Non-Alcoholic Fatty Liver Disease

NON-ALCOHOLIC FATTY LIVER DISEASE

Synopsis:
Background
Nutritional & Supplemental Support 
Suggested Supplementation
References

Approximately 10 – 35% of the population (depending on countries) suffers from non-alcoholic fatty liver disease or NAFLD. Many of its victims do not know they have it. NAFLD can go undetected for years and may eventually progress to inflammation and scarring of the liver (cirrhosis) and, in some cases, full-blown liver failure.

A formerly rare condition, its rapid emergence has been linked to skyrocketing rates of metabolic syndrome and “diabesity,” the term many experts use for co-occurring diabetes and obesity (Younossi 2008, Kaser et al 2010, Bondini and Younossi 2006).

While poor dietary choices are often to blame, research suggests that genetic factors may also play a role, as some people do not metabolize polyunsaturated fats properly, resulting in fatty deposits in the liver (Puri et al 2009).

As mainstream medicine continues to struggle in the search for drugs to manage this widespread condition, emerging scientific evidence has shed light on effective natural interventions that may halt or even reverse its progress.

 

Fat Overload, Liver Damage, and the Inflammatory Storm

NAFLD is defined as deposition of fat in the liver cells of patients with minimal or no alcohol intake and with no other known cause (Lirussi et al 2007). The term “NAFLD” refers to a group of related and progressive conditions closely associated with overweight and obesity (Schuppan et al 2010).

NAFLD starts off as a low-level disturbance characterized by dull right upper-quadrant abdominal discomfort and fatigue in most patients, but it is hardly benign (Raszeja-Wyszomirska et al 2008). Early NAFLD can ultimately progress to a more serious condition, nonalcoholic steatohepatitis (NASH) (Musso et al 2010). About a third of people with NAFLD will develop NASH (Raszeja-Wyszomirska et al 2008), and about 20% of people with NASH will go on to liver fibrosis and cirrhosis, with its accompanying risk of liver failure and even liver cancer (Schuppan et al 2010, Raszeja-Wyszomirska et al 2008, Mark et al 2010). Overall, people with NAFLD stand a 12% increased risk of liver-related death over 10 years (Raszeja-Wyszomirska et al 2008).

NAFLD has multiple interrelated causes. Primary mechanisms include obesity leading to steadily increasing insulin resistance coupled with an overabundance of circulating fatty acids. These factors fuel one another in a destructive cycle (Kaser et al 2010). Together with advanced glycation end-products (AGEs), these events lead to increased oxidant stress and ultimately inflammation, cell death, and fibrous destruction of liver tissue (Younossi 2008, Kaser et al 2010, Raszeja-Wyszomirska et al 2008).

Too much fatty acids and abnormal lipid profiles creates “lipotoxicity” and directly poison liver tissue (Musso et al 2010, Schaffer 2003, Perez-Martinez 2010). As fat builds inside liver cells, they begin churning out a storm of fat-related cytokines known as adipokines, which fan the inflammatory of metabolic syndrome and NAFLD (Polyzos et al 2010).

Of course, what we eat is as important as the calories it contains. One of the major bad factor in our diet today is fructose, found in high quantities in high-fructose corn syrup (Parker-Pope 2010). Fructose promotes formation of new fat molecules in the liver, blocks breakdown of existing fats, stimulates free radical production, and promotes insulin resistance (Lim et al 2010). An increasing number of studies are linking increased fructose consumption with NAFLD and its deadlier consequence, non-alcoholic steatohepatitis (NASH) (Abdelmalek et al 2010). Patients with NAFLD consume 2-3 times as much fructose as do control patients (Ouyang et al 2008).

 

Diagnosis of NAFLD

In order to make a diagnosis of NAFLD, a physician considers both clinical data about the patient, and, when appropriate, data from a liver biopsy (for definitive diagnosis). The first indication that NAFLD might be present is rarely a symptom, but rather a finding of elevated levels of liver enzymes in the blood, indicating early liver cell damage. Other treatable causes of liver disease must be ruled out by appropriate testing (e.g., hepatitis B or C), and other liver functional parameters (e.g., blood clotting factors) should also be measured. Some physicians will do an imaging study such as a liver ultrasound, but normal appearance of the liver does not rule out NAFLD. Alcoholic fatty liver, which can closely resemble NAFLD, must be ruled out. This can be done by reliably establishing the absence of substantial alcohol intake (less than 20-40g of alcohol per day, equivalent to 2-3 drinks).

 

Treatment of NAFLD

Medical science has proved relatively helpless at preventing or treating NAFLD and NASH. Lifestyle interventions such as steady, gentle weight loss and regular exercise have been the only interventions that offered any hope (Schuppan et al 2010, Musso et al 2010). The only successful pharmaceutical intervention for dealing with NAFLD has been metformin (used for diabetes).

 

In contrast to the failure of most pharmacological therapies, numerous nutritional approaches show real promise in slowing the development and progression of NAFLD.  Eight interventions have scientifically validated effectiveness.

 

Vitamin E

Scientists began a series of studies on NASH (the advanced middle stage of NAFLD) and vitamin E in 2004. Based on their knowledge that NASH arises from persistent insulin resistance and oxidative stress, they examined the effects of pioglitazone (Actos®), an insulin-sensitizing drug, and vitamin E. Patients receiving both vitamin E (400 IU per day) and pioglitazone (30 mg per day) had improvements in more parameters than did patients on vitamin E alone (Sanyal et al 2004).

In a follow-up study, subjects received either vitamin E (800 IU per day) or pioglitazone (30 mg per day), or placebo, for 96 weeks.

Both treatments improved levels of liver cell-injury markers in blood, and both reduced liver fat levels and inflammation. But only vitamin E produced significant improvements in the appearance of liver tissue on biopsies (Sanyal et al 2010). Here are some clues that explain these otherwise startling results.

Vitamin E is a powerful antioxidant, and an obvious choice once the role of oxidant stress was made clear in NAFLD (Medina and Moreno-Otero 2005). People with fatty liver disease and NASH have depressed levels of vitamin E in their blood, the result of increased oxidation (Bell et al 1992, Bahcecioglu et al 2005). Even relatively low-dose vitamin E (450 IU/day) can reduce circulating liver enzymes, a chemical marker of liver cell injury (Hasegawa et al 2001, Bernal-Reyes and Escudero 2002).

Important animal studies refine our understanding of how vitamin E works. One study provided the first evidence that vitamin E can prevent NAFLD before it develops, largely by reducing oxidative stress, inflammation, and liver cell death by apoptosis (Nan et al 2009). Another study demonstrated a vitamin E-related reduction in oxidative damage and tissue levels of the inflammatory mediator TNF-alpha, while beneficially reducing PPAR-gamma activity (Raso et al 2009). This wealth of animal and now human data clearly supports daily use of 800 – 1,200 IU of vitamin E for prevention and treatment of NAFLD and NASH.

 

Omega-3 Fatty Acids

Omega-3 fatty acids attack the problem of lipotoxicity, while contributing considerable anti-inflammatory activity of their own (Perez-Martinez 2010). People and experimental animals with insufficient omega-3 in their diets are prone to NAFLD and type 2 diabetes, suggesting that supplementation might reverse (or prevent) the process (Perez-Martinez 2010, Pachikian et al 2008, Zelber-Sagi et al 2007, Cortez-Pinto et al 2006).

Increasing the amount of unsaturated fats like omega-3s in cell membranes is associated with improved insulin sensitivity (Martin de Santa Olalla et al 2009). And supplementation with omega-3 rich fish oil results in activation of the important metabolic sensor, called PPAR-alpha, in liver cells, suppressing production of new fat molecules (Larter et al 2008). Omega-3s also contribute to improved insulin sensitivity, a reduction in serum triglycerides, and stimulation of fat utilization in liver tissue and skeletal muscle (Ukropec et al 2003).

A long-term human trial, using 1,000 mg per day of omega-3, revealed significant decreases in serum markers of liver cell damage, triglyceride levels, and fasting glucose. Most impressively, supplemented patients display improvement of their livers’ appearance and blood flow on ultrasound exams, providing graphic evidence of the supplements’ benefits (Capanni et al 2006). Another study found that supplementation with 751 mg eicosapentaenoic acid (EPA) and 527 mg docosahexaenoic acid (DHA) 3 times daily for 24 weeks decreased triglyceride levels in individuals with NAFLD (Hatzitolios et al 2004). Olive oil also decreases accumulation of triglycerides in the liver during NAFLD, but fish oil provided better antioxidant activity (Hussein et al 2007). Olive oil also independently improves postprandial triglyceride levels in blood and upregulates glucose transporter in liver. At the same time, it improves insulin resistance by decreasing liver inflammation (Assy et al 2009). And long-term consumption of olive oil enriched with omega-3 fats in patients with NAFLD is able to improve liver texture on ultrasound exams, while improving serum markers of liver injury and increasing protective adiponectin levels (Sofi et al 2010).

Clearly the omega-3 fatty acids have earned their designation as an innovative therapy for nonalcoholic fatty liver disease (Xin et al 2008).

 

S-Adenosylmethionine (SAMe)

Their constant exposure to oxidant and toxic stresses makes liver cells especially vulnerable to depletion of glutathione (GSH), a natural antioxidant that participates in many liver detoxification reactions (Kwon do et al 2009, Caballero et al 2010). The nutrient SAMe can replenish GSH levels and restore liver cell protection to normal (Oz et al 2006). In individuals with alcoholic or non-alcoholic liver disease, supplementation with 1,200 mg SAMe daily increased liver glutathione levels (Vendemiale et al 1989). Studies using agents that increase SAMe levels are known to reduce severity of NAFLD (Kwon do et al 2009, Abdelmalek et al 2001).

SAMe and other liver antioxidants improve levels of liver enzymes, an early marker of cell damage (Chang et al 2006). SAMe supplements improve microscopic features of NAFLD associated with fatty degeneration, inflammation, and tissue death. And SAMe also down-regulated damaging pro-inflammatory genes in an animal model of NAFLD (Oz et al 2006).

A major discovery about SAMe is that it directly stops progression of relatively mild NAFLD to dangerous NASH (Wortham et al 2008).

 

Silymarin (Milk Thistle)

Extracts of milk thistle have long been used for liver protection. Silymarin is composed of six major active molecules such as silybin, which are known as flavolignans, having exceptional antioxidant and anti-inflammatory activity (Schrieber et al 2008, Feher et al 2008).

One very effective combination is silymarin plus vitamin E and phospholipids (such as phosphatidylcholine); this approach improves the overall antioxidant activity of the compound (Loguercio et al 2007). In animal studies the combination limited liver depletion of the natural antioxidant glutathione, and reduced mitochondrial stress damage (Serviddio et al 2010). Human trials have shown that a preparation providing 376 mg silybin, 776 mg phosphatidylcholine, and 360 mg vitamin E produces therapeutic effects in patients with a variety of different forms of liver damage, improving insulin resistance, reducing liver fat accumulation, and reducing blood levels of markers of liver scarring (Trappoliere et al 2005, Federico et al 2006, Trappoliere et al 2005).

 

Phosphatidylcholine and PPC

Phospholipids—fat molecules with phosphate groups attached—are major constituents of cell membranes in mammals. One of the most important phospholipids in humans is phosphatidylcholine (PC). Higher amounts of PC in cell membranes help to assure membrane integrity in the face of oxidative and other stresses; they also help limit the progression of NAFLD into NASH (Li et al 2006).

A particularly rich source of PC molecules is a mixture called polyenylphosphatidylcholine (PPC), derived from soybeans (Lieber 2004). PPC supplements in animals attenuate nonalcoholic liver fibrosis and even accelerate its regression (Ma et al 1996). PPC appears to exert this effect in part by blocking oxidant damage to cell membranes (Aleynik et al 1997, Lieber et al 1997, Navder et al 1999). A separate mechanism is reduction in the high cholesterol levels that precede NAFLD formation (Polichetti et al 2000). PPC also prevents proliferation of scar tissue in NAFLD and other forms of liver toxicity (Brady et al 1998). And PPC restores liver cell levels of SAMe, providing additional liver protection (Aleynik et al 2003).

 

Resveratrol

Resveratrol protects liver tissue against the ravages of alcoholic fatty liver disease through its antioxidant effects, buffering the impact of alcohol (Kasdallah-Grissa et al 2007). It also activates two critical signaling molecules, SIRT1 and AMPK, which are inhibited by alcohol, and are also dysfunctional in metabolic syndrome (Ajmo et al 2008, Buettner et al 2010, de Kreutzenberg et al 2010, Kraegen et al 2009). Those effects make it highly promising for prevention of NAFLD, the liver manifestation of metabolic syndrome. In animal studies, resveratrol activates AMPK, which in turn reduces liver fat accumulation, suppresses new liver fat formation, and reduces insulin resistance (Aoun et al 2010, Bujanda et al 2008, Shang et al 2008).

 

 

NAFLD and NASH are progressive conditions that require patient collaboration with a qualified physician. The goals of therapy are:

• Reduce the accumulation of fat in liver tissue by decreasing new fat synthesis and increasing utilization of existing fat stores in the liver.
• Minimize free radical production, and enhance free radical scavenging in liver tissue.
• Reduce or eliminate the inflammatory responses of liver tissue to prevent progression of NAFLD to the more deadly NASH, which is a precursor of liver failure.

The following supplements have been shown to boost liver health and help manage NAFLD:

Vitamin E: 800 IU daily includes at least 200 mg gamma tocopherol.

Omega-3 fatty acids: 700 mg EPA and 500 mg DHA daily

S-adenosylmethionine (SAMe): 1200 mg daily

Silymarin (milk thistle extract) with Phospholipids:  900 mg daily

Polyenylphosphatidylcholine (PPC): 900 mg daily

Trans-resveratrol: 500 mg daily

 

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