Determinismul genetic al răspunsului nutrițional în NAFLD: PNPLA3 și TM6SF2

Introduction

Non-alcoholic fatty liver disease (NAFLD) – recently redefined under the broader term metabolic-associated steatotic liver disease (MASLD) – has become the most prevalent chronic liver disorder worldwide, affecting nearly one in four adults. It encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC).

The condition arises from a complex interplay between metabolic factors, such as obesity, insulin resistance and dyslipidemia, and genetic predisposition. Increasing evidence suggests that interindividual variability in disease onset, severity and treatment response is not solely metabolic but deeply rooted in genetic determinants^(1,2,3,12).

Two gene variants – Patatin-Like Phospholipase Domain-Containing Protein 3 (PNPLA3) I148M and Transmembrane 6 Superfamily Member 2 (TM6SF2) E167K – represent the most consistently validated genetic drivers of hepatic fat accumulation. The PNPLA3 I148M substitution impairs triglyceride hydrolysis and promotes lipid droplet accumulation in hepatocytes, while TM6SF2 E167K reduces very-low-density lipoprotein (VLDL) secretion, leading to intrahepatic fat retention despite lower circulating lipids. These mechanisms explain the “lipid trade-off” phenotype – worsened liver disease but paradoxically lower cardiovascular risk – observed in some carriers^(5,6,8,9).

The discovery of these variants has shifted the paradigm of NAFLD from a purely metabolic to a genetically modulated disease. Yet, lifestyle and nutritional therapy remain the foundation of management. Recent studies reveal that genetic variants may modulate dietary responsiveness: PNPLA3 risk carriers exhibit heightened sensitivity to carbohydrate and fructose intake, while TM6SF2 carriers respond more favorably to Mediterranean-type dietary patterns. Nevertheless, caloric restriction and weight reduction continue to confer significant benefits across all genotypes, emphasizing the overriding influence of energy balance and behavioral change^(4,11,15,16).

Understanding these gene-diet interactions opens the door to precision nutrition – tailoring dietary strategies to an individual’s genetic profile to optimize metabolic and hepatic outcomes. However, evidence gaps remain concerning genotype-stratified randomized trials, dose-response data and ancestry-specific effects. In this context, integrating genetic testing into clinical nutrition practice, supported by robust counseling and ethical safeguards, may enhance personalized care for NAFLD patients^(5,17,18).

This article provides a concise synthesis of current evidence on PNPLA3 and TM6SF2 in relation to nutritional response, and presents a clinical case illustrating genotype-informed dietary management in NAFLD. For clarity, key genetic and metabolic terms used throughout this manuscript are defined in the Appendix.

Materials and method

This manuscript integrates a narrative review of the literature with an individual N-of-1 clinical case report. The objective of the review was to summarize current evidence on the interaction between PNPLA3 and TM6SF2 variants and nutritional response in NAFLD/MASLD, while the clinical case illustrates the practical application of genotype-informed dietary counseling.

A comprehensive literature search was conducted between January 2010 and December 2024, using three major scientific databases: PubMed, Scopus and Web of Science. The search focused on studies examining the genetic determinants of NAFLD, nutrient-gene interactions and dietary or lifestyle interventions relevant to PNPLA3 and TM6SF2.

The search strategy combined medical subject headings and free-text terms, including:

• “PNPLA3”, “TM6SF2”, “HSD17B13”
• “nutrigenetics”, “gene-diet interaction”
• “NAFLD”, “MASLD”, “hepatic steatosis”
• “dietary intervention”, “Mediterranean diet”
• “fructose”, “omega-3”, “caloric restriction”
• “VLDL secretion”, “hepatic lipid metabolism”.

Reference lists of included papers were manually reviewed to identify additional relevant studies.

Eligibility criteria

• Inclusion criteria.
• Human studies involving adults or pediatric populations.
• Observational, cross-sectional, prospective, interventional, or randomized controlled trials.
• Studies reporting the effects of diet, nutrients, or structured lifestyle interventions on NAFLD in relation to PNPLA3, TM6SF2, or HSD17B13 variants.
• Full-text articles published in English.

Exclusion criteria

• Non-human studies unless providing indispensable mechanistic insights.
• In vitro-only studies.
• Case reports not involving nutrigenetic mechanisms.
• Narrative reviews without primary data (used only for context when needed).
• Study selection and data extraction.

• Study design and sample characteristics.
• Genotype(s) assessed.
• Type and duration of dietary intervention.
• Hepatic outcomes (MRI-PDFF, CAP, ALT, histology).
• Metabolic outcomes (DNL, insulin sensitivity, lipid profile).
• Genotype-diet interactions and effect sizes where available.

Due to heterogeneity in study methodologies, dietary protocols and outcome measures, a narrative synthesis approach was used rather than meta-analysis.

Clinical case component

The clinical case represents a real-world N-of-1 nutritional intervention performed in independent dietetic practice through online consultation. Data collection included medical history, anthropometric measurements, biochemical tests, FibroScan para­meters (CAP) and results from nutrigenetic testing. The purpose of the case is illustrative – to highlight how genotype-informed nutrition can be integrated into individualized dietary management. The patient provided written informed consent for use of anonymized clinical data in this publication.

Limitations of methodology

As a narrative review, this work does not follow the strict protocol of systematic reviews. The available evidence is limited by heterogeneity between studies and the small number of genotype-stratified randomized trials. Nevertheless, the integration of mechanistic, observational and interventional data provides a comprehensive overview suitable for clinical application.

Glossary of key terms

• PNPLA3 (Patatin-Like Phospholipase Domain-Containing Protein 3): a lipid droplet-associated enzyme with triglyceride hydrolase activity. The I148M variant impairs function and represents the strongest genetic risk factor for NAFLD.
• TM6SF2 (Transmembrane 6 Superfamily Member 2): an endoplasmic reticulum-resident protein involved in VLDL lipidation and secretion. The E167K variant reduces VLDL export, leading to hepatic lipid accumulation.
• NAFLD (Non-Alcoholic Fatty Liver Disease): hepatic steatosis ≥5% in the absence of significant alcohol consumption or secondary causes of liver disease.
• NASH (Non-Alcoholic Steatohepatitis): a progressive form of NAFLD characterized by inflammation, hepatocyte ballooning and varying degrees of fibrosis.
• MRI-PDFF (Magnetic Resonance Imaging-Proton Density Fat Fraction): gold-standard noninvasive method for quantifying hepatic fat content.
• FibroScan: a transient elastography device measuring liver stiffness (fibrosis) and controlled attenuation parameter (CAP) for assessing steatosis.
• SREBP-1c (Sterol Regulatory Element-Binding Protein 1c): master transcription factor regulating de novo lipogenesis.
• DNL (De Novo Lipogenesis): hepatic synthesis of fatty acids from carbohydrates (glucose, fructose).
• VLDL (Very Low-Density Lipoprotein): triglyceride-rich lipoprotein secreted by the liver to deliver lipids to peripheral tissues.
• HSD17B13: gene encoding 17β-hydroxysteroid dehydrogenase 13; loss-of-function variants protect against NAFLD progression.
• HOMA-IR (Homeostatic Model Assessment of Insulin Resistance): index estimating insulin resistance calculated from fasting glucose and insulin.

Results

Genetic mechanisms in NAFLD

Non-alcoholic fatty liver disease develops through a complex interplay between metabolic, environmental and genetic factors that collectively determine hepatic lipid homeostasis. Among the numerous genetic variants identified through genome-wide association studies, PNPLA3 I148M (rs738409) and TM6SF2 E167K (rs58542926) represent the two most powerful and reproducible determinants of hepatic fat accumulation and disease progression. Both variants directly influence intracellular lipid handling through distinct mechanisms, explaining the wide heterogeneity observed in NAFLD severity among individuals exposed to similar metabolic conditions^(11,17,18).

The PNPLA3 gene encodes Patatin-Like Phospholipase Domain-Containing Protein 3, an enzyme expressed predominantly in hepatocytes and hepatic stellate cells. Under normal physiological conditions, PNPLA3 functions as a triglyceride lipase involved in lipid droplet remodeling and triglyceride mobilization for very-low-density lipoprotein (VLDL) secretion. The I148M substitution (isoleucine-to-methionine) caused by the rs738409 variant abolishes the enzyme’s hydrolase activity and leads to the accumulation of inactive PNPLA3 protein on lipid droplets. This “loss-of-function” defect impairs triglyceride mobilization, promoting lipid droplet enlargement and hepatocellular steatosis. In hepatic stellate cells, mutant PNPLA3 interferes with retinoid metabolism, enhancing fibrogenic activation and collagen deposition – mechanistic evidence linking this variant not only to steatosis but also to fibrosis and progression toward NASH and cirrhosis^(19,22-25).

The TM6SF2 gene encodes Transmembrane 6 Superfamily Member 2, an endoplasmic reticulum protein crucial for VLDL lipidation and secretion. The E167K (glutamate-to-lysine) substitution decreases protein stability and disrupts VLDL assembly, resulting in reduced export of triglyceride-rich lipoproteins. Consequently, carriers of the TM6SF2 risk allele accumulate fat within hepatocytes while exhibiting lower circulating triglyceride and LDL-cholesterol levels – a paradoxical “lipid trade-off” phenotype characterized by increased liver disease risk but a lower burden of atherosclerotic cardiovascular disease. The impaired secretion of triglycerides further enhances intrahepatic lipid retention and increases susceptibility to oxidative stress, inflammation and hepatocellular carcinoma^{(8-10,21,27,28)}.

Notably, the effects of PNPLA3 and TM6SF2 variants are additive rather than redundant. Individuals carrying risk alleles in both genes exhibit markedly higher hepatic fat content and a substantially greater risk of NASH, advanced fibrosis and liver-related mortality compared with single-variant carriers. In contrast, loss-of-function variants in HSD17B13 (17β-hydroxysteroid dehydrogenase 13) appear to confer protection by reducing hepatocellular injury and inflammation, partially offsetting the deleterious impact of PNPLA3 and TM6SF2. This illustrates how hepatic lipid metabolism is governed by a delicate genetic balance of prosteatotic and hepatoprotective mechanisms^(26-30).

Nutritional factors modulate the expression and activity of these genetic pathways through key metabolic regulators. Carbohydrate-rich and hyperinsulinemic states activate the Sterol Regulatory Element-Binding Protein 1c (SREBP-1c), a transcription factor that upregulates PNPLA3 expression and promotes de novo lipogenesis (DNL). Conversely, omega-3 fatty acids and fasting states stimulate the Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α), enhancing fatty acid oxidation and mitigating hepatic fat accumulation. Activation of PPAR-γ in adipose and hepatic tissues improves insulin sensitivity and redistributes lipid storage away from the liver. These nutrient-gene interactions provide a mechanistic framework, explaining why PNPLA3 carriers are particularly sensitive to fructose and carbohydrate excess, while diets rich in unsaturated fats – especially Mediterranean patterns – counterbalance the metabolic consequences of TM6SF2 variants^(13,31-35).

Collectively, PNPLA3 and TM6SF2 exemplify how genetic variation dictates hepatic lipid flux and modifies dietary response. Understanding these mechanisms allows clinicians to anticipate differential treatment outcomes and to personalize nutritional strategies aimed at restoring hepatic metabolic balance in genetically predisposed NAFLD patients. A concise summary of major gene functions and their nutritional modulators is presented in Table 1.

Nutritional interactions and response evidence

Diet remains the cornerstone of therapy for non-alcoholic fatty liver disease (NAFLD), but interindividual variability in response to nutritional interventions has increasingly been linked to genetic background. The two major NAFLD-associated variants, PNPLA3 I148M and TM6SF2 E167K, not only influence lipid metabolism at a molecular level, but also modify how individuals respond to specific dietary patterns, macronutrient composition and energy restriction. Understanding these gene-diet interactions provides a foundation for precision nutrition approaches in hepatology^(4,14,16).

PNPLA3 and carbohydrate metabolism

Among PNPLA3 risk carriers, excessive intake of carbohydrates – particularly fructose – has been shown to exacerbate hepatic steatosis. Fructose is a potent activator of de novo lipogenesis (DNL) through the induction of SREBP-1c and ChREBP, both of which upregulate PNPLA3 expression in hepatocytes. Experimental and clinical data demonstrate that individuals homozygous for the I148M variant accumulate more intrahepatic triglycerides when consuming high-fructose diets compared to non-carriers, independent of total caloric intake. In pediatric and adult cohorts, habitual fructose intake correlates with increased liver fat only among PNPLA3 carriers, confirming a strong gene-nutrient interaction. Conversely, carbohydrate restriction, especially the reduction of added sugars below 25-30 g/day, has been associated with pronounced decreases in hepatic fat in this group. These findings suggest that dietary modulation of carbohydrate quality and quantity can partially overcome the genetic predisposition toward lipid storage^{(19,20,23,24,31)}.

TM6SF2 and dietary fat composition

The TM6SF2 E167K variant impairs hepatic VLDL secretion, leading to lipid accumulation in the liver but lower plasma triglycerides. Nutritional patterns rich in monounsaturated and polyunsaturated fatty acids (PUFA), characteristic of the Mediterranean diet, may attenuate these abnormalities by improving hepatic fatty acid oxidation and membrane lipid turnover. Observational studies indicate that adherence to the Mediterranean diet reduces hepatic fat content and normalizes transaminases across genotypes, though TM6SF2 carriers may display a less pronounced serum lipid reduction. This “partial compensation” underscores the need for tailored macronutrient distribution – emphasizing high-quality fats, reduced saturated fatty acids (SFA <10% of energy) and adequate omega-3 intake – to counterbalance impaired VLDL export in genetically predisposed individuals^{(14,15,21,27,28,32)}.

Evidence from dietary intervention trials

Although genotype-stratified randomized controlled trials remain limited, accumulating data highlight consistent benefits of structured lifestyle interventions across genotypes^(13,14,15).

These findings collectively reinforce that lifestyle modification – through caloric moderation, carbohydrate restriction and adherence to Mediterranean dietary principles – remains effective across genotypes. Nonetheless, PNPLA3 and TM6SF2 carriers may require stricter dietary targets or longer intervention durations to achieve comparable metabolic and hepatic improvements^(3,12). The main interventional studies assessing genotype-diet responses are summarized in Table 3.

Integrative perspective

At the molecular level, nutrients act as regulators of transcriptional pathways that intersect with genetic mechanisms. High insulin and carbohydrate availability activate SREBP-1c and DNL, amplifying the deleterious impact of PNPLA3 I148M. In contrast, unsaturated fats and omega-3 fatty acids modulate PPAR-α and PPAR-γ activity, enhancing fatty acid oxidation and reducing hepatic lipogenesis. Antioxidant nutrients such as vitamin E and polyphenols exert hepatoprotective effects through the Nrf2-ARE pathway, mitigating oxidative stress aggravated by TM6SF2-induced lipid retention. These interactions underscore that while genetic variants predispose to hepatic steatosis, dietary factors remain powerful epigenetic modulators capable of modifying gene expression and metabolic phenotype. Figure 1 illustrates the molecular interplay between PNPLA3 and TM6SF2 variants, hepatic lipid fluxes and key dietary regulators^(30,33).

Key message

Lifestyle interventions are universally effective in NAFLD management, irrespective of genotype. However, individuals carrying PNPLA3 or TM6SF2 risk alleles often require more intensive caloric restriction, meticulous carbohydrate control and sustained adherence to Mediterranean dietary patterns to achieve optimal liver outcomes. Personalized nutrition informed by genotype can thus refine treatment precision, bridge variability in therapeutic response, and represent a pragmatic step toward individualized NAFLD care^(1,7).

Clinical case report (individual N-of-1 study)

Background and patient profile

A 48-year-old male, office employee with predominantly sedentary lifestyle, presented for nutritional and metabolic assessment following incidental detection of hepatic steatosis on abdominal ultrasound during routine screening. His medical history included dyslipidemia and stage 1 hypertension controlled with an angiotensin receptor blocker. There was a strong family history of type 2 diabetes, obesity, chronic kidney disease and cardiovascular disease on both parental sides. The patient reported moderate alcohol consumption (

On examination, body weight was 98 kg, height 1.73 m, resulting in a Body Mass Index (BMI) of 32.7 kg/‌m², consistent with class I obesity. Waist circumference measured 108 cm, reflecting visceral adiposity. Baseline laboratory tests showed elevated alanine aminotransferase (ALT: 76 U/L) and aspartate aminotransferase (AST: 54 U/L), mild hypertriglyceridemia (TG: 186 mg/dL), low HDL-cholesterol (38 mg/dL), fasting glucose 112 mg/dL and HOMA-IR 3.2, consistent with insulin resistance. Transient elastography (FibroScan) demonstrated a controlled attenuation parameter (CAP) of 330 dB/m (S2-S3 steatosis) and liver stiffness measurement (LSM) of 6.8 kPa, suggesting mild fibrosis (F1-F2).

Genetic testing and interpretation

Given the strong familial metabolic history and the moderate severity of steatosis, nutrigenetic testing was performed using a validated PCR-based panel. The patient was found to be homozygous for the PNPLA3 I148M (GG) variant and heterozygous for TM6SF2 E167K (CT). No risk variants were identified in HSD17B13 (protective allele absent). This genotype combination is recognized as conferring a high predisposition to hepatic fat accumulation and fibrotic progression, with increased sensitivity to carbohydrate overload and impaired VLDL export capacity. The results were discussed with the patient, and the informed consent was obtained for genotype-informed nutritional management and clinical documentation.

Personalized nutrition and lifestyle program (intervention)

A 24-week lifestyle intervention was designed according to genetic and metabolic profile. The plan followed a Mediterranean-low-fructose dietary model, with an energy deficit of 500-600 kcal/day, targeting gradual weight loss of 0.5-1 kg/week. Macronutrient distribution was set at 40% carbohydrates (≤25 g/day free sugars), 30-35% fats (predominantly monounsaturated and polyunsaturated fatty acids) and 25% protein. Saturated fat intake was restricted to <10% of total energy, and trans fats were eliminated. The diet emphasized vegetables, legumes, whole grains, fatty fish (≥3 servings/week), olive oil as main fat source, nuts, and coffee in moderation. Alcohol and sugar-sweetened beverages were excluded.

Supplementation with omega-3 fatty acids (2 g EPA+DHA/day) and vitamin E (400 IU/day) was initiated, both supported by evidence of benefit in steatotic liver disease. Physical activity was progressively increased to 150 minutes per week of moderate-intensity aerobic exercise, mainly brisk walking and cycling. The patient attended monthly dietary counseling sessions for behavioral reinforcement and adherence monitoring.

Outcomes and clinical follow-up

After 24 weeks, the patient achieved a weight reduction of 9.2 kg (-9.4% from baseline) and a decrease in waist circumference of 10 cm. Laboratory follow-up demonstrated notable biochemical improvement: ALT decreased to 34 U/L, AST to 29 U/L, fasting glucose normalized (98 mg/dL), HOMA-IR dropped to 1.9, triglycerides reduced to 128 mg/dL, and HDL-cholesterol increased to 45 mg/dL. CAP value declined from 330 to 258 dB/m (S1-S2 steatosis), and LSM improved to 5.6 kPa, indicating regression of liver fat and stabilization of fibrosis. No adverse effects were observed, and treatment adherence was estimated at >85% based on food diaries and counseling logs. As shown in Figure 2, liver enzyme normalization and substantial CAP reduction were achieved after 24 weeks of personalized nutritional intervention.

The patient reported improved energy levels, better sleep quality and reduction in postprandial fatigue. Importantly, despite high-risk genotypes, hepatic and metabolic parameters improved substantially with consistent adherence to diet and exercise, underscoring the modifiable nature of gene expression through lifestyle.

Discussion

This case exemplifies how integrating genetic data into nutritional practice can personalize the management of NAFLD and enhance therapeutic motivation. The PNPLA3 I148M variant predisposes to triglyceride retention and heightened sensitivity to fructose and saturated fats; thus, dietary carbohydrate control and Mediterranean lipid composition were prioritized. The TM6SF2 E167K heterozygosity, associated with defective VLDL secretion and lower circulating triglycerides, warranted attention to omega-3 intake and reduction of hepatic lipid accumulation.

The observed improvement aligns with recent nutrigenetic evidence demonstrating that even in genetically susceptible individuals, caloric restriction, low-fructose intake and Mediterranean-style eating can reverse hepatic steatosis and metabolic dysregulation. This supports the paradigm that, while genetics define susceptibility, lifestyle determines disease trajectory. Moreover, the patient’s strong familial predisposition highlights how early screening and personalized interventions could prevent intergenerational transmission of metabolic disorders.

The patient provided informed consent for genetic testing, counseling and anonymous publication of clinical data. No pharmacological treatments were initiated beyond standard supplements. Data were handled in accordance with the Declaration of Helsinki and national regulations on patient confidentiality.

This case illustrates the practical value of genotype-informed dietary intervention in NAFLD management. Even in a high-risk PNPLA3 and TM6SF2 carrier, sustained adherence to a Mediterranean-low-fructose regimen combined with weight loss and physical activity resulted in clinically meaningful improvement, reaffirming the central role of nutrition and lifestyle as therapeutic levers capable of overriding genetic predisposition.

The present review and clinical case highlight the emerging significance of nutrigenetics in the management of non-alcoholic fatty liver disease (NAFLD). The evidence synthesized demonstrates that the most common genetic determinants – PNPLA3 I148M and TM6SF2 E167K – profoundly influence hepatic lipid metabolism and modulate individual responses to nutritional and lifestyle interventions. However, the case study illustrates that even in genetically predisposed individuals, targeted dietary modifications and sustained behavioral change can achieve substantial metabolic and hepatic improvements^(2-6).

Integrating genetic mechanisms with dietary response

The PNPLA3 I148M variant leads to impaired triglyceride hydrolysis and accumulation of lipid droplets in hepatocytes, whereas the TM6SF2 E167K variant impedes VLDL secretion, promoting intrahepatic lipid retention. Both mechanisms intensify when dietary environments are rich in carbohydrates, fructose or saturated fats – conditions that activate SREBP-1c and de novo lipogenesis. Conversely, nutrient patterns that enhance PPAR-α activity, such as omega-3 supplementation or the Mediterranean diet, counteract these effects by increasing fatty acid oxidation and improving lipid trafficking. This interaction between genotype and diet exemplifies the concept of gene-environment synergy: while the genetic background creates susceptibility, the metabolic milieu determines phenotypic expression^(25,26).

The clinical case underscores this principle. Despite carrying both PNPLA3 and TM6SF2 risk alleles, the patient experienced marked improvement after 24 weeks of a personalized Mediterranean-low-fructose diet combined with weight reduction and exercise. The observed biochemical normalization (ALT, HOMA-IR, triglycerides) and regression of hepatic steatosis on FibroScan confirm that lifestyle interventions can effectively “silence” deleterious genetic signals. This case reinforces that nutritional therapy does not lose relevance in genetically driven NAFLD; rather, it gains precision when guided by genetic information.

Toward genotype-informed nutritional therapy

Integrating genetic data into clinical nutrition practice allows more precise identification of at-risk individuals and tailoring of dietary prescriptions. For PNPLA3 carriers, strategies should emphasize restriction of simple carbohydrates and fructose, promotion of unsaturated fats, and maintenance of an energy deficit adequate to achieve at least 7-10% body weight loss. For TM6SF2 carriers, focus should be placed on optimizing lipid quality (high PUFA-to-SFA ratio), ensuring adequate omega-3 intake and avoiding excessive alcohol consumption.

Genotype-informed counseling can also enhance patient motivation. Explaining to patients that “genes load the gun, but lifestyle pulls the trigger” provides a personalized rationale for adherence, transforming prevention and treatment from generic advice into a tailored health plan. Nutrigenetic guidance thus bridges the gap between molecular understanding and behavioral change, improving therapeutic engagement and long-term outcomes.

Genes as modulators, not determinants

A central theme emerging from both evidence and case observation is that genes act as modulators rather than immutable determinants. The presence of PNPLA3 or TM6SF2 risk alleles increases vulnerability, but does not dictate disease progression in isolation. Lifestyle factors – energy balance, macronutrient quality and physical activity – remain the most powerful influences on hepatic outcomes. Genetic predisposition can amplify the consequences of poor dietary habits but can also magnify the benefits of targeted intervention. This dynamic interplay reaffirms the plasticity of metabolic health and the therapeutic potential of nutrition as an epigenetic regulator.

Limitations and gaps in current evidence

Despite promising insights, most current data on gene-diet interactions in NAFLD derive from cross-sectional or small interventional studies with heterogeneous methodologies. Few randomized controlled trials have stratified participants by genotype, and the available ones often include limited sample sizes and short durations. The lack of standardized dietary assessment tools and consistent outcome measures further constrains interpretation. Additionally, population differences in ancestry, lifestyle and environmental exposures influence allele frequency and phenotypic expression, limiting generalizability.

Our case study provides clinical plausibility but remains anecdotal by nature; it illustrates feasibility and potential, not proof of causality. Future research should aim for large, genotype-stratified randomized trials integrating precise dietary quantification, metabolomic and transcriptomic profiling and long-term follow-up to assess sustainability and fibrosis progression. Moreover, interactions between genetic variants and other biological modulators – such as gut microbiota composition, circadian rhythm and hormonal signaling – warrant systematic exploration, as they may represent key determinants of dietary responsiveness beyond the genome itself.

Future directions

The next decade of hepatometabolic research should focus on translating genetic and omics discoveries into pragmatic clinical tools. Incorporating nutrigenetic testing into standard NAFLD evaluation could refine risk stratification, identify “high responders” to specific interventions, and inform early prevention in families with strong metabolic clustering. Combining genotype data with digital dietary tracking, artificial intelligence-driven risk modeling, and microbiome profiling may usher in a new era of personalized, systems-based hepatology. In clinical practice, establishing multidisciplinary pathways involving hepatologists, nutritionists and genetic counselors will be essential for implementing genotype-informed care responsibly and effectively.

Conclusions

Non-alcoholic fatty liver disease represents a heterogeneous condition in which genetic background and lifestyle factors intersect to determine disease expression and therapeutic outcomes. The PNPLA3 I148M and TM6SF2 E167K variants are among the most influential genetic determinants of hepatic fat accumulation, yet their impact is highly modifiable through dietary and behavioral interventions⁽⁷⁾.

Genotype-based testing may enhance risk assessment by identifying individuals more susceptible to steatosis, inflammation or fibrosis. However, lifestyle modification – through caloric restriction, carbohydrate control and adherence to the Mediterranean diet – remains the cornerstone of management for all patients, regardless of genotype.

The present synthesis and clinical illustration demonstrate that integrating nutrigenetic insights into dietary planning can individualize therapy, improve adherence and optimize clinical outcomes. While larger genotype-stratified trials are needed to confirm these findings, the convergence of molecular genetics and nutritional science holds promise for transforming NAFLD care. Personalized nutrition based on PNPLA3 and TM6SF2 profiles represents a pragmatic step toward precision hepatology – where understanding genetic vulnerability empowers, rather than limits, the potential for disease reversal and long-term metabolic health.

Autor corespondent: Narcisa-Anamaria Covataru E-mail: narcisacovataru@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.