort may continue as an assessment of patients not taking oral therapeutic drugs.
Notes
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
NAFLD
nonalcoholic fatty liver disease
CLIONE
Clinical Outcome Nonalcoholic Fatty Liver Disease
MASLD
metabolic dysfunction-associated steatotic liver disease
CVD
cardiovascular disease
NASH–CRN
Nonalcoholic Steatohepatitis Clinical Research Network
BMI
body mass index
SLD
steatotic liver disease
HOMA-IR
Homeostatic Model Assessment for Insulin Resistance
Hs-CRP
high-sensitivity C-reactive protein
SGLT-2i
sodium-glucose cotransporter-2 inhibitors
GLP-1RA
glucagon-like peptide-1 receptor agonists