The Silent Epidemic of NAFLD: What Family Physicians Need to Know Now

The Silent Epidemic of NAFLD: What Family Physicians Need to Know Now

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Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in the United States, affecting up to 30% of adults. [1] This staggering prevalence shows a dramatic shift in the landscape of chronic liver disease, transforming what was once considered a relatively uncommon condition into a global health epidemic. NAFLD global prevalence is 30% and increasing which requires urgent and comprehensive strategies to raise awareness and address all aspects of NAFLD on local, regional, and global levels. [2]

The significance of NAFLD extends far beyond liver health alone. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease). [3]

Family physicians occupy a unique position in addressing this epidemic. Although it is the research focus of the hepatology field, it is clear that primary care physicians are seeing the majority of NAFLD patients and are in a pivotal position to provide quality care. [4] NAFLD is a major public health problem that will only worsen in the future, as it is closely linked to the epidemics of obesity and type 2 diabetes mellitus. Given this link, endocrinologists and primary care physicians are in an ideal position to identify persons at risk on to prevent the development of cirrhosis and comorbidities. [5]

The clinical challenge lies in the largely asymptomatic nature of early NAFLD, earning it the designation as a “silent epidemic.” Although NAFLD is common and typically asymptomatic, screening is not currently recommended, even in high-risk patients. [6] This paradox creates a key opportunity for family physicians to implement targeted case-finding strategies and early intervention approaches that could prevent disease progression and associated complications.

This review aims to provide family physicians with a comprehensive, evidence-based understanding of NAFLD, from its pathophysiology and epidemiology to practical diagnostic and management strategies suitable for primary care settings. We will examine the latest guidelines, emerging therapeutic options, and the critical role that family medicine can play in addressing this growing health challenge.

 

Epidemiology and Burden of Disease

Global Prevalence and Trends

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide with a reported prevalence ranging 6-33%, depending on the studied populations. [7] The variability in prevalence rates reflects differences in diagnostic methods, population characteristics, and regional factors, but the overall trend is unmistakably upward across all demographics.

Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is a leading cause of cirrhosis and hepatocellular carcinoma. [8] [9] Recent systematic reviews and meta-analyses have provided more precise estimates, with the estimated overall global prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and is projected to reach 33.5% in 2030. [10]

The increasing prevalence of NAFLD parallels the global epidemics of obesity and type 2 diabetes mellitus. Nonalcoholic fatty liver disease (NAFLD) is becoming a frequent liver disease, especially in patients with metabolic syndrome and especially in Western countries. [11] However, this is not limited to Western populations, as emerging economies experiencing rapid lifestyle transitions are also witnessing dramatic increases in NAFLD prevalence.

Population-Specific Risk Factors

The burden of NAFLD is not equally distributed across populations. Individuals with obesity are at highest risk of NAFLD. Other established risk factors include metabolic syndrome and type 2 diabetes mellitus. [12] A large proportion of individuals with type 2 diabetes and the metabolic syndrome develop NAFLD. [13]

Specific high-risk populations include:

1. Diabetes Population: Diabetes is a driver of non-alcoholic fatty liver disease (NAFLD) and fibrosis. We determine current practices in examining liver fibrosis in people with diabetes and record prevalence levels in primary and secondary care. [14] Studies have shown particularly high rates of fibrosis in diabetic patients, with Fibrosis markers were requested in only 1.49% (390/26,090), of which 29.7% (n = 106) had evidence of fibrosis via NIT. TE and biopsy data showed that 80.6% of people with raised fibrosis markers had confirmed fibrosis. [15] [16]
2. Type 1 Diabetes: Even patients with type 1 diabetes show high NAFLD prevalence. NAFLD prevalence in individuals with T1D is 16.2%, with approximately one in 10 featuring elevated LSM. NAFLD prevalence is 16.2%, and is associated with metabolic syndrome and BMI. [17] [18]
3. Obese Populations: Obesity remains the strongest single risk factor, with prevalence rates approaching 90% in severely obese individuals undergoing bariatric surgery.

Economic and Healthcare Burden

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, and it can proceed to cirrhosis and hepatocellular carcinoma, as well as cardiovascular disease, chronic renal disease, and other complications, resulting in a massive economic burden. [19] [20]

The healthcare burden extends beyond direct liver-related costs to include management of associated comorbidities and complications. Over the last decade, it has been shown that the clinical burden of NAFLD is not only confined to liver-related morbidity and mortality, but there is now growing evidence that NAFLD is a multisystem disease, affecting extra-hepatic organs and regulatory pathways. [21]

 

Pathophysiology and Natural History

Disease Spectrum and Progression

There are two forms of NAFLD: nonalcoholic fatty liver (NAFL), defined as 5% or greater hepatic steatosis without hepatocellular injury or fibrosis, and nonalcoholic steatohepatitis (NASH), defined as 5% or greater hepatic steatosis plus hepatocellular injury and inflammation, with or without fibrosis. [22]

NAFLD encompasses a disease continuum from steatosis with or without mild inflammation (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH), which is characterised by necroinflammation and faster fibrosis progression than non-alcoholic fatty liver. [23] This progression demonstrates a critical transition point, as NASH carries higher risks for advanced fibrosis, cirrhosis, and hepatocellular carcinoma.

The natural history of NAFLD varies considerably among individuals. Although previously under-recognized accumulating evidence suggests that NAFL may also progress, suggesting a higher number of patients at risk than previously appreciated. [24] This finding has important implications for risk stratification and monitoring strategies in primary care.

Metabolic Pathophysiology

NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. [25] The pathogenesis involves complex interactions between genetic predisposition, environmental factors, and metabolic dysregulation.

Intensive research could identify insulin resistance, lipotoxicity and dysbiosis of the gut microbiota as major pathophysiological mechanisms, leading to the development of promising targeted therapies which are currently investigated in clinical trials. [26]

The “multiple hit” hypothesis has evolved to explain NAFLD pathogenesis, incorporating:

• Insulin resistance and metabolic dysfunction
• Lipotoxicity from altered fatty acid metabolism
• Oxidative stress and mitochondrial dysfunction
• Inflammatory cascades
• Gut microbiome dysbiosis
• Genetic and epigenetic factors

Fibrosis as the Key Prognostic Factor

Once NAFLD is diagnosed, the presence of liver fibrosis is the central determinant of hepatic prognosis. Severe liver fibrosis requires aggressive clinical management. [27] In these patients, advanced fibrosis is the major predictor of morbidity and liver-related mortality, and an accurate diagnosis of NASH and NAFLD is mandatory. [28]

Fibrosis staging has become the cornerstone of NAFLD management, as it determines both prognosis and treatment intensity. This emphasis on fibrosis assessment has led to the development of numerous non-invasive testing methods suitable for primary care use.

 

 

Diagnostic Approaches in Primary Care

Clinical Presentation and Case-Finding

Clinical guidelines have expanded the indications for nonalcoholic fatty liver disease (NAFLD) screening to type 2 diabetes mellitus and obesity, which are conditions common in populations who receive care in urban safety-net settings. [29] However, No guidelines recommended routine screening for NAFLD, while 14 guidelines recommended case finding in high-risk groups. [30]

Guidelines disagree on the utility of case-finding for NAFLD in high-risk groups, but most agree that risk factors primarily consist of diabetes, obesity, and metabolic syndrome. [31] This creates a practical framework for family physicians to identify at-risk patients during routine clinical encounters.

The most commonly accepted high-risk groups for case-finding include:

• Type 2 diabetes mellitus
• Obesity (BMI ≥30 kg/m²)
• Metabolic syndrome
• Unexplained elevation of liver enzymes
• Imaging findings suggestive of hepatic steatosis

Laboratory and Imaging Assessment

Liver Enzymes and Basic Assessment

It is the most common cause of elevated liver enzymes in U.S. adults, and is diagnosed after ruling out other causes of steatosis (fatty infiltration of liver), particularly infectious hepatitis and alcohol abuse. [32] However, normal liver enzymes do not exclude NAFLD, as many patients with the disease have normal ALT and AST levels.

Non-Invasive Fibrosis Testing

Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events. [33] [34] Several scoring systems have been validated for use in primary care:

1. Fibrosis-4 (FIB-4) Index: The fibrosis-4 index (FIB-4) and the NAFLD fibrosis score (NFS) have been used as noninvasive screening methods for advanced fibrosis in patients with NAFLD. [35] [36] Both AACE and AGA recommend using the FIB-4 for initial evaluation in patients with T2D due to cost-effectiveness, and its ability to rule out advanced fibrosis and predict clinical outcomes. [37]
2. NAFLD Fibrosis Score (NFS): Of the simple risk stratification models to assess for fibrosis, the fibrosis-4 score was the most frequently recommended, followed by the NAFLD fibrosis score. [38]

Practical Implementation in Primary Care

When the fibrosis-4 index (FIB-4) is <1.3, patients can be followed in the primary care setting and reassessed periodically. Patients without prediabetes/type 2 diabetes mellitus (T2DM) and 1–2 metabolic risk factors can be reassessed every 2–3 years. Patients with prediabetes/T2DM or 2 or more metabolic risk factors are at higher risk for disease progression, and more frequent FIB-4 monitoring (eg, every 1–2 y) should be considered. [39]

Imaging Modalities

Abdominal ultrasonography is the most commonly used method to diagnose fatty liver. [40] We found that ultrasound is the best test to diagnose NAFLD. Based on MRS as reference standard, US identified individuals with NAFLD with an AUROC of 0.98 (95% CI 0.95–1.00, sensitivity: 1.00, specificity: 0.96). [41] [42]

Alternative imaging approaches include:

• Controlled Attenuation Parameter (CAP) via FibroScan
• Magnetic resonance imaging (MRI) with proton density fat fraction
• Computed tomography (though less preferred due to radiation exposure)

Diagnostic Algorithms for Primary Care

Patients with steatosis noted on imaging or for whom there is a clinical suspicion of NAFLD, such as those with metabolic risk factors or unexplained elevation in liver chemistries, should undergo further evaluation. In settings with a low prevalence of advanced fibrosis, such as in the primary care setting, the emphasis is on excluding advanced fibrosis using a test with a high negative predictive value. [43]

The practical approach involves:

1. Case-finding in high-risk populations
2. Initial non-invasive fibrosis assessment (FIB-4)
3. Risk stratification based on results
4. Appropriate referral for intermediate to high-risk patients
5. Ongoing monitoring for low-risk patients

 

Risk Stratification and Patient Assessment

Multidisciplinary Approach

Optimal care of the patient with NAFLD requires a multidisciplinary approach. The majority of patients are in the primary care/endocrine setting, in which management of medical comorbidities should be optimized, with preference given to treatments for type 2 diabetes mellitus, hypertension, or obesity that likely also have beneficial effects on NAFLD. [44]

In this setting, at-risk patients should be identified and initial risk stratification performed [ie, fibrosis-4 index (FIB-4) ± vibration controlled elastography or Enhanced Liver Fibrosis]. [45]

Assessment Tools and Implementation

Primary Care Assessment Strategy

The best formula to use in two-step diagnostic NAFLD screening was AVI, which showed a low false negative rate and a higher percentage of identified NAFLD. Other studies evaluating the economic advantages of this screening method are warranted. [46]

Screening Efficiency

The US reductions percentage were 52.2% (WHtR), 52.1% (HIS), 51.8% (FLI), 50.8% (BRI), 50.7% (BMI and WHt_5R), 46.5% (WC) and 45.2% (AVI). The false negative percentage were 8.5% (WHtR), 7.9% (BRI), 7.3% (WHt_5R), 7.2% (BMI), 6.7% (HIS), 6.6% (FLI), 5.6% (WC) and 5.2% (AVI). The best percentage of NALFD identified was obtained using AVI (83.6%) before US, then WC (82.2%), FLI (79%), HIS (78.9%), BMI (77.3%), WHt_5R (76.9%), BRI (74.8%) and WHtR (73%). [47]

Knowledge Gaps and Training Needs

Knowledge gaps may hamper uptake of new guidelines for NAFLD screening in primary care and endocrinology clinics in an urban safety-net health care system. Implementation strategies focused on training and educating clinicians and informed by behavioral economics may increase screening. [48]

Primary care physicians (PCPs) are well suited to manage patients with non-alcoholic fatty liver disease (NAFLD), but the limited, existing research suggests inadequate knowledge about the natural history, diagnostic methods, and management of NAFLD. The purpose of this qualitative study is to further understand the knowledge and practices for the diagnosis and management of NAFLD among PCPs. [49]

Research has identified several barriers to optimal NAFLD care in primary care:

• Most respondents underestimated or did not know the prevalence of NAFLD (68%), did not use the recommended noninvasive tests for risk stratification (65%), and few were comfortable with scr [50]eening approaches
• Limited awareness of current guidelines and risk stratification tools
• Uncertainty about when to refer to specialists
• Time constraints in busy primary care practices

 

 

Treatment and Management Strategies

Lifestyle Interventions: The Foundation of Care

In the absence of approved pharmacological therapies, effective lifestyle interventions for NAFLD, such as dietary strategies and exercise training, are currently the therapeutic strategies of choice. [51] [52] Lifestyle, including dietary habits and physical activity, is a modifiable risk factor and thus stands as the main target for the prevention and treatment of NAFLD. [53]

Weight Loss Targets and Efficacy

Weight loss decreases cardiovascular and diabetes risk and can also regress liver disease. Weight reductions of ⩾10% can induce a near universal non-alcoholic steatohepatitis resolution [54]and fibrosis improvement. Weight reductions of ⩾10% can induce a near universal non-alcoholic steatohepatitis resolution and fibrosis improvement by at least one stage. However, modest weight loss (>5%) can also produce important benefits on the components of the NAFLD activity score (NAS). [55]

Dietary Interventions

Following a Mediterranean diet can reduce liver fat even without weight loss and is the most recommended dietary pattern for NAFLD. The Mediterranean diet is characterised by reduced carbohydrate intake, especially sugars and refined carbohydrates (40% of the calories vs. 50–60% in a typical low fat diet), and increased monounsaturated and omega-3 fatty acid intake (40% of the calories as fat vs. up-to 30% in a typical low fat diet). [56]

Physical Activity and Exercise

Both TV sitting (a reliable marker of overall sedentary behaviour) and physical activity are associated with cardio-metabolic health, NAFLD and overall mortality. A ‘triple hit behavioural phenotype’ of: i) sedentary behaviour, ii) low physical activity, and iii) poor diet have been defined. [57]

Real-World Effectiveness

Weight reduction was observed in 85.2% of the patients. Dietary reduction and physical exercise in the form of walking 5 km per day were effective for weight reduction in 85.2% of the patients and an overall 5.33% reduction of their baseline body weight. Decrease in liver stiffness was observed in 67.9% of the patients, and a one-stage reduction in fibrosis was observed in 40.5% of the patients, while a 2-point reduction in liver stiffness was observed in 52% of the patients; reversal of hepatic steatosis occurred in 16.4% of the patients. [58] [59] [60]

Evidence for Lifestyle Intervention Efficacy

To date lifestyle intervention is the only proven therapy to treat nonalcoholic fatty liver disease (NAFLD). In this study, we retrospectively analyze the influence of a structured, multimodal 52-week lifestyle intervention program on NAFLD fibrosis score (NFS) as a marker for liver fibrosis. [61]

The present study demonstrates that participants of structured multimodal lifestyle intervention programs with formula diets can improve their metabolic parameters, such as body weight, fasting glucose, HbA1c, and lipids, and substantially reduce their risk of advanced liver fibrosis. Primary care providers must be aware of the close link between impaired glucose metabolism and increased liver-related risk and refer their metabolically ill patients to effective programs. [62]

Pharmacological Interventions

Currently Available Options

No pharmacologic agents have regulatory approval in the United States for the treatment of NAFLD or NASH. Management is centered on efforts to reduce underlying obesity (lifestyle, medications, surgical or endoscopic interventions) and metabolic derangements (prediabetes, type 2 diabetes, hypertension, hyperlipidemia, and others). Current pharmacologic therapy for NAFLD is limited mainly to the use of vitamin E and pioglitazone, although other agents are being investigated in clinical trials. [63]

Based on the most recent American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver Diseases (EASL) guidelines, pioglitazone and vitamin E are approved as NAFLD treatment options. Apart from Vitamin E and Pioglitazone, trials over the past few years have tested mechanistically different drug types for NAFLD and shown promising results. [64]

Emerging Therapeutic Options

• GLP-1 Receptor Agonists

A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. [65] [66] This study found that the effect of GLP-1RAs on histologic resolution of NASH with no worsening of liver fibrosis (n=2 RCTs; WMD:4.08, 95%CI 2.54–6.56, p < 0.00001) has statistical significance. These results suggest that GLP-1RAs may be a potential and viable therapeutic approach as a targeted agent to intervene in disease progression of NAFLD and NASH. [67] [68]

Endocrinologists should lead multidisciplinary teams to implement recent consensus statements on NAFLD that call for screening and treatment of clinically notable fibrosis to prevent cirrhosis, especially in the high-risk groups (ie, people with obesity, prediabetes, or T2D). With no US Food and Drug Administration (FDA)-approved agents, weight loss is central to successful management, with pharmacological treatment options limited today to vitamin E (in people without T2D) and diabetes medications that reverse steatohepatitis, such as pioglitazone or GLP-1RAs.

• Resmetirom: First FDA-Approved Therapy

On March 14, 2024, after more than 25 years of intense research and a long series of failures, the Food and Drug Administration approved resmetirom as first drug for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis (now Metabolic-Associated Steatotic Liver Disease – MASLD). The present review covers this difficult process, finally providing a drug to complement lifestyle intervention, that has long been the sole approved therapeutic intervention. [69]

Resmetirom (Rezdiffra™) is an oral thyroid hormone receptor-β (THR-β) agonist being developed by Madrigal Pharmaceuticals, Inc., to target the key underlying causes of metabolic dysfunction associated steatohepatitis (MASH) [previously known as nonalcoholic steatohepatitis (NASH)]. In March 2024, resmetirom was approved for use (under accelerated approval) in conjunction with diet and exercise for the treatment of adults with noncirrhotic NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis) in the USA.

Mechanism of Action and Clinical Impact

The success of resmetirom highlights the potential advantages of targeting THR-beta, which exerts pleiotropic effects on multiple pathways involved in NASH pathogenesis, including lipid metabolism, glucose homeostasis, and inflammation. In the phase 3 MAESTRONASH trial, resmetirom notably improved NASH resolution, fibrosis, and LDL cholesterol levels compared to placebo, with a favorable safety profile.

 

Complications and Prognosis

Liver-Related Complications

Complications of NAFLD comprise progressive fibrosis, cirrhosis and hepatocellular carcinoma. [70] [71] Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhosis, liver failure, and complicated hepatocellular carcinoma. [72] [73]

Hepatocellular Carcinoma Risk

The relationship between NAFLD and hepatocellular carcinoma (HCC) reveals one of the most concerning long-term complications. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industr [74]ialized countries.

Importantly, The overall prevalence of cases without cirrhosis was 37% (95%CI 28 to 46). The overall prevalence of cases without cirrhosis was 37% (95%CI 28 to 46). One in three subjects with NAFLD-associated HCC presented without cirrhosis. [75] [76] [77] This finding has important implications for surveillance strategies and emphasizes the need for careful monitoring even in non-cirrhotic patients.

Patients with NAFLD without cirrhosis nor advanced fibrosis have a low incidence of HCC. [78] However, The incidence of hepatocellular carcinoma in patients with NAFLD without fibrosis is very low (0.15 per 1000 person-years), it is much higher in those with advanced fibrosis and cirrhosis (14.46 per 1000 person-years), while NASH is associated with an incidence of hepatocellular carcinoma that is ten times that of simple steatosis (10.41 per 1000 person-years vs 1.03 per 1000 person-years). [79]

Extrahepatic Complications

Cardiovascular Disease

NAFLD is also an independent risk factor for cardiovascular disease, extrahepatic neoplasia and other organ damage, such as renal insufficiency. [80] In addition, NAFLD is a risk factor for the development of other serious diseases, such as diabetes or cardiovascular disease. [81] [82]

NAFLD has a bidirectional association with components of the metabolic syndrome, and type 2 diabetes increases the risk of cirrhosis and related complications. [83] This bidirectional relationship complicates risk assessment and requires comprehensive metabolic management.

Diabetes and Metabolic Complications

The relationship between NAFLD and diabetes is particularly complex. Patients with NAFLD, diabetes, obesity, hypertension, and dyslipidaemia have HR 3·9 (95% CI 2·2–7·2) for hepatocellular carcinoma compared with patients with NAFLD and none or only one of these metabolic risk factors. In multivariate analysis, diabetes was the only one of these metabolic traits independently associated with hepatocellular carcinoma. This impact of diabetes on hepatocellular carcinoma risk was also found in patients with NAFLD who did not have cirrhosis. [84]

Prognostic Factors

Fibrosis as Key Determinant

There seems to be an increasing gradient of risk for hepatocellular carcinoma with increasing disease severity, particularly with hepatic fibrosis, although the incidence of hepatocellular carcinoma in individuals with non-cirrhotic NAFLD falls short of recommendations for hepatocellular carcinoma surveillance. Ideally, risk-prediction models can be developed with a focus on identifying patients with NAFLD without cirrhosis, in whom hepatocellular carcinoma surveillance is indicated. [85]

Long-term Outcomes

Currently, data are scarce regarding the long-term impact of histological progression or regression of non-alcoholic fatty liver disease (NAFLD) on subsequent risk of adverse clinical outcomes, including the development of end-stage liver disease and mortality. [86] However, emerging evidence suggests that patients with advanced fibrosis face increased risks of liver-related mortality and complications.

 

 

Future Directions and Research Priorities

Emerging Therapeutic Targets

The limited progress in approved drugs for treating NAFLD can be related to the multifactorial nature of the disease. The urgent need for new drugs for NAFLD treatment fosters the exploitation of new molecular targets. Rational Drug Design/Drug Repositioning based on new targets is a step forward for the discovery of pharmacological agents. [87] [88] [89]

Development of multitarget drug candidates with impact on NAFLD pathophysiology can reduce the disease burden. [90] This approach recognizes the complex, multifactorial nature of NAFLD pathogenesis and suggests that future therapeutic success may require combination strategies targeting multiple pathways simultaneously.

Nomenclature Evolution

The field has seen recent changes in disease nomenclature that reflect evolving understanding of pathophysiology. An international consensus panel has recently proposed to rename the disease to metabolic dysfunction associated with fatty liver disease (MAFLD). [91] 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical [92], indicating that the transition to new terminology (MASLD – Metabolic dysfunction-Associated Steatotic Liver Disease) does not substantially change patient populations or clinical approach.

Precision Medicine Approaches

However, the availability of a drug shown to reduce disease progression in advanced stages of diseases opens a series of questions that deserve even more intense research. How to generate an appropriate use of resmetirom in the community, limiting treatment according to predefined criteria and according to individual risk assessment? How to guarantee that both hepatic and non-hepatic comorbidities are appropriately targeted? [93] [94]

The approval of resmetirom is just the beginning of a new era in NAFLD therapeutics. Future research priorities include:

1. Development of biomarkers for patient stratification
2. Combination therapy approaches
3. Prevention strategies for high-risk populations
4. Cost-effectiveness analyses of screening and treatment programs
5. Integration of artificial intelligence and machine learning in risk assessment

Implementation Science

The approval of resmetirom has opened new avenues for NASH drug development and has provided valuable insights into the design of future clinical trials and treatment strategies. Given the complex nature of MAFLD, combining drugs with complementary mechanisms of action may provide a more effective approach to treatment.

Successful implementation of NAFLD care improvements will require:

• Enhanced primary care education and training programs
• Development of clinical decision support tools
• Streamlined referral pathways between primary and specialty care
• Cost-effective screening strategies
• Patient education and engagement programs

 

The Role of Family Physicians

Current Challenges and Opportunities

General practitioners will increasingly play a key role in dealing with this evolving but serious epidemic of NAFLD and associated metabolic complications. However, success will depend on the appropriate systems and mechanisms being in place in primary care and the proper motivation, support and education of the patient. [95]

Family physicians are uniquely positioned to address NAFLD through their longitudinal relationships with patients and their expertise in managing multiple comorbidities. Primary care is the ideal setting to institute multidisciplinary care, especially the involvement of dietitians and physical activity trainers in lifestyle intervention, as well as initiating the discussion of bariatric surgery in patients with severe obesity. [96]

Practical Implementation Strategies

Systematic Approach to Case-Finding

This review provides the primary care physician with: (a) a step-by step guide of how to identify NAFLD, (b) information to exclude common other causes of liver fat accumulation and (c) additional insight into relationships between NAFLD and other conditions such as obesity, cardiovascular disease and type 2 diabetes. [97]

Key implementation strategies include:

1. Integration of NAFLD screening into routine diabetes and obesity care
2. Use of standardized risk assessment tools (FIB-4, NFS)
3. Development of office-based protocols for lifestyle counseling
4. Establishment of clear referral criteria for specialty care
5. Longitudinal monitoring systems for disease progression

Clinical Decision Support

Simple fibrosis scores have high negative predictive values in excluding advanced liver fibrosis and future liver-related events and can be used in primary care as initial evaluation. An abnormal result should be followed by subsequent workup or specialist referral. [98]

Quality Improvement Opportunities

The primary purpose of this quality improvement project was to increase identification of NAFLD among patients with T2D followed in an endocrinology practice using an evidence-based algorithm to risk stratify patients. Pre- and post-intervention analysis revealed a 36% increase in screening for NAFLD post-intervention (P < 0.001). [99]

This demonstrates the potential for systematic quality improvement interventions to enhance NAFLD care in primary care settings. Successful programs typically incorporate:

• Provider education and training
• Clinical decision support tools
• Performance feedback and monitoring
• Patient engagement strategies
• Integration with existing workflow systems

 

 

Clinical Practice Guidelines and Recommendations

 

 

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Conclusion

NAFLD represents a growing challenge for family physicians and the broader healthcare system. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that is predicted to become also the most frequent indication for liver transplantation by 2030. [106] The disease’s silent progression and strong association with metabolic disorders place family physicians at the forefront of early detection and management efforts.

The evidence presented in this review demonstrates that effective NAFLD management requires a comprehensive approach combining lifestyle interventions, risk stratification through non-invasive testing, and emerging pharmacotherapeutic options. Clinical evidence strongly supports the role of lifestyle modification as a primary therapy for the management of NAFLD and NASH. This should be accompanied by the implementation of strategies to avoid relapse and weight regain. [107]

The recent approval of resmetirom marks a watershed moment in NAFLD therapeutics, providing the first FDA-approved medication specifically for NASH with fibrosis. However, this advancement also highlights the complexity of implementing precision medicine approaches in primary care settings and the need for continued research into optimal patient selection and treatment algorithms.

Family physicians have several key responsibilities in addressing the NAFLD epidemic:

1. Case-Finding and Early Detection: Implementing systematic screening approaches in high-risk populations, particularly those with diabetes, obesity, and metabolic syndrome.
2. Risk Stratification: Utilizing validated non-invasive tools like FIB-4 to identify patients requiring specialist referral and those suitable for primary care management.
3. Lifestyle Intervention Leadership: Providing evidence-based counseling on weight loss, dietary modifications, and physical activity, recognizing that lifestyle intervention remains the cornerstone of NAFLD therapy.
4. Multidisciplinary Coordination: Collaborating with specialists, dietitians, and other healthcare providers to deliver comprehensive care addressing both hepatic and extrahepatic manifestations of NAFLD.
5. Long-term Monitoring: Establishing systems for ongoing assessment of disease progression and treatment response, adapting care plans as new therapeutic options become available.

The challenges facing family physicians in NAFLD management include knowledge gaps, time constraints, and the need for enhanced clinical decision support tools. Knowledge gaps may hamper uptake of new guidelines for NAFLD screening in primary care and endocrinology clinics in an urban safety-net health care system. Implementation strategies focused on training and educating clinicians and informed by behavioral economics may increase screening. [108]

Addressing these challenges will require sustained efforts in medical education, quality improvement initiatives, and healthcare system redesign. The development of clinical decision support tools, standardized protocols, and enhanced communication pathways between primary and specialty care will be essential for optimizing NAFLD outcomes.

Looking ahead, several research priorities emerge:

• Development of more precise risk prediction models incorporating genetic, metabolic, and clinical factors
• Investigation of combination therapeutic approaches targeting multiple pathophysiological pathways
• Implementation science research to optimize care delivery models
• Cost-effectiveness analyses of screening and treatment strategies
• Long-term outcomes research to guide treatment decisions

The silent epidemic of NAFLD demands immediate attention from family physicians and the broader primary care community. By embracing evidence-based approaches to case-finding, risk stratification, and management, family physicians can play a pivotal role in preventing disease progression and improving outcomes for the millions of patients affected by this condition. The time for action is now, as the window for preventing the predicted surge in NAFLD-related complications remains open but is rapidly narrowing.

Success in addressing this epidemic will ultimately depend on the ability of family physicians to integrate NAFLD care into their existing practice models while maintaining focus on the comprehensive, patient-centered care that defines family medicine. This integration requires not only clinical knowledge and skills but also advocacy for healthcare system changes that support effective chronic disease management and prevention strategies.

The journey from recognition of NAFLD as a silent epidemic to effective clinical management represents one of the most remarkable opportunities in contemporary family medicine. By rising to meet this challenge, family physicians can demonstrate their essential role in addressing complex, multisystem diseases and their commitment to improving population health outcomes through evidence-based, patient-centered care.

 

 

 

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