INL Education - Treatment of NASH


A tiered approach to the treatment of Non-Alcoholic Steato-Hepatitis (NASH)

In this feature we will be looking further into the role that both herbal, nutritional and dietary interventions play for NAFLD and NASH patients. We will also be looking to help readers to understand the stages of nutraceutical therapies that match the causes and stages of these progressive liver diseases.

Non-alcoholic steato-hepatitis (NASH) is a more aggressive and advanced form of fatty liver disease and can impact whole-body health

It is currently estimated that around 25% of NALFD patients will progress to NASH over 3 years without intervention. (1)

The most common cause of death for NAFLD and NASH patients is cardiovascular disease via the effects on triglycerides and LDL cholesterol elevations leading to a consequence of arteriosclerosis and hypertension.(2) Even in NAFLD the increased risk of cardiovascular disease is by some three times in men and fourteen times in women. Women are also more prone to NAFLD than men. This in turn makes them more susceptible to become diabetic as a comorbidity.

Insulin-resistance present in the earlier stages of metabolic syndrome is the driver of triglyceride accumulation in adipose tissues and the liver. AS the triglycerides elevate, the LDL also increases, eventually becoming the more cardio-toxic small dense LDL’s, responsible for triggering arteriosclerosis and hypertension. The oxidative stress associated with diabetes speeds this process.

Other associated risk factors causing increased NASH likelihood include obesity, older age, female sex, non-African American race/ethnicity, diabetes mellitus and hypertension, high ferritin or mercury and to the genetic polymorphism for NASH relating to an excess in ubiquitination and lipogenesis – PNPLA3 (rs738409 C). This gene is especially prevalent in Hispanics, who are therefore more prone to NASH.

Differentiating NASH and non-alcoholic fatty liver disease can be difficult with liver biopsy considered to be the only reliable way to do so. (3) However, the development of the Fibroscan has made the accurate diagnosis of NASH less invasive. The overall accuracy of Fibroscan is high and significantly higher than that of blood biomarkers in predicting cirrhosis. (4)

NALFD incorporates either of the following:

  •      Steatosis alone,
  •      Steatosis with lobular or portal inflammation, without ballooning, or
  •      Steatosis with ballooning but without inflammation. (5)


Diagnosis of NASH requires the joint presence of steatosis, ballooning and lobular inflammation. (6)

Early screening is essential: Who should be screened for fatty liver and liver fibrosis?

Those patients with the following:

  •      Insulin resistance, metabolic syndrome and diabetes (HBA1C over 5.7)
  •      Children with obesity
  •      Elevated BMI – over 25 with abdominal obesity and sedentary lifestyle
  •      Elevated blood lipids (Triglycerides, LDL-C)
  •      Hypertension with obesity
  •      Family history of fatty liver (especially in Hispanic lineages)
  •      Hypothyroidism (an independent cause of NAFLD, triglycerides and LDL-C increases)
  •      High ferritin levels and/or C-RP, IgA, or IgM levels – all of which are related to inflammation
  •      Elevated AST, ALT, GGT
  •      Elevated Homocysteine levels (above 12 in the blood)
  •      High blood mercury or other toxic exposures such as dioxins, chemotherapy


At least 25% of NAFLD develop NASH, so early detection is vital, as advanced fibrosis can lead to the cirrhosis stage (NASH goes to cirrhosis in 15% cases) or worse still, hepatocellular carcinoma. (7)

People rarely have symptoms when they have NAFLD or NASH, symptoms appearing only at the cirrhosis stage, when it is too late. Often once this progression is seen we can miss an opportunity to use natural medicine interventions, with diet and lifestyle changes to either reduce further progression or, in some cases, attenuate the inflammatory and fibrotic processes within the liver.

NALFD can impair detoxification processes leading to a faster progression to NASH

First it is necessary to manage the calories and insulin resistance and then turn to remove and manage any other toxic insults and inflammatory processes that launch the progression from the first stage of simple triglyceride and LDL accumulation to the second stage of liver inflammation and LDL oxidation.

Numerous different environmental insults can speed up the development of NAFLD and NASH. For example, excess iron, alcohol, mercury, pesticides, dioxins, solvent exposure, some drugs and steroids can be responsible. A high saturated fat diet especially burned fats and trans fats will accelerate lipid peroxidation. These have been found to deplete liver SAM, as well as consume food and enzymatic antioxidants such as vitamin E, and glutathione, encouraging NASH development.

This then makes the methylation and glutathione conjugation pathways of the liver an important consideration when managing NASH and it seems there is a way to do both via SAMe. (8)

NASH has been referred to as the hepatic injury of metabolic syndrome with disordered lipid metabolism being another key factor in its formation. (9)

 

 

A focus on the management of persistently elevated AST and ALT and SAMe

A key hallmark for NALFD before the progression to NASH is the increased levels of transaminases, with alanine aminotransferase (ALT) levels surpassing those of aspartate aminotransferase (AST). With the progression hepatic steatosis to NASH, however, AST levels increase with a resultant rise in the ALT:AST ratio. (10)

In a previous newsletter on the management of fatty liver and choline, we explored a direct link between diets low in choline and the development of fatty liver. Supplementation of phosphatidylcholine (PC) enables gall bladder health, lowers triglycerides levels and supporting fat digestion in general. Phosphatidylcholine is also hepatoprotective. (11)

One of the key factors that makes choline so important is its interaction with betaine and methionine to S-Adenosyl Methionine (SAM), commonly known in supplemental form as SAMe.

SAMe synthesis is depressed in chronic liver disease potentially exacerbating liver damage offering a potential gate way for its use as a therapeutic agent to prevent further stiffening of the liver. Especially as SAMe depletion is associated with the progression from fatty liver to NASH. (12)

SAMe can be most useful when both of transaminases, ALT and AST are elevated, indicating that liver cells are being damaged to the point of apoptosis (cell death) under toxic overload. This can be done with 800-1200mg of SAMe daily, which effectively protects the liver and reduces the transaminase levels, as has been shown in chemotherapy cases. (13)

Also, SAMe has been shown to increase intracellular glutathione in patients with liver disease. (14) Importantly, SAMe can replenish hepatic mitochondrial glutathione and normalize fluidity of the inner mitochondrial membrane, which is critical for maintenance of function. (15), (16)

SAMe and the combination of phosphatidylcholine (PC) and a methylated B Complex

Whilst SAMe can be better at the detoxification of the liver than PC, once the ALT has responded and lowered, using PC as a hepatoprotective nutrient after SAM therapy to maintain the benefits – plus a high dose of an activated B Complex can work well to naturally maintain levels of SAM over the longer term, preventing the return of liver symptoms.

 

A focus on homocysteine elevations and hypercholesterolemia

 

Homocysteine over 12 is considered a risk factor for NAFLD becoming NASH. Furthermore, plasma homocysteine has been demonstrated to be a statistically significant as a predictor of necroinflammatory activity in NASH. (17)
Higher plasma homocysteine levels have been associated with lower levels of the “good” high-density lipoproteins (HDL) cholesterol – a key characteristic of metabolic syndrome. Low HDL cholesterol in combination with raised triglycerides levels is considered a heart damaging lipid profile.

 

When homocysteine is elevated, consider advising a low saturated diet to reduce risk of NAFLD becoming NASH. Add a high potency B complex for homocysteine management such as Homocysteine Supreme.

 

N-Acetyl Cysteine is another aid in reducing the homocysteine damage to vascular and liver tissues.

 

Annatto – E or Delta-Gold tocotrienols and the management of oxidation and excess inflammation in NAFLD and NASH

 

Vitamin E is considered to be one of the key therapies in the management of the oxidative stress component of NASH.

O
xidation is driven by the enhanced cytochrome P450 enzyme CYP2E1 expression and activity leading to an important source of reactive oxygen species (ROS) with impaired hepatic mitochondrial function as a consequence.
Vitamin E has been clinically trialed along with pioglitazone and placebo for its therapeutic effect on NASH.

 

Patients in the Vitamin E group were given 800IU daily over the course of 96 weeks and assessed for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis.
The study demonstrated that Vitamin E at the abovementioned administration was superior to placebo for the treatment of NASH in adults without diabetes. This is also importantly when compared with pioglitazone. (18)

 

Interestingly, another randomized, double blind controlled study was conducted over a similar timeframe with either a dose of 600mg of tocotrienols or placebo.
Tocotrienols showed a greater effect than the placebo by enhancing liver function. Importantly when it comes the NASH progression significant improvements were also demonstrated in stress reduction related to the liver. Both CRP and MDA, both indicators of inflammation and fat oxidation, reduced by 18% and 14% after three months, respectively. (19)

 

Tocotrienols, being the strongest fat-based antioxidants, have the best capacity to manage oxidised lipids and lipid membranes such as in the case of dense mitochondrial metabolism of hepatocytes. Tocotrienol supplementation increases in the mitochondrial glutathione, just as dose N-acetyl cysteine, vitamin C and lipoic acid.

 

Tocotrienols are advised over regular vitamin E formulations to correct NASH.
Milk thistle and the management of fibrosis within the liver
Silymarin from Silybum marianum or milk thistle has been shown to have antioxidant, anti-inflammatory and antifibrotic effects in both animal and human studies. (20)

In a randomized, double-blind, placebo-controlled trial to evaluate silymarin’s potential in the treatment of NASH, participants were randomly assigned to receive 700mg silymarin three times daily or placebo for 48 weeks, along with counselling about lifestyle factors such as diet and weight loss.
Whilst there was an improvement of at least 30% in NAFLD activity scores between the silymarin group and placebo, these changes did not reach statistical significance. However, and importantly significantly more people in the silymarin group experienced NASH resolution.
Fibrosis scores decreased significantly in the silymarin group compared to no notable change in the placebo group.
This led to a conclusion that a significantly higher percentage of patients experienced NASH resolution and improvement in the fibrosis stage after 48 weeks of treatment with silymarin compared to placebo. (21)
As I hope you have seen natural medicine offers many valid and easy to apply interventions to halt and, along with the patient’s lifestyle modification, reverse the progression from NAFLD to NASH.

 


Designs for Health B-Supreme

This very powerful B vitamin combination formula supplies most of the B vitamins in their coenzymated forms so the body does not have to phosphorylate them in order to be used in biochemical reactions.


 

Designs for Health Phosphatidylcholine

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

 

Designs for Health Homocysteine Supreme

Synergistic nutrients found in Homocysteine Supreme facilitate the efficient metabolism of homocysteine, preventing toxic levels of homocysteine from accumulating.

 

MediHerbs Silymarin Milk Thistle

Milk Thistle Forte is manufactured from Milk Thistle extract which contains flavanolignans (collectively known as silymarin), flavonoids and other compounds. This product is standardized to contain 168 mg of flavanolignans per tablet to ensure optimal strength and quality.