Essential phospholipids and enzyme-based staging in nonalcoholic fatty liver disease: A call to action

Abstract

Nonalcoholic fatty liver disease, recently termed metabolic dysfunction-associated steatotic liver disease, affects 25% of adults globally, with a prevalence reaching 93% in obese individuals. The MANPOWER study, a post hoc analysis of 2843 Russian patients with newly diagnosed nonalcoholic fatty liver disease, evaluated Essentiale Forte N^® [essential phospholipids (EPLs)] therapy and a liver enzyme-based staging algorithm. Using generalized linear regression and McNemar tests, EPLs reduced liver enzyme levels (alanine aminotransferase: -20.4 U/L, aspartate aminotransferase: -16.9 U/L, gamma-glutamyl transferase: -17.1 U/L at 24 weeks, P < 0.001) and improved ultrasonography findings (76.8% reduction in hyperechogenicity, P < 0.001). A logistic regression algorithm using alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels achieved 72.3% accuracy, 75.6% sensitivity, 71.0% specificity, and an area under the receiver operating characteristic curve of 0.74 (95% confidence interval: 0.71-0.77) for identifying nonalcoholic steatohepatitis. These findings advocate EPLs as a safe, effective therapy and propose a scalable diagnostic tool, urging validation to reduce the reliance on biopsy.

Key Words: Nonalcoholic fatty liver disease; Metabolic dysfunction-associated steatotic liver disease; Essential phospholipids; Liver enzymes; Noninvasive diagnostics; Ultrasonography

Core Tip: The MANPOWER study demonstrated that Essentiale Forte N^® reduces liver enzyme levels (alanine aminotransferase: 20-37 U/L, aspartate aminotransferase: 17-29 U/L, gamma-glutamyl transferase: 17-24 U/L, P < 0.001) and improves ultrasonography findings in patients with nonalcoholic fatty liver disease, with greater efficacy in severe cases. A liver enzyme-based algorithm offers 72.3% accuracy for noninvasive staging, prompting clinicians to adopt essential phospholipids and researchers to refine scalable diagnostics to address nonalcoholic fatty liver disease’s global burden.

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease to emphasize its metabolic roots, affects approximately 25% of adults worldwide, with the prevalence increasing to 75%-93% in obese individuals[1,2]. When simple steatosis is spanned to prevent nonalcoholic steatohepatitis (NASH), NAFLD increases the risk of fibrosis, cirrhosis, and hepatocellular carcinoma[3,4]. Lifestyle interventions, such as diet and exercise, remain the primary management strategy, but poor adherence in real-world settings underscores the need for effective pharmacotherapies and noninvasive diagnostics[2,5]. The MANPOWER study[4], a post hoc analysis of 2843 Russian patients with newly diagnosed NAFLD, fills a critical gap in real-world evidence, particularly for severe NAFLD, by evaluating Essentiale Forte N^® [essential phospholipids (EPLs)] and introducing a liver enzyme-based staging algorithm[6]. This editorial synthesizes these findings, incorporating recent literature on metabolic dysfunction-associated steatotic liver disease nomenclature and pharmacotherapy[2], to advocate for integrating EPLs and innovative diagnostics into NAFLD care and to spark dialog on their global adoption.

THERAPEUTIC EFFICACY OF EPLS

This post hoc analysis of the MANPOWER study (2015-2016) included 2843 adults (aged 18-60 years) with newly diagnosed NAFLD across 174 Russian medical centers[4]. Patients received Essentiale Forte N^® (300 mg EPLs) as adjunctive therapy to standard care. Data on liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), in U/L] and ultrasonography parameters (diffuse liver hyperechogenicity, heterogeneous liver structure) were collected at baseline, week 12, and week 24 via paper-based case report forms. Generalized linear regression models adjusted for age, body mass index, comorbidities (obesity, hypertension, hypercholesterolemia, type 2 diabetes), and NASH diagnosis were used to assess changes in enzyme levels. McNemar tests were used to evaluate improvements in ultrasonography. Statistical significance was set at P < 0.05, with exact P-values reported for P > 0.001. The MANPOWER cohort (62.2% female, mean age 48.4 ± 8.59 years) had prevalent comorbidities: Obesity (80.1%), hypercholesterolemia (72.6%), hypertension (57.8%), and type 2 diabetes (16.8%). EPLs significantly reduced the following enzyme levels by week 24: ALT by 20.4 U/L (P < 0.001), AST by 16.9 U/L (P < 0.001), and GGT by 17.1 U/L (P < 0.001). Patients with physician-diagnosed NASH (n = 712) showed greater reductions, with ALT decreasing by 37.2 U/L (P < 0.001). Ultrasonography findings improved significantly, with 76.8% of patients showing reduced diffuse liver hyperechogenicity (P < 0.001) and 70.6% of NASH patients showing improved heterogeneous liver structure (P = 0.002). No adverse events were reported, which is consistent with EPL’s established safety profile[7].

DIAGNOSTIC ALGORITHM

A logistic regression-based algorithm was developed to stage NAFLD severity via the statistical distributions of ALT, AST, and GGT levels (categorized as normal, mild, moderate, or high increases). The algorithm was trained on 70% and tested on 30% of the cohort (n = 2076 with complete enzyme data). Calibration was performed via the Hosmer-Lemeshow test. Diagnostic performance was assessed against physician-diagnosed NASH via sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve. The algorithm achieved 72.3% accuracy, 75.6% sensitivity, 71.0% specificity, 46.2% positive predictive value, 88.7% negative predictive value, and an area under the receiver operating characteristic curve of 0.74 [95% confidence interval (CI): 0.71-0.77]. Younger patients (< 50 years) and those with type 2 diabetes had greater odds of having abnormal enzyme levels [odds ratio (OR) = 1.33, 95%CI: 1.06-1.67; OR = 1.61, 95%CI: 0.99-2.59, respectively].

Strengths

The large sample size (N = 2843) and real-world observational design increased the applicability of the study to clinical practice. The algorithm’s high sensitivity prioritized early detection of NASH, potentially reducing the need for invasive liver biopsies.

Limitations

The cohort, predominantly Caucasian Russian individuals (> 95%), may not fully represent NAFLD phenotypes in diverse populations, limiting its external validity. Spectrum bias arises from the underrepresentation of late-stage NAFLD. Reliance on clinical NASH diagnosis, rather than liver biopsy, introduced potential variability, and missing ultrasonography data may have reflected operator-dependent limitations.

Implications for clinical practice

The Essentiale Forte N^® offers a safe adjunctive therapy for NAFLD, with no adverse events reported in this cohort, which aligns with its inclusion in Russian clinical guidelines[8]. However, the European Association for the Study of the Liver and American Association for the Study of Liver Diseases guidelines (2023-2024) do not yet endorse EPLs due to the limited number of large-scale randomized controlled trials[2,8]. EPLs’ affordability supports their use in resource-constrained settings, although cost-effectiveness data remain sparse. The enzyme-based algorithm complements existing noninvasive tools such as the fibrosis-4 score, offering a scalable approach for NAFLD staging in primary care. Clinicians should consider integrating EPLs into treatment protocols, while researchers must validate the algorithm across diverse populations and assess long-term EPL outcomes to align with global guidelines. This editorial urges the hepatology community to engage in critical discourse on overcoming regulatory and economic barriers to EPL adoption and prioritizing scalable diagnostics to address the global burden of NAFLD.

CONCLUSION

The MANPOWER study underscores the efficacy of Essentiale Forte N^® in reducing liver enzyme levels and improving ultrasonography findings in patients with NAFLD, alongside a promising liver enzyme-based algorithm for noninvasive staging. These findings call for clinicians to adopt EPLs, researchers to refine diagnostic tools, and policy makers to ensure equitable access. By embracing these innovations, the hepatology community can transform NAFLD management and mitigate its escalating global impact.