Chronic Liver Disease (NAFLD/NASH). Symptoms, Causes, Diagnostic Testing, Treatment

Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. It is a condition characterized by the accumulation of fat in the liver without a history of significant alcohol consumption. When this condition progresses to inflammation and hepatocellular damage, it is referred to as non-alcoholic steatohepatitis (NASH). NAFLD encompasses a wide spectrum of conditions, ranging from simple steatosis to progressive hepatic fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma.

Although for many years it was considered relatively benign, both NAFLD and especially NASH have been shown to be significant risk factors for cardiovascular disease, type 2 diabetes, and an overall increase in mortality.

Early diagnosis and intervention can significantly prevent disease progression. In this context, the application of specialized testing, both conventional diagnostic tools and tools from the field of functional medicine, plays a critical role in prevention, monitoring, and personalized treatment.

Epidemiological Data

The global incidence of NAFLD has increased dramatically in recent decades, primarily due to the obesity epidemic and the rise of metabolic syndrome. According to specific meta-analyses (Chalasani et al., 2018), the global prevalence of NAFLD is estimated at 25-30% of the general population, while NASH affects approximately 5–7%.

In Europe, the average prevalence of NAFLD ranges between 20% and 30%, with higher rates observed in Northern and Eastern countries. In Greece, although epidemiological data are limited, the estimated prevalence is also around 25% of the general population. Among specific groups, such as patients suffering from type 2 diabetes or obesity, prevalence exceeds 60%.

NAFLD is currently the leading cause of elevated liver enzymes in asymptomatic adults and the second most common cause of liver transplantation in the United States, with expectations that it will soon take the lead.

Factors influencing epidemiology:

Age: More common in individuals over 40 years old.
Sex: Slightly more prevalent in men, but NASH is more frequent in postmenopausal women.
Metabolic syndrome: Present in 70% of cases.
Sedentary lifestyle and poor diet: Key contributing factors.

Recent advances in the understanding of NAFLD have led to its reclassification under the term MAFLD (Metabolic Associated Fatty Liver Disease), to highlight its metabolic basis.

Symptoms and Signs of NAFLD / NASH

Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are characterized by a long asymptomatic course, especially in the early stages. For this reason, the condition is often incidentally discovered during routine checkups or examinations performed for unrelated reasons.

Common symptoms (when present)

Fatigue: Generalized, chronic fatigue without an apparent cause is one of the most common but non-specific symptoms of NAFLD.
Sensation of heaviness or discomfort in the right upper quadrant of the abdomen: Often due to mild hepatomegaly (enlargement of the liver), patients may experience pressure or discomfort in the liver area.
Loss of energy and concentration: Especially in advanced stages, liver detoxification capacity may be compromised, affecting cognitive function.
Indigestion or bloating: In patients with metabolic syndrome, these symptoms may occur not necessarily due to liver dysfunction, but as comorbid manifestations.

Clinical signs (mainly in advanced stages)

Mild hepatomegaly: Detected through physical examination or abdominal ultrasound.
Elevated liver enzymes (ALT, AST): Laboratory findings that often raise initial suspicion for NAFLD.
Insulin resistance: A frequent finding in patients with NAFLD, closely related to the hepatic lipogenesis mechanism.
Obesity, increased waist circumference, and hypertension: Common clinical presentations accompanying NAFLD, as part of the metabolic syndrome.

Signs indicating disease progression

Jaundice: Appears in cases of advanced fibrosis or cirrhosis.
Ascites, lower extremity edema: Signs of liver decompensation.
Spider angiomas, palmar erythema: Classic signs of chronic liver disease.
Coagulation disorders: May appear in advanced stages due to decreased synthesis of clotting factors by the liver.

It is important to note that the absence of symptoms does not exclude the presence of disease progression. For this reason, a preventive approach, through laboratory testing, is critical, especially in individuals with high cardiometabolic risk.

Deeper Causes of NAFLD / NASH

Non-alcoholic fatty liver disease is not merely a result of lipid accumulation in hepatocytes. It is a multifactorial syndrome intricately linked to metabolic, hormonal, dietary, and genetic disturbances. The deeper causes contributing to both the onset and progression of the disease go far beyond obesity and involve a complex interplay of biological and environmental factors.

Insulin Resistance
Insulin resistance is the central pathophysiological mechanism in NAFLD. It leads to increased lipolysis in adipose tissue, raising the influx of free fatty acids to the liver. This results in hepatocellular lipid overload, endoplasmic reticulum stress, and inflammation. Insulin resistance is also associated with increased production of atherogenic lipoproteins, worsening cardiovascular risk.

Obesity and Sedentary Lifestyle
Visceral fat accumulation promotes hepatic lipogenesis and disrupts liver microcirculation. Obesity is linked to subclinical inflammation, hormonal imbalance (e.g., leptin, adiponectin), and oxidative stress. Physical inactivity further decreases insulin sensitivity and worsens the metabolic profile.

Western-type Diet
Excess intake of saturated fats, sugars, and particularly fructose increases hepatic de novo lipogenesis and intracellular fat storage. Fructose is metabolized almost exclusively in the liver, leading to the production of uric acid and inflammatory cytokines. Simultaneously, the lack of antioxidants and fiber exacerbates oxidative stress and reduces hepatic resilience.

Gut Dysbiosis: The Gut-Liver Axis
Increased intestinal permeability ("leaky gut") allows endotoxins (e.g., LPS) to enter the portal circulation, activating Kupffer cells and triggering inflammation. Dysbiosis (microbiome imbalance) has been implicated in NAFLD pathogenesis via altered bile acid metabolism and short-chain fatty acid (SCFAs) profiles.

Hormonal Factors
In women, estrogen deficiency after menopause is associated with increased hepatic lipogenesis. Hypercortisolemia and hypothyroidism are also endocrine disorders that predispose to NAFLD. Polycystic ovary syndrome (PCOS) is linked to the development of NAFLD even in normal-weight women.

Genetic and Epigenetic Factors
Several gene variants have been implicated in NAFLD susceptibility, most notably PNPLA3, which is associated with an increased risk of fibrosis and hepatocellular carcinoma. Epigenetic mechanisms, including DNA methylation and microRNAs, influence gene expression related to lipid metabolism and hepatic inflammation.

Pharmaceutical and Environmental Factors
Medications, such as corticosteroids, tamoxifen, and amiodarone, can induce drug-related steatosis. Additionally, exposure to environmental toxins, such as endocrine disruptors (e.g., BPA), can impair hepatic enzyme function and contribute to the disease process.

Diagnostic Testing for NAFLD / NASH

A thorough diagnostic approach is essential for assessing the severity of NAFLD, identifying contributing mechanisms, and designing personalized interventions. Evaluation involves a combination of conventional biochemical tests, advanced functional analyses, and imaging methods.

(a) Conventional Laboratory Tests
The standard tests used in the diagnostic evaluation of NAFLD primarily include biochemical markers of liver function, lipid profile parameters, and indicators of inflammation or metabolic dysfunction, such as:

SGPT (ALT). Alanine aminotransferase is a liver-specific enzyme. It tends to rise in early stages of NAFLD and serves as a marker of hepatic inflammation.
SGOT (AST). Aspartate aminotransferase is less liver-specific than ALT but increases in more advanced hepatic injury. The AST/ALT ratio may offer clues to the presence of fibrosis.
gamma-Glutamyl Transferase (GGT). A sensitive marker of hepatic dysfunction, often elevated in fatty liver cases—particularly those of metabolic origin, and associated with oxidative stress.
Ferritin. Though a marker of iron stores, ferritin levels rise during chronic inflammatory or metabolic stress. Elevated ferritin is linked to increased fibrosis risk in NASH.
Total Cholesterol. Reflects overall lipid status. Often elevated in patients with NAFLD as part of a broader dyslipidemic profile.
Triglycerides. High levels are associated with increased hepatic lipogenesis and are common in metabolic dysfunction, which often accompanies NAFLD.
Glycosylated Hemoglobin (HbA1c). Reflects average blood glucose over the past 2–3 months. Elevated values suggest impaired glucose metabolism and may indicate disease progression.
FIB-4 Fibrosis Index. A non-invasive marker calculated using age, AST, ALT, and platelet count. It helps stratify fibrosis severity in NAFLD patients and determine who may need further testing (e.g., elastography). Widely used and clinically validated.

(b) Functional Medicine Tests

Liver Detoxification Function (Phase I & II) - DetoxScan®
A comprehensive panel consisting of specialized tests, including markers of oxidative stress, antioxidant enzyme activity, glutathione levels, methylation capacity, and biomolecular damage indicators. Such a multi-dimensional approach is valuable for evaluating the liver's capacity to metabolize and eliminate toxic substances, and it supports the design of personalized nutritional or supplement-based interventions.

Gut Microbiome - EnteroScan®
Analyzes the composition of the intestinal microbiota. Disruptions in the gut microbiome play a significant role in the pathogenesis of NAFLD through the gut–liver axis.

Fatty Acid Profile (Ω3, Ω6, Saturated) - ΩmegaScan®
Analyzes the balance between inflammatory and anti-inflammatory fatty acids. A key tool for therapeutic nutritional planning in NAFLD. Imbalance in fatty acid profiles may promote hepatic inflammation and fibrosis.

Advanced Metabolic Syndrome Testing
-EnteroScan® Obesity (Obesity & Metabolic Disorders)
-Insulin Resistance Testing, HOMA-IR Index
These are critical assessments for evaluating insulin resistance and other metabolic dysfunctions, which represent key pathophysiological mechanisms underlying NAFLD.

(c) Other Tests - Imaging Methods to investigate NAFLD / NASH

Abdominal Ultrasound
Liver Elastography (FibroScan)
Magnetic Resonance Imaging (MRI–PDFF)
Computed Tomography (CT)
Liver Biopsy

Therapeutic Approaches for NAFLD / NASH

The primary therapeutic strategy for NAFLD focuses on addressing the underlying causes, improving the metabolic profile, and preventing progression to fibrosis or cirrhosis. As of today, no pharmaceutical treatment has received formal approval specifically for NAFLD or NASH, so therapy is based on a combination of conventional and natural approaches.

Metformin. Used to manage insulin resistance. While it helps improve glycemic control, studies have not shown significant histological improvement in NAFLD. Commonly prescribed in type 2 diabetes.
Pioglitazone. A thiazolidinedione that reduces hepatic inflammation and fibrosis in NASH patients, particularly those with type 2 diabetes. Not recommended for patients with heart failure.
Vitamin E (800 IU/day). Demonstrates antioxidant effects and histological improvements in non-diabetic NASH patients. Long-term use should be monitored due to potential cardiovascular risks.
GLP-1 analogs (e.g., Liraglutide, Semaglutide). Antidiabetic agents that promote weight loss and have shown promise in reducing liver fat and inflammation. Currently under investigation for broader application in NAFLD.
Statins. Safe for most patients with NAFLD. Used to manage hypercholesterolemia and reduce cardiovascular risk. Do not worsen liver function and may provide additional vascular benefits.
Nutrition: Dietary intervention is the most impactful tool in NAFLD management. The goal is to reduce liver fat, improve insulin sensitivity, and prevent disease progression.
- Mediterranean Diet: Rich in monounsaturated fats (olive oil, fish), antioxidants (fruits, vegetables), and dietary fiber. Shown to significantly reduce hepatic fat accumulation.
- Fructose, trans fat, and refined carbohydrate avoidance: Critical for reducing hepatic lipogenesis and oxidative stress.
- Coffee consumption, without sweeteners: Associated with a reduced risk of hepatic fibrosis.
- Low-glycemic load eating patterns: Help regulate insulin levels and control de novo lipogenesis.
- Weight Loss Recommendations:
  - ≥7% body weight loss improves inflammation
  - ≥10% can induce fibrosis reversal
Exercise and Physical Activity: Regular physical activity improves insulin sensitivity, reduces visceral fat, and enhances anti-inflammatory responses.
- Aerobic exercise (e.g., walking, cycling, swimming): At least 150 minutes per week.
- Resistance training (e.g., weights, resistance bands): Helps reduce abdominal adiposity and improves metabolic markers, even without weight loss.
- Combined aerobic and resistance training: Offers the most effective results for liver and metabolic health.
Omega-3 Fatty Acids: Reduce triglyceride levels and improve hepatic steatosis. Recommended dose: 2-4 g/day. Especially useful in patients with hypertriglyceridemia or metabolic syndrome.
Silymarin (Milk Thistle): A botanical extract with antioxidant and hepatoprotective properties. Typical dose: 140-420 mg/day. Suitable for mild-to-moderate liver dysfunction.
N-Acetylcysteine (NAC): An antioxidant precursor to glutathione. Dose: 600-1200 mg/day. Can be combined with Vitamin E for enhanced effect.
Vitamin D: Deficiency is associated with NAFLD. Supplementation is advisable when levels are suboptimal. Monitor for overdosage.
Probiotics/Prebiotics: Help regulate gut microbiota. Recommended especially in patients with dysbiosis and gastrointestinal symptoms. May influence liver inflammation through the gut-liver axis.

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