INL Education - Non-Alcoholic Fatty Liver and Nutraceutical Intervention

New ideas on Non-Alcoholic Fatty Liver and its treatment with nutraceutical intervention

Nonalcoholic fatty liver disease (NALFD) affects about 30% of adults and over half those over 50 and some 70% of those with diabetes. It is now estimated in 2020 to have a worldwide prevalence of 25%.(1)

A more alarming statistic from the largest prospective cohort of nonalcoholic steatohepatitis (NASH) showed that a larger number of patients with NAFL are likely to progress to NASH (46.9%) than previously thought as well as confirming that fibrosis improves of progresses in approximately 30% during a mean period of 4.9 years. (2).
The association between NAFLD and obesity

The Faculty of Medicine at Chinese University Hong Kong (CUHK) conducted two prospective studies from 2006 to 2015. In the first study, 911 citizens were randomly selected from the general population. They underwent magnetic resonance imaging and had their liver fat and fibrosis measured with a FibroScan machine. Using the Asian definition of obesity (BMI, ≥ 25kg/m2), 210 subjects of the study were classified as obese and 701 as non-obese. Findings showed that 61% of obese subjects suffered from NAFLD.(3)

CUHK published the world’s largest study on Epidemiology of NAFLD in Diabetic Patients shows fatty liver causing NASH or Cirrhosis in 1 out of 5 patients. It is worth noting that 19% of the non-obese subjects also suffered from NAFLD. The non-obese NAFLD patients had lower markers of liver injury and fibrosis, suggesting that the severity of their disease was less.(4)

Moreover, the study findings identified enlarged waist circumference, elevated blood sugar (HbA1c), insulin resistance, higher ferritin level, and the presence of polymorphism of the PNPLA3 gene as risk indicators of NAFLD in non-obese patients.

Recent studies emphasize the role of insulin resistance, triglyceride accumulation, adipokines, oxidative stress to LDL and subsequent lipid peroxidation as well as smaller LDL particle size and infiltration to the endothelium, release of pro-inflammatory cytokines, plus mitochondrial dysfunction in the development and progression of NAFLD into CVD. The pathogenesis of NAFLD and metabolic syndrome has common pathophysiological mechanisms, with insulin resistance as a key factor.(5)
The 2-hit hypothesis, comorbidities and the pathogenesis of fatty liver
The pathogenesis of NAFLD is unclear although it is closely related to excess consumption of calories relative to needs, obesity and related metabolic risk factors (diabetes and high LDL cholesterol).

Initial theories regarding its development have been based on the ‘2-hit hypothesis’, where the “first hit” involves hepatic lipid accumulation, and insulin resistance is proposed to be the key contributing factor for steatosis development.

Oxidative stress followed by lipid peroxidation, as well as the action of proinflammatory cytokines (e.g. tumor necrosis factor [TNF]-α), adipokines and mitochondrial dysfunction initiate the second hit, which progresses from simple steatosis to nonalcoholic steatohepatitis (NASH). A “third hit”, also caused by oxidative stress, inhibits the replication of mature hepatocytes resulting in the over population of the hepatic oval cells.(6)

Another key hallmark of NALFD is the variable prevalence, presentation and causation over different populations, most of which are attributable to the PNPLA3 gene mutation but also environmental and microbiome-oriented factors. The table below highlights the extent of these vary factors and their associated evidence bases.
It is worthwhile to consider fatty liver as the liver manifestation of metabolic syndrome. Thus it’s best to include a fibroscan investigation should the patients fasting insulin, HbA1c, lipids, LFT and/or blood pressure show even minor elevations – as are usual in metabolic syndrome. With the appropriate assessment it is possible to minimize later diabetic and cardiovascular manifestations.
Gut microbiota, dysbiosis and probiotics for fatty liver
As referred to the above table, hepatic triglyceride accumulation is not always derived from obesity; gut microbiota can also play a role in the development of insulin resistance, hepatic steatosis, microinflammation and fibrosis.(7)
Recently, it has been reported that NAFLD might be linked to small intestinal bacterial overgrowth (SIBO), which induces liver injury by gut-derived lipopolysaccharides (LPS) and TNF- α production.(8) It has also been suggested that gut microbiota increases the liver’s exposure to endotoxins, thus promoting steatohepatitis.(9)
On the other hand, probiotics can strengthen the intestinal wall, reducing its permeability, bacterial translocation, and endotoxemia according to animal and human studies. They can also reduce oxidative and inflammatory liver damage, while improving the histological state in certain situations. Research that has been conducted on probiotics and NAFLD, highlights their efficacy as a novel therapeutic option for the treatment of this condition.

On the other hand, probiotics can strengthen the intestinal wall, reducing its permeability, bacterial translocation, and endotoxemia according to animal and human studies. They can also reduce oxidative and inflammatory liver damage, while improving the histological state in certain situations. Research that has been conducted on probiotics and NAFLD, highlights their efficacy as a novel therapeutic option for the treatment of this condition.
The potential pathophysiology that links gut dysbiosis to NAFLD can be summarized as:

(1) disrupting the balance between energy harvest and expenditure,
(2) promoting hepatic inflammation (impairing intestinal integrity, facilitating endotoxemia, and initiating inflammatory cascades with cytokines releasing)
(3) altered biochemistry metabolism and GM-related metabolites (i.e., bile acid, short-chain fatty acids, aromatic amino acid derivatives, branched-chain amino acids, choline, ethanol)
(4) the association between gut microbiota dysbiosis and metabolic syndrome, obesity, type 2 diabetes, NAFLD. For instance, patients with NASH had a lower percentage of Bacteroidetes compared to both NAFLD and healthy controls. and Ruminococcus is linked to liver fibrosis.(11)
(5) NASH patients also had an increased abundance of alcohol-producing bacteria that could increase serum alcohol levels and oxidative stress, resulting in liver injury.(12)
(6) NAFLD patients had higher concentrations of fecal propionate and isobutyric acid and serum 2-hydroxybutyrate and L-lactic acid.(13)

Due to the hypothesis that probiotics / synbiotics could normalize GM and reverse dysbiosis, there have been efforts to investigate the therapeutic effect of probiotics/synbiotics in patients with NAFLD. Recent randomized clinical trials suggest that probiotics/synbiotics improve transaminases (ALT/AST), hepatic steatosis, and reduce hepatic inflammation.(14)
Despite these promising results, future studies are necessary to understand the full role gut microbiota plays in NAFLD development and progression.
Berberine and a therapeutic role in fatty liver and insulin resistance

A meta-analysis of berberine and its role in fatty liver showed its positive efficacy on blood lipids, blood glucose, liver function, insulin resistance, and fatty liver condition of NAFLD patients.(15)
The paper pointed to a few studies in particular. In the study of Li et al., berberine can promote the excretion of cholesterol from liver to bile and, as a result, blood lipid, particularly LDL can be reduced. Furthermore, berberine can regulate lipid metabolism and improve hepatic steatosis through increasing the expression of low-density lipoprotein receptor (LDLR).(16)
In the study of Pérez-Rubio et al., berberine enhanced patients' insulin sensitivity through PPAR-γ pathway and promote tyrosine phosphorylation in insulin receptor substrate (IRS); thus, insulin resistance can be improved. Meanwhile, berberine can increase the amount of glucose transporter 4 (Glut-4) which can accelerate the ingestion of glucose and, as a result, blood glucose can be reduced.(17) Like Metformin, berberine activates AMPK(18), the fat burning protein, which otherwise declines in activity with age.(19) Through this activation, berberine effectively assists weight loss.

I find berberine to be the most potent phytonutrient for correction of metabolic syndrome-induced NAFLD.

Dietary deficiency of choline can be corrected via supplementation and is an important consideration in fatty liver

The average human diet is 150 mg short of choline. Choline mitigates triglyceride production and helps fats and cholesterol to be released from the liver in the bile. If the choline deficiency is severe accumulation of triglycerides in the liver occurs quite rapidly.(20)
When we are well fed state, and especially when we have eaten carbohydrates, elevated insulin causes our liver to synthesize triglycerides particularly if overweight, but if there is sufficient choline (as phosphatidyl-choline) it will safely package these into very low-density lipoproteins (VLDLs), and send them into the bloodstream. Most people do not eat insufficient choline to pump out the fat from their liver, and this is a direct cause of fatty liver in many cases, especially for vegetarians and those who avoid egg yolks, salmon or meats which are the primary food sources.
Choline forms into phosphatidyl-choline (PC) via methylation, and PC is found in eggs and fish roe, and is concentrated from soy or sunflower oils. It can then be taken as supplement. Phosphatidylcholine is regularly used in Russia for fatty liver.
In a British Medical Journal study recently published on 2827 Russian NAFLD patients, given 1.8 grams of PC tid, which resulted in significant improvement in liver echogenicity and structure after 24 weeks. Improvements ranged from 42% to 68% depending on the number of comorbidities (namely obesity, hypertension, type 2 diabetes and hypercholesterolaemia).(21)
Phosphatidylcholine supplementation is very helpful for preventing or reversing fatty liver disease,(22) supporting gall bladder health, lowering triglycerides(23) and supporting fat digestion. A supplement of phosphatidylcholine at 2 capsules two to three a day proves to be helpful in the majority of fatty liver cases and can be utilized as the only treatment in simple cases of elevated triglycerides not associated with metabolic syndrome. This is common in vegetarians, where choline is very low in the diet. Some individuals with inadequate methylation fail to produce sufficient PC, but respond well to supplementation of 2-4 grams daily, often sparing more expensive supplementation with SAMe. PC is also a nutrient with extra demand during pregnancy, and its shortage may partly account for the increase in gallbladder associated illness during pregnancy and after the birthing.
With berberine, phosphatidylcholine, and probiotics, significant strides towards managing NAFLD with nutraceuticals is possible. Weight loss is also generally needed (5-10% reduction is required, depending on level of obesity).
Next time my note will be on NASH, the result of an inflamed liver, often following prolonged NAFLD.
PS: INL has produced a Webinar on Berberine for Metabolic Syndrome, soon to be available.

Graeme's Dose: 500mg initially tid, reducing to bid after 6 months

Berberine is a potent plant-derived alkaloid that offers a wide range of benefits.* Traditionally, Berberine been used to support regular and normal bowel function in healthy individuals*

Graeme's Dose: 2 capsules tid initially, reducing to 2 capsules as maintenance after 6 months.

Phosphatidylcholine softgels are excellent for emulsifying fat, making this nutrient extremely valuable for liver health.** It is ideal for supporting absorption of all fat soluble nutrients.

Graeme's dose: 25-50 billion daily

Ther-Biotic® Complete is a robust, broad-spectrum, hypoallergenic blend of 12 probiotic species in a base of inulin. Designed to supply a complete component of synergistic and complementary species, each capsule provides 25 billion CFU protected by our proprietary InTactic® technology for maximum viability throughout the intestinal tract.