Year: 2025
Type: editorial
Abstract: This editorial refers to ‘Steatotic liver disease as a risk enhancer in the presence of metabolic syndrome’, by G. Zeng et al., https://doi.org/10.1093/eurjpc/zwaf330 Our world is confronted with an escalating syndemic, characterized by the concurrence and complex interplay of obesity and Type 2 diabetes (T2D), leading to the number one killer—cardiovascular disease—and aggravated by social/behavioural determinants of health, including alcohol abuse disorder. The epidemiological study by Zeng et al.1 clarifies an important aspect of this syndemic, namely, whether there is a significant impact of metabolic syndrome (MetS) on the mortality risk of steatotic liver disease (SLD), particularly when parsed out into clinical subtypes. Component risk factors of MetS according to International Diabetes Federation (IDF) criteria comprise (i) two features of abnormal adiposity: central obesity (>94 cm in men or >80 cm in women) or high body mass index (>30 kg/m2); (ii) hypertriglyceridaemia (≥150 mg/dL), low HDL cholesterol levels (≤40 mg/dL in men and ≤50 mg/dL in women), or use of lipid-lowering medications; (iii) elevated systolic blood pressure [(≥130 mm Hg) or diastolic blood pressure (≥85 mm Hg)] or taking anti-hypertensive medications; and (iv) hyperglycaemia (fasting glucose ≥ 100 mg/dL, haemoglobin A1c ≥ 5.7%, or taking anti-diabetes medications).2 Residual risk factors of MetS comprise inflammation, atherothrombosis, and malnutrition, among others, which combined with the above component risk factors predispose to a total risk of systemic medical illnesses (and their complications) such as T2D, atherosclerotic cardiovascular disease and heart failure with preserved left ventricular ejection fraction, chronic kidney disease (CKD), and SLD.2 This concept evolved into the cardiometabolic-based chronic disease (CMBCD) model, which reconfigures risk (in terms of interacting drivers), predisease, disease, and complications according to pathophysiological/causative endotypes into a longitudinal representation of chronic disease that exposes early opportunities for prevention.3 Most recently, the European Atherosclerosis Society (EAS) refined these systemic metabolic disorder stages as (i) insulin resistance/prediabetes or overweight with one either hepatic steatosis, hypertension, or atherogenic dyslipidaemia; (ii) T2D, metabolic dysfunction-associated SLD (MASLD), microalbuminuria, CKD Stage 1 or 2, or subclinical atherosclerosis; and (iii) heart failure with preserved ejection fraction, cirrhosis/hepatic failure, reduced renal function/failure and CKD Stages 3–5, or clinically manifest atherosclerotic cardiovascular disease.4 Although the CMBCD and EAS frameworks emphasize primary drivers such as genetic and socioeconomic, the contribution of alcohol on cardiovascular risk has been controversial and its modulating effect on SLD uncertain.5 The aim of the Zeng et al.1 study was to compare cause-specific and all-cause mortality across the overarching SLD subtypes stratified by IDF MetS criteria and alcohol consumption. The SLD subtypes were MASLD, MASLD with increased alcohol intake (MetALD), and alcohol-related liver disease (ALD). In their analysis of the National Health and Examination Survey (NHANES III) conducted in US adults between 1988 and 1994, a total of 9217 of 33 994 participants were included. These eligible participants were 20–74 years of age and had hepatic ultrasound data, fasting blood samples, weight, and follow-up information. This study excluded women who were pregnant, as well as participants without cardiometabolic risk factors, MASLD-related data, or other liver diseases. Hepatic steatosis was determined by ultrasound and categorized into four strata: normal, mild, moderate, or severe. The fibrosis (FIB)-4 score, an estimate of hepatic fibrosis, was grouped into three categories: no fibrosis (≤1.30), intermediate (1.30 < FIB-4 < 2.67), and advanced fibrosis (≥2.67). For MASLD, alcohol consumption was <30 g/d for men and <20 g/d for women; for MetALD, 30–60 g/d for men and 20–50 g/d for women; and for ALD, >60 g/d for men and >50 g/d for women. Over the median follow-up of 26.4 years, there were 3521 deaths. After multivariate adjustment, MetS was accompanied by higher mortality across all SLD subtypes with the following hazard ratios (HRs) and 95% confidence intervals: MASLD 1.52 (1.34–1.72), MetALD 1.92 (1.41–2.62), and, notably the highest, ALD 2.80 (1.56–5.05). There was no increased mortality risk in patients with any SLD subtype who did not have MetS. There are several important clinically relevant insights from this study. First, in support of the Global Burden of Disease Study from 2016, we must acknowledge the deleterious consequences of any alcohol consumption on health6 and emphasize the particularly high mortality risk in patients with MetS who have imaging evidence of MASLD. Thus, since MetS is an aggregate of multiple risk factors that increases with age, it is important to emphasize the foundational approaches of healthy lifestyle counselling on alcohol avoidance, as well as dietary patterns with low intake of refined carbohydrate and saturated fats, and regular moderate-to-high intensity aerobic exercise with resistance training.7 Second, when selecting pharmacotherapy, treatment with currently approved incretin-mimetic drugs (IMDs) improves multiple MetS traits and reduces hepatic fat (next-generation IMDs promise more efficacy on SLD).8 Also, hypertriglyceridaemia, which is highly correlated with hepatic fat, may be targeted in the future with agents such as angiopoietin-like protein 3 inhibitors that not only lower triglycerides but also reduce hepatic fat.9 Third, since MASLD and MetALD diagnostic criteria already include one other MetS component (e.g. obesity, T2D, or hypertension), it is not surprising that the HR for mortality in patients with ALD and MetS (2.80) was highest. One may then surmise that the main take-home message of this study is that patients who consume alcohol must be more aggressively counselled about and managed to prevent MetS. Future studies probing aspects of this cardiometabolic syndemic should focus more on pathophysiological endotypes as the authors succinctly point out (e.g. patatin-like phospholipase domain-containing-3 gene rs738409 C>G polymorphism in SLD10 within enriched CMBCD/EAS cardiometabolic risk frameworks), rather than clinical subtypes that can be confounded by subjectivity and detection errors (Figure 1). Comparison of syndemic modelling of cardiometabolic risk based on clinical subtypes vs. pathophysiological endotypes. The steatotic liver disease and metabolic syndrome examples are based on cross-sectional occurrences of a limited number of clinical features (left circles). Driver-based chronic disease frameworks are based on causal, longitudinal, and more complex relationships over time, with a specific endotype (dotted circle with components) based on the role of PNPLA3 and alcohol on steatotic liver disease and cardiometabolic risk (right circle and network). CVD, cardiovascular disease; HCC, hepatocellular carcinoma; MetS, metabolic syndrome; PNPLA3, patatin-like phospholipase domain-containing-3 gene; SLD, steatotic liver disease. None declared. There are no new data associated with this article.
Authors: Robert S Rosenson, Jeffrey I Mechanick
Institution: Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4411651582