Wednesday, July 8, 2015

NAFLD, Non-Alcoholic Fatty Liver Disease, the Gateway to Diabesity - Which Supplements Help? A Dozen Suggestions

There's a whole arsenal of vitamins & herbals that's supposed to either protect you from or even cure NAFLD.
NAFLD is emerging as one of the most common chronic liver diseases worldwide, and represents one of main cause of hepatology referral in some centers. NAFLD is a clinical syndrome that ranges from simple fatty liver, to non-alcoholic steatohepatitis, to advanced fibrosis, and cirrhosis.

It's directly liked to diabesity by its ties to insulin-resistance, obesity, and dyslipidemia, which are the main features of the metabolic syndrome (MS). NAFLD and MS are often seen in the same individual, and it has been reported that nearly 90% of the subjects affected by NAFLD, have more than one component of metabolic syndrome.
You can learn more about NAFLD at the SuppVersity

6 Bananas A Day = No Problem For the Liver!

Can We Blame NALFD on Fructose?

Insulin Sensitivity is Determined in the Liver

Saturated Fat & NAFLD - Is there a Link?

Snack Your Way to a Non-Alholic Fatty Liver

No Choline, No Healthy Liver, But Heart Attacks
In that, the reasons for developing NAFLD are not fully elucidated, but observational studies clearly point to the high(er)energy, and in particular to a greater carbohydrate intake of NAFLD patients compared with the healthy subjects (Tarantino. 2013). In spite of the fact that Abenavoli is right when he says that supplements can only be an adjunct to lifestyle modifications, i.e. modifications and physical exercise, or as he specifies it,
  • an individualization of the diet aim to achieve energy restriction of 500-1000 kcal/d,
  • a reduction of total fat and reduced saturated fat intakes to less than 30% of the total energy input, 
  • an increase in soluble fibre intake, and 
  • most importantly, a decrease or total elimination of refined sugars from the diet
These dietary modifications alongside physical activity of at least 60 min/d on initially 3 d/wk, later 5 d/wk should aim for a weight loss of 5% to 10%, which in turn will ameliorate the effects of NAFLD, even before any weight is lost (Keating. 2012).
Table 1: Meta-analysis of the pooled effect of exercise vs. control on liver fat with sub-analysis of: the effect of combined exercise and diet vs. diet and exercise vs. non-exercise control (Keating. 2012).
Only in conjunction with significant and permanent weight reductions, though it is possible you can hope to send NAFLD into remission.

Compared to the profound changes in how you life, medications and supplements are of reduced importance - if you don't change the former, the latter are not going to save you.

To understand which supplements are and which aren't useful NAFLD treatments, we have to initially learn about the pathogenesis of this ailment:
The pathogenesis of NAFLD is complicated and while its exact mechanism remains largely unknown, different genetic factors and/or environmental elements seem to influence it. The “two-hit hypothesis” of NASH, originally explained by Day and James suggests that lipid deposition in the liver (first hit) is followed by a series of other, oxidative and hepatotoxic processes (second hit), caused by a mechanism currently not known. Several factors such as genetics, epigenetic mechanisms, as well as environmental elements, appear to promote hepatocyte fat deposition and insulin resistance, both of which further lead to the secondary pathologic events, such as oxidative stress, lipid peroxidation, increased inflammatory responses, hepatic fibrosis and apoptosis. Other triggers such as lipotoxicity, endotoxemia, and adipocytokines or other inflammatory signals released from fat-infiltrated hepatocytes and adipose tissue, may promote oxidative stress in the liver, inducing the progression of NAFLD to NASH (Eslamparast. 2015 | my emphases).
In view of the oxidative / inflammatory component of NAFLD, it is little surprising that the wide range of drugs and supplements that has been trialed as NAFLD treatment includes antioxidants and anti-inflammations. Likewise on the list of agents with positive short-term, but lacking long-term data on their efficacy are insulin sensitizers, and lipid lowering agents (Gossard. 2011). Accordingly, I do advise you to take none of the following agents, the description of which I partly borrowed from Eslamparast et al. (2015), not as proven NAFLD treatments, but as suggestions that may support the inevitable life-style changes described before:
  • Vitamin E and vitamin C - not promising: No additional advantage over diet and exericse, alone for vitamin C supplements. A recent review article concluded that vitamin E is only recommended in adults with NASH who do not have diabetes or cirrhosis, or an aggressive histology (Pacana. 2012).
    Table 2: The meta-analysis comparing the effect of vitamin E to the placebo for the proportion of participants with normalized ALT is more than disappointing, because there's no effect of vitamin E (Sarkhy. 2015)
    In a meta-analysis, adjuvant vitamin E was not shown to have a significant effect on normalizing serum ALT levels. Using higher doses of vitamin E, a longer duration of therapy or adding vitamin C did not alter the effect of these antioxidants on the measured outcomes either (Sarkhy. 2014). As Elsamparast et al. (2015) point out, there's a paucity of evidence "on the long-term effects of vitamin E use on histological improvements of NAFLD patients, which calls for larger, well-designed randomized controlled trials (RCTs) with histological endpoints, to really determine the efficacy of its use".
  • Resveratrol - only low dose, long term: Just as it is always the case with resveratrol (3,5,4-trihydroxystilbene), a natural phenol produced by certain plants and found in the skin of red grapes, we do have promising rodent studies, in humans, however, clinical trials evaluating the effects of Resveratrol supplementation on NAFLD characteristics are scarce.

    As Elsamparast et al. (2015) war, "a recent study, administering Resveratrol vs placebo for eight weeks, not only failed to show any significantly improvements in any NAFLD features in the Resveratrol group", what's worse, the study by Chachay et al. (2015) which used a high dose of 3,000mg of resvertrol per day also showed an increase in hepatic stress.
    Table 3: The effects of resveratrol and placebo intake on serum level of liver enzymes and bilirubin at baseline and after 12-week treatment; in contrast to high dose short-term resvertrol treatments that even had detrimental effects, the Fagihzadeh study (2014) shows unmistakable benefits.
    In view of the fact that a different trial did find a significant improvement in NAFLD characteristics after 12 wk of supplementation with 500 mg Resveratrol (Faghihzadeh. 2014), it does yet appear logical to assume that dose and duration of Resveratrol administration is important in its efficacy.
  • Anthocyanin - possible benefits: Anthocyanins (ACNs) are water-soluble bioactive compounds of the polyphenol class that are present in many plant based products such as blueberries, purple sweet potatoes and other dark blue / purple fruits and veggies. It has been reported that ACNs decrease hepatic lipid accumulation and may counteract oxidative stress and hepatic inflammation in animal studies.

    Evidence from human studies is, you've guessed it, quasi non-existent. As Eslamparast et al. point out, "[t]here is only one study evaluating the effects of ACN on NAFLD patients; Suda et al. (2008) found that a high intake of a purple sweet potato beverage containing 400mg of acylated ACNs can reduce the levels of liver enzymes, in particular gamma-glutamyl transferases in patients with NAFLD - direct evidence of decreased liver damage or reductions in liver fat were yet not diagnosed, because they were simply not evaluated. 
  • Green tea extract - insufficient evidence, but promising: In spite of a whole host of studies in mice and rats, there is no convincing evidence that green tea  and EGCG helps with NAFLD in humans.

    In contrast to what Eslamparast et al. say, there are yet studies that prove that green tea with high-density catechins can improves liver function and fat infiltration in non-alcoholic fatty liver disease (NAFLD) patients when it's consumed for 12 weeks (Sakata. 2013).
    Figure 1: It's not as if there was no human data suggesting that consuming high polyphenol green tea for 12 weeks can have beneficial effects no NAFLD patients like this (Sakata. 2013), but the number of randomized controlled studies is still low and the evidence inconclusive.
    With the Sakata study being the only double-blind placebo-controlled study in humans, the evidence must still be considered preliminary, though, and could be related (solely?) to the reduction in body fat of which the only longer-term study investigating correlates of NAFLD remission says that it is the #1 (if not only) predictor of NAFLD remissin (Zelber-Sagi. 2012). In addition the possibility of heavy metal contamination may more than reverse any beneficial effect and have green tea and green tea extracts - as it has previously been demonstrated, by the way (Molinari. 2006) - contribute to instead of relieve liver disease.
  • Coffee - protective effects proven, acute benefits exist, as well: While epidemiological and animal data leave little doubt that regular coffee consumption can protect you from developing NAFLD and T2DM, direct evidence as it is available in the form of a recent case-control study that compared coffee vs non-coffee drinkers and found that fatty liver occurred less frequently in coffee drinkers, and that drinking coffee was inversely associated with the degree of liver brightness, as well as obesity and insulin resistance is scarce (Catalano. 2010).
    Figure 2: Scatter plot of fibrosis as a function of regular coffee caffeine (mg/day) - the more coffee he / she consumes the lower an NFLD patients risk of fibrosis (Molloy. 2012).
    What is beyond doubt, though, is that among NASH patients, coffee consumption has been shown to be significantly associated with a reduced risk of fibrosis (Molloy. 2012).

    Nevertheless, ,ore research is needed to determine the NAFLD protective properties of caffeine and/or other coffee constituents like certain phytochemicals with potential antioxidant properties, which may also be protective against cardiovascular and liver diseases, and malignancies. 
  • Garlic - smells promising, but proven only in in animal models: Garlic-derived S-allylmercaptocysteine (SAMC) has a therapeutic role in diabetes and nonalcoholic fatty liver disease due to its properties in the regulation of lipogenesis and glucose metabolism, it's effecs have been proven only in rodents (Xiao. 2013). In addition SAMC has more of ameliorative than protective effects and slows the progression, but does not block the development of NAFLD.
    Figure 3: Graphical overview of the potential mechanisms by which garlic oil protects rodents from developing fatty liver; RCTs in human beings are still lacking (Lai. 2014). 
    The same can and must be said for garlic essential oil (GEO) and its major organosulfur component diallyl disulfide (DADS), which has anti-obesity and anti-hyperlipidemic and may thus slow down the progression of NAFLD (Lai. 2014).
  • Ginger  - promising, but unproven: In theory ginger is an excellent anti-NAFLD agent that acts via both the activation of peroxisome proliferator-activated receptor gamma and the suppression of the fructose-stimulated overexpression of carbohydrate response element-binding protein (ChREBP) at the mRNA and protein levels in hepatocytes to reduce the inflammation and the development of fatty streaks in the liver.

    Randomized clinical trials to confirm beneficial (long(er) term) effects in patients with NAFLD are yet missing... but I guess you already expected that ;-)
  • Insulin & lipid lowering supplements and anti-inflammatory agents like cinnamon, curcumin, quercetin, berberine, lipoic acid, coq10carnitin and, as previously discussed, enough choline and whey protein - all promising, but insufficient evidence: Will probably help control many of the side effects of NAFLD and thus slow down it's progression. The evidence can be considered conclusive only for choline or rather the avoidance of choline defiency, though.

    For the others, the only thing we have are impressive rodent studies with often exorbitant amounts of the active ingredients and a lack of clinical human studies like small scale study by Bortoletti et al. showing sign. reductions in liver fat in response to 60 g/day whey protein supplement (WPS) for 4-weeks in women with NAFLD (Bortolotti. 2011).
    Figure 4: Between-group comparisons of changes in biochemical and anthropometric variables in 44 men and women with NAFLD after 4 weeks on 100mg/day CoQ10 (Farhangi. 2014).
    In addition, if there's evidence that something works, like CoQ10, for example, the human data that's available for CoQ10 (see Figure 4) may be considered problematic, because many other studies have been heavily sponsored.
Complement A-C by ALA and vitamin E to protect yourself | more
"Insufficient evidence"... that's what you can say for most items! If you had to compile a top list, (A) coffee, ALA (+E) and whey would be on it. The same goes for (B) a reduction of the unnaturally high omega-6/3 ratio in the standard American diet and an increased intake of mono-unsaturated fatty acids at the expense of both saturated fat and carbohydrates (specifically sugar and HFCS) to reduce the blood pressure and glucose concentrations, and increases serum high-density lipoprotein (HDL) levels (Hancu. 2003). And last but not least (C) pre- and probiotics, which may stop the bacterially-driven inflammatory attacks of a dysbiotic gut on the liver (Gratz. 2010).

As previously stated, though, the lack of convincing evidence that any of the aforementioned interventions can totally protect you / even revers NAFLD is not the only reason you mustn't rely solely on supplements and minor changes of your diet. If you want to rid yourself of NAFLD, the most important thing you have to to is to rid yourself of the sedentary lifestyle and diet that's at the heart of (almost) all modern diseases | Comment on Facebook!
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