A Functional Medicine Non Alcoholic Fatty Liver Disease (NAFLD) Protocol: Testing, Nutrition, and Supplements

In non-alcoholic fatty liver disease (NAFLD), liver cells may be replaced by fat due to metabolic imbalances. These changes in the liver tissue occur due to metabolic factors rather than from other insults to the liver, such as excessive alcohol use, other liver-damaging substances, or viral infections. A functional medicine approach may address this excess fat buildup in the liver by identifying and managing underlying metabolic dysfunction and imbalanced inflammation.

As related metabolic dysfunctions such as obesity and type 2 diabetes increase around the world, the number of people impacted by NAFLD is also rapidly rising. NAFLD can affect people of all ages, including children. NAFLD affects up to 46% of people in the United States and is becoming one of the most frequent causes of chronic liver disease and liver transplantation in the United States and Europe. 

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What is Non-Alcoholic Fatty Liver Disease (NAFLD)?

Non-alcoholic fatty liver disease refers to a group of conditions that occur when the liver gets filled with fat. NAFLD is subdivided into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) and is an increasing cause of liver dysfunction. In these conditions, the fatty changes in the liver tissue occur due to causes other than excessive alcohol use or other liver-damaging substances

The liver has many important functions, including metabolizing and regulating many chemical and nutrient levels in the blood, manufacturing coagulation factors to help balance blood clotting and bleeding, and excreting bile into the intestines to assist with the digestion of fats and carrying waste away from the liver. 

Early on, when fat replaces liver tissue with little or no inflammation or liver damage, it is known as non-alcoholic fatty liver (NAFL). As more and more fat builds up over time, along with imbalanced inflammation, it can contribute to liver injury and impair liver function as NAFL evolves into non-alcoholic steatohepatitis (NASH). When this chronic inflammation causes scarring in the liver, cirrhosis and liver failure can occur. 

Symptoms of Non-Alcoholic Fatty Liver Disease (NAFLD)

Especially in the early stages, NAFLD may not cause many noticeable symptoms. Once too much fat accumulates, it can cause pain from enlargement of the liver, which is felt in the center or the right upper part of the abdomen and can also cause fatigue.

If fat continues to accumulate along with an increase in inflammation, NAFL may evolve into NASH as the liver becomes damaged with impaired function. At this stage, people may experience symptoms reflecting liver damage like:

• Severe tiredness and weakness
• Weight loss
• Long-lasting itching

A physical exam may show signs of NAFL or NASH like: 

• Palpable, enlarged liver 
• Signs of insulin resistance, such as darkened skin patches over the knuckles, elbows, and knees (acanthosis nigricans)
• Yellowing of the skin or eyes
• Spider-like blood vessels on the skin
• Large amounts of fat around the waist
• Signs of cirrhosis, such as feeling an enlarged spleen, muscle loss, or fluid buildup in the abdomen.

If inflammation and damage persist over time, it can eventually lead to liver failure that may require a liver transplant. NASH can turn into cirrhosis as the liver develops scarring that impairs its functioning and causes symptoms like:

• Fluid retention 
• Bleeding inside of the body 
• Muscle wasting  
• Confusion

As fat takes over the liver with NAFLD, this further worsens inflammation and may increase the risk for diseases beyond the liver, such as: 

• type 2 diabetes mellitus 
• heart conditions
• chronic kidney disease

What Causes Non-Alcoholic Fatty Liver Disease (NAFLD)?

NAFLD and its associated conditions may arise from metabolic dysfunction and inflammation. Metabolic imbalances, including being overweight, having high levels of fat in the blood, especially triglycerides or LDL (“bad”) cholesterol, and having blood sugar issues like metabolic syndrome, prediabetes, and type-2 diabetes (T2DM), all may increase the risk of NAFLD.

Genetics

Genetics plays a role in NAFLD and may help explain why NAFLD is more common in certain racial and ethnic groups. Although NAFLD occurs in people of all races, it is most common among Hispanic individuals. 

Dysbiosis

Since there is a bidirectional crosstalk between the gut-liver, diet and gut health are key factors involved in the development of the metabolic dysfunction underlying NAFLD. The gut-liver axis is influenced by genetic, environmental, and lifestyle factors. Your diet, balance of microbes in your digestive tract, microbial metabolites, and bile acids all help to regulate metabolism and immunity in the gut and liver, which can influence the development of NAFLD. 

Different species of bacteria in the gut metabolize nutrients differently and impact how glucose and lipids are metabolized, so imbalances in bacteria in the intestines (dysbiosis) may contribute to metabolic syndrome, T2DM, and NAFLD. Imbalanced microbes in the gut can allow for an overgrowth of pathogens, increased intestinal permeability (leaky gut), chronic inflammation, and increased metabolic and detoxification demands on the liver. 

Small Intestinal Bacterial Overgrowth (SIBO) is a common type of intestinal dysbiosis that can contribute to increased intestinal permeability, potentially leading to the progression and development of NAFLD.

Leaky Gut 

Several factors can cause intestinal inflammation and damage, including stress, toxic exposures, inflammatory diets, medications, alcohol, food sensitivities, and low stomach acid. When the intestinal barrier becomes leaky or disrupted, more toxins may circulate in the blood and burden the liver. 

Processed Sugars & Fructose

Although fat takes over the liver tissue, consuming excess processed carbohydrates and sugars is a main dietary factor that may lead to the metabolic dysfunction associated with NAFLD. These processed sugars may switch on fat production in the liver. 

In particular, diets high in fructose may increase the risk of NAFLD since fructose goes directly to the liver when consumed, where it is converted into fat. In the form of high-fructose corn syrup, this sugar is commonly used to sweeten drinks and processed foods.

As sugars are converted into fat in the liver, more inflammation may develop, which can trigger worsening metabolic problems with blood sugar regulation, insulin resistance, and pre-diabetes. These excess sugars also contribute to increased fat in the belly (visceral fat) which has further metabolic consequences. In addition, these metabolic changes can involve elevated triglycerides and LDL (dangerous cholesterol particles associated with heart attacks) in the blood. 

Functional Medicine Labs to Test for Root Cause of Non-Alcoholic Fatty Liver Disease (NAFLD)

In addition to a physical exam and imaging studies like ultrasound or MRI of the liver that may show fat deposits and later scarring, functional medicine testing can assess the liver’s functioning and evaluate underlying metabolic dysfunction and dysbiosis that may contribute to NAFLD.

Hepatic Function Tests

A Hepatic Function Panel assesses liver function by measuring liver enzymes (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), proteins, and bilirubin (a substance in bile) in the blood may be normal in NAFL or begin to show elevations reflecting dysfunction or damage. Gamma Glutamyl Transferase (GGT) is another enzyme primarily made in the liver that can reflect that the body is trying to generate greater levels of glutathione to deal with detoxification or oxidative stress.

Blood Sugar Balance and Metabolic Markers

A comprehensive evaluation of metabolic health can help with targeting the underlying causes of NAFLD. The NutraEval FMV provides insights into cellular health, mitochondrial function, how the body is handling oxidative stress, methylation imbalances, and toxin exposure. 

Several tests are used to assess how the body handles sugars, including fasting glucose, hemoglobin A1c which measures average blood sugar level over the previous six weeks, fasting insulin, and C-peptide, a marker that the body is producing insulin.

These can help to identify insulin resistance, where sugars remain in the blood, potentially causing inflammation and damage to blood vessels, which over time, may lead to type 2 diabetes and NAFLD. Glucose tolerance testing and insulin tolerance testing can further look at how the body handles and processes sugars.

To further assess metabolic balance, a lipid panel including total cholesterol, HDL (“good” cholesterol), LDL (“bad” cholesterol), and triglycerides looks at the balance of fats and cholesterol in the blood. Additional lipid metabolism indicators include Lipoprotein(a), LDL particle number, and ApoB-containing lipoproteins (ApoB).

Inflammatory Markers

In spite of its non-specific nature, hs-CRP is a sensitive indicator of inflammation in the body and can therefore be used over time to determine trends in inflammation. 

Vitamin D

Vitamin D plays an important role in many bodily functions, including immunity, metabolic, and liver health. A deficiency in Vitamin D is common in chronic liver diseases, including NAFLD. Vitamin D influences the production of inflammatory cytokines and how the fat cells respond to inflammation, making it a possible contributing factor to fat build-up in the liver.

Assess Gut Health

Unaddressed food sensitivities, exposure to chemicals, antibiotics, a highly-processed diet, and other factors can make the gut leaky, which allows food particles and other substances directly into the bloodstream, where they may lead to the release of pro-inflammatory cytokines that tax the liver. A Comprehensive Stool Test like the GI-MAP measures gut bacteria, inflammatory and leaky gut markers, parasites, and yeast to assess the gut and guide individualized treatment aimed at restoring balance to the gut-liver axis.

SIBO Test

Testing for SIBO with a breath test can assess for any overgrowth of gut bacteria in the small intestine and should be considered since the imbalance of bacteria, inflammation, and gut permeability that occurs in SIBO can contribute to increased intestinal permeability, potentially leading to the progression and development of NAFLD.

Any Other Lab Test to Check 

The definitive test for diagnosing NAFLD is a liver biopsy to examine a tissue sample of the liver for fat, inflammation, and scarring. Imaging studies, like ultrasound or MRI, of the liver may show fat deposits and later scarring.

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Functional Medicine Treatment Protocol for Non Alcoholic Fatty Liver Disease (NAFLD)

A functional medicine approach to NAFLD may address the common underlying dysregulated metabolism, inflammation, and gut bacteria that underlie the condition. In addition to maintaining good blood sugar and insulin function as well as balancing high cholesterol/triglycerides, the most effective treatment for NAFLD may involve therapeutic changes to diet and lifestyle. 

Therapeutic Diet and Nutrition Considerations for NAFLD

While nutrition is a principal contributing factor in the development of the metabolic dysfunction underlying NAFLD, diet and lifestyle changes can often help manage or reduce the fat buildup in the liver. 

Anti-Inflammatory Diet for NAFLD

The Mediterranean diet is an anti-inflammatory diet that consists of healthy fats, vegetables, fruits, nuts, legumes, whole grains, fish, and seafood. It also aims to reduce red and processed meat intake, as well as limit excess sugars. A Mediterranean dietary pattern modified to include all low-glycemic index foods has beneficial effects on the risk factors associated with metabolic syndrome, insulin resistance, and NAFLD. It emphasizes the consumption of organic citrus fruit, vegetables, legumes, and complex carbohydrates. It also places a moderate emphasis on fish and olive oil as the primary fat source. When compared to the standard of care and a low-fat diet, the Mediterranean diet offered improved liver marker parameters, including liver function tests, insulin, blood sugar, lipid parameters, and liver stiffness in those with NAFLD/NASH. 

The Mediterranean diet can be adapted to provide nutrients that further support healthy liver function. Studies show that supplementing a Mediterranean-style diet with additional "green polyphenols," plant compounds found in green vegetables, further enhanced dietary health markers protective against cellular stress involved in fatty liver disease. 

Cruciferous vegetables like broccoli, cauliflower, kale, and Brussels sprouts as well as garlic and onions, are sulfur-rich to help with liver detoxification. 

Choline is needed for fat transport from the liver to cells throughout the body and for mitochondrial function. Low choline diets or a microbiome that produces less choline may lead to fat depositing in the liver. Choline is abundant in egg yolks, animal protein, chickpeas, and other legumes.

Sustainable Weight Loss

Caloric restriction, weight reduction of 5-10% in those who are overweight, and exercise have also been shown to improve liver function and histologic features of liver tissue in those with NAFLD. Slowly losing and maintaining a balanced weight can help reduce inflammation, and scarring in the liver. Following a personalized whole foods-focused diet like the Mediterranean diet that eliminates processed foods and common food allergens, including gluten, can help with sustainable weight loss while also improving the handling of sugars and gut health. 

Avoiding Liver Toxicants

Avoiding alcohol, high-fructose corn syrup, processed carbohydrates, and other substances that stress the liver may help to improve parameters reflecting NAFLD.

Supplements Protocol for NAFLD

Research suggests that supplementation with nutraceuticals such as silymarin, vitamin D, vitamin E, artichoke, curcumin, and probiotics may benefit patients with NAFLD and NASH. 

Silymarin

Silymarin is a powerful antioxidant extracted from milk thistle (Silybum marianum), which has been traditionally used for centuries for supporting liver and gallbladder health. In addition to its antioxidant properties that may help prevent free-radical damage to the liver and optimize mitochondrial function in the liver, silymarin is also anti-inflammatory and may help prevent fibrosis of liver tissue. It also has beneficial metabolic effects, potentially improving insulin resistance and accumulation of lipids in the liver after three months of use. Complexing silymarin in a phytosome with phosphatidylcholine increases its solubility for better oral bioavailability while maintaining its antioxidant properties. In a randomized double-blind study conducted on 180 patients with confirmed diagnosis of NAFLD/NASH, silymarin and vitamin E (silibine 188 mg, phosphatidylcholine 388 mg, vitamin E 180 mg) administered for 12 months resulted in the normalization of liver enzymes (transaminase), a significant reduction of gamma-glutamyl transferase levels, and the significant decrease of liver steatosis measured with ultrasound scan and liver biopsy. This protocol also resulted in improvement in fasting glucose, insulin levels, and insulin resistance. 

Silymarin Prescription

Dose/Duration:

Non-proprietary standardized extracts

• 420 mg/day for up to four years
• 2,100 mg for up to 48 weeks with measurable improvement in fibrosis and liver function at this dosing

Combination products

• Silibine 188 mg, phosphatidylcholine 388 mg, vitamin E 180 mg for 12 months

Vitamin D

Vitamin D is a fat-soluble hormone that plays a key role in regulating bone mineralization, immune response, cell differentiation, and inflammation, with important repercussions for liver health. In the human body, 90% of vitamin D is derived from the conversion of 7-dehydrocholesterol to cholecalciferol/Vitamin D3. This cholecalciferol is then hydroxylated in the liver and in the kidney, resulting in the activation of 1,25-hydroxy-cholecalciferol or calcitriol vitamin D. Calcitriol is the most active form of Vitamin D. 

Vitamin D may improve sensitivity to insulin and also has anti-inflammatory properties. In patients with confirmed NAFLD, taking oral vitamin D3 50,000 IU weekly for 12 weeks resulted in decreased liver enzymes and inflammation, as reflected by CRP levels, suggesting that vitamin D is an effective adjunctive treatment to improve metabolic, chemical, and inflammatory parameters. 

Vitamin D Prescription

Dose/Duration: 

50,000 IU once per week for 12 weeks, and 2,100 IU per day for up to 48 weeks, have been shown to be effective

Vitamin E

Because of its anti-inflammatory and antioxidant properties, vitamin E may help reduce fibrosis, liver enzymes, steatosis, and inflammation in patients with NAFLD. Vitamin E is frequently used in combination with silymarin. This is because the most effective dosage of Vitamin E to reduce inflammation and liver fibrosis is 40 times higher (800 IU/day) than the Recommended Daily Allowance (RDA). Doses 20 times higher than the RDA (400 IU/day) have been associated with an increased mortality risk. Therefore, vitamin E is often used at a lower, less-effective, but safer dosage in combination with other nutraceuticals like silymarin.  

Vitamin E Prescription

Dose/Duration: 

‍800 IU, once per day, minimum 2 years for nondiabetic adults with biopsy-proven NASH. Before starting therapy, the risks and benefits of high dose vitamin E therapy should be discussed with each patient.

Artichoke

Artichoke (Cynara scolymus) is an herb that has traditionally been used to support liver health. Studies show that supplementing with purified extract of fresh artichoke leaf juice may improve lipid levels and liver enzymes in patients with NASH and may improve liver structure on ultrasound imaging and liver enzyme and function markers (ALT, AST, total bilirubin) in patients with NAFLD.

Artichoke Prescription

Dose/Duration:

‍600 mg, once per day, minimum 2 months

Curcumin

Curcumin (Curcuma longa) is a natural polyphenol from turmeric with lipid-modifying, antioxidant, and anti-inflammatory properties that have shown protection against the development of hepatic steatosis and its progression to steatohepatitis. Studies suggest that curcumin supplementation may result in a significant reduction in liver enzymes, waist circumference, body mass index, and hepatic steatosis. 

Curcumin Prescription

Dose/Duration:

‍500-1000 mg, total per day, minimum 8 weeks

Probiotics

Since the microbiota has a significant influence over intestinal barrier integrity, dysbiosis, inflammation, immune tolerance, and the gut-liver axis, supplementation with probiotics can be helpful for NAFLD management. The literature suggests that probiotic supplementation to support a healthy microbiome may improve insulin resistance, liver enzyme levels, and the degree of lipid infiltration of the liver. For example, a meta-analysis suggested that probiotics improved liver enzymes, hepatic inflammation, hepatic steatosis, and hepatic fibrosis in those with NAFLD and NASH. 

Various specific strains have been studied for their impacts on liver health and fatty liver disease. For example, VSL #3, a high-potency multi-strain probiotic, may decrease triglycerides, inflammatory markers, and liver enzyme levels (ALT, AST, and GGT) and support liver health in those with NAFLD. Similarly, treatment with L. bulgaris or S. thermophilus may reduce the levels of liver function markers such as alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase. Other strains of probiotics like L. acidophilus and B. lactis obtained from yogurt resulted in significant improvements in liver function markers and cholesterol levels when consumed for 8 weeks.

Probiotics Prescription

Dose/Duration:

‍VSL #3 2 sachets/day for 3 months OR 1 tablet/day of 500 million of Lactobacillus bulgaricus and Streptococcus thermophilus for 3 months

When to Retest Labs

While there are no global consensus guidelines to screen for liver fibrosis in patients at high risk of NAFLD, such as those with diabetes, obesity, or metabolic syndrome, noninvasive screening tests can be followed. If markers of fatty liver disease are detected, appropriate lifestyle and diet changes should be considered with continued surveillance and repeat testing in 3 months to a year, depending on risk factors.

In those at high risk with elevated liver enzymes, liver function tests should be repeated after 3-6 months.

Since NAFLD often progresses silently, current guidelines recommend ultrasound screening and lab testing every six months to assess disease progression.

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Summary

NAFLD occurs when the liver becomes filled with fat. NAFLD can be divided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) and is an increasing cause of liver dysfunction and failure. 

While often there are no specific symptoms early in the disease, NAFLD can cause chronic liver dysfunction and lead to serious complications like liver failure if the underlying metabolic imbalances are not addressed. Since liver cells may be replaced by fat due to metabolic imbalances in NAFLD, a functional medicine approach may help identify and manage underlying metabolic dysfunction and imbalanced inflammation to individualize treatment for each patient.