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Saturday, 22 December 2012

L-Valine, Zinc supplementation, the Fructose Lipid Hypothesis, and the n=1 Updated

There's a paper casing a big buzz in the Hep C forums, with good cause.

Valine, a Branched-Chain Amino Acid, Reduced HCV Viral Load and Led to Eradication of HCV by Interferon Therapy in a Decompensated Cirrhotic Patient


The HCV viral load plummeted, from 5 log to less than 1.2, by the twelfth week of treatment (and only then was the patient given Interferon-alpha, one of the usual antiviral drugs, not very effective at all used on its own). This required fairly high intake of l-Valine, peaking at 12g/day. Which probably isn't something you'd want to do for more than 12 weeks. Alpha-fetoprotein also dropped back to normal, which is all to the good as elevated AFP is considered a risk marker for hepatocellular cancer. 
OK, so this is just one patient. An n=1 case study, so it's properly documented and peer-reviewed (not to be mistaken for any kind of an anecdote). Case studies tell us what CAN and DOES actually happen, but not how often it might be expected to happen (RCT study) or why it might happen (animal testing, usually).

How might it work? The authors suggest various mechanisms, but there is no detail as to how, for example, l-Valine might activate dendritic cells or improve liver function. I would like to suggest one. This is not a theory, it is not even a hypothesis, just something it might be rewarding to look at.

carbohydrate: pathways for utilization

When amino acids, carbohydrates and (to a lesser extent) fats are metabolized by cells, the energy blocks (called substrates) are fed into the TCA (tricarboxylic acid), or Krebs (after its discoverer), or citric acid cycle. (at the bottom of the above diagram). This cycle generates energy (ATP and GTP), a variety of substrate building blocks for making sugars, amino acids and lipids etc, and reducing equivalents (NADH+ and FADH2) that are used to keep the cycle working and to reduce oxidised ubiquinone (co-enzyme Q10) to ubiquinol.
The TCA cycle generates NADH+ and ATP at a few points but only generates GTP (in hepatocytes) and significant amounts of FADH2 in two consecutive reactions. These are the conversion of succinyl-CoA to succinate, and the conversion of succinate to fumarate, respectively (have a look at table 13 in this paper, where FADH2 is called FPH2, to see what I mean. 484 of 562 mitochondrial FPH2 are generated at this step). Substrates can be removed from the cycle or added to it at many points (and it will presumably run unevenly or at a reduced rate if this intake/exhaust system is out of balance). If the succinyl-CoA substrate was drastically undersupplied, for example by removal of a previous substrate or by inhibition of a previous enzyme, there would be a deficiency of FADH2 (which might lead to inhibition elsewhere in the cycle). 
(The purpose of GTP in hepatocytes is something I know nothing about, but it must have a function distinct from ATP).
Now, how is extra succinyl-CoA made available to the TCA normally? (it's called an anaplerotic reaction, by the way). From propionate supplied by the breakdown of l-Valine mostly. Some also comes from metabolism of odd-chain fatty acids and phytanic acid, which are mainly present in the diet from dairy foods and ruminant fat (note that the l-valine, as far as I know, could be metabolized elsewhere, e.g. muscle, but.the propionate finds its way to the hepatic mitochondria). 
Feeding succinyl-CoA into the TCA cycle might be expected to increase the ratio of FADH2 to NADH+ in the mitochondrial respiratory complex. Peter at Hyperlipid has speculated at length on the implications of the FADH2:NADH+ ratio in his recent Protons series.

Disclosure:
There was a corroborating paper but I lost it. Something about succinate inhibiting viral replication in vitro (as did DHA, AA, and EPA in that order). Or, maybe it was suppressing excess gluconeogenesis in infected hepatocytes (another function of long-chain EFAs) - as l-Valine is a gluconeogenic animo acid this isn't as likely, but I can't rule it out. The first time I've lost a paper and, to my shame, not been able to quickly search it up again. I found it a few weeks before I read the l-Valine paper, while researching fish oil and krill oil. If anyone knows what paper I'm referring to... Anyway, there is definitely a succinate-counters-HCV connection on record out there somewhere.


So is "fixing" the TCA cycle undoing something that HCV has manipulated for its own benefit? Does HCV virion assembly require lots of alpha-oxoglutarate, depleting succinyl-CoA? Does the extra supply of succinyl-CoA mean an equal amount of another substrate has to come out of the cycle (cataplerosis), and if so, what? And does this also apply to dendritic cells? Is l-valine synergistic with alpha-lipoic acid in this scenario (which would tend to confirm the succinyl-CoA mechanism)? I could go on (about HCV core protein inhibiting mitochondrial respiratory complex I and FADH2 feeding complex II, for example), but I've given you enough homework for the Xmas break.


This makes sense because HCV sequesters zinc in one of its proteins, and a zinc metalloprotein is required to break down collagen (fibrosis is a repair process and the extra collagen scaffolding - scarring - is meant to be removed). You won't recover from fibrosis if you don't get enough zinc (you need more than just zinc, but these studies show that zinc alone can give significant protection). They used polaprezinc, which is a carnosine-zinc chelate supplying 33mg/day.

A recent review from New Zealand summarizes the evidence that sugar (and high-GI starches), not fat or salt, is the main dietary cause of cardiovascular disease (PDF). John Yudkin's ghost is smiling.

An update on the hygeine hypothesis n=1. I have had one day of hay fever, moderate by previous standards but there nonetheless. I modified my protocol by restricting cheese (the obvious hole in the first n=1 post) and by restoring probiotics (either lactobacillus/bifidus or Del Immune V), which hadn't prevented hay fever without "raw water" therapy, but which seem to be synergistic in combination with it. And everything has been fine since. it's high pollen weather, midsummer, everything's flowering, other people have hay fever but mine is minimal. (updated: another baddish day today. Water gave some relief eventually - I didn't expect it to work like an inefficient drug. Can disease states tend back to homeostasis - is that why drugs often stop working eventually? Next time I write about this I hope to be able to assess it properly)

P.S. Just a little Christmas bonus: 


Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma



We investigated the association between fish and n-3 PUFA consumption and HCC incidence (n = 398) in a population-based prospective cohort study of 90,296 Japanese subjects (aged, 45–74 y). Hazard ratios and 95% confidence intervals (CIs) for the highest vs the lowest quintile were estimated from multivariable adjusted Cox proportional hazards regression models. We also conducted subanalyses of subjects with known hepatitis B virus (HBV) or hepatitis C virus (HCV) status, and of subjects who were anti-HCV and/or hepatitis B surface antigen positive. All tests of statistical significance were 2-sided.

Results

Among all subjects, consumption of n-3 PUFA-rich fish and individual n-3 PUFAs was associated inversely with HCC, in a dose-dependent manner. Hazard ratios for the highest vs lowest quintiles were 0.64 (95% CI, 0.42–0.96) for n-3 PUFA-rich fish, 0.56 (95% CI, 0.36–0.85) for EPA, 0.64 (95% CI, 0.41–0.98) for DPA, and 0.56 (95% CI, 0.35–0.87) for DHA. These inverse associations were similar irrespective of HCV or HBV status.

35 comments:

Jack Kruse said...

George I am glad to see you finally looking at seafood for HCV. For ten years I have been fascinated with HCV patients because in my day job they have more degenerative disease than one would normally expect and it is tied to the Zn and mitochondrial issues you are beginning to explore. I have used my mitochondrial Rx with them with some success but I remain convinced that the Virus is doing something else to mitochondria of their muscles and nerves that cause easy fatigue. I have noticed they the worse their fatigue their lower their riboflavin levels are and the lower their CoEnzQ10 levels are and the lower their HC levels are. This has made me look at them quite differently because I think they are quite different in how they handle electrons at their complexes.

George G said...
This comment has been removed by the author.
George G said...

"A 65-year-old Japanese woman was being treated for HCV genotype 2a-related liver cirrhosis at Kurume University Hospital. .. the disease was progressive and aggravated to decompensated liver cirrhosis with ascites .. we offered her the option of participating in a phase II clinical trial of oral valine agent (VAL).
Two years after the end of the clinical trial, hepatocellular carcinoma (HCC) had developed, which was successfully treated by radiofrequency ablation.
The 36-week interferon treatment resulted in successful eradication of HCV. The patient's Child-Pugh score gradually decreased from 10 to 5, and no recurrence of HCC has been seen for 5 years"

I would very like to see any results from the clinical trial of Valine (VAL).
This seems to have been completed around 7 years ago.
This would be better than one unusual case.
I can't find any published results.

George Henderson said...

@ Jack, I found that Co-q10, carnitine relieved hep C muscle fatigue and improved oxygenation. And generally a low-carb diet makes exercise a lot easier. The mito complex I is inhibited by the virus, fat-burning prefers traffic through complex 2.
There is also an immunological component, immune complexes and various autoimmune syndromes, which require a grain-free diet and live or killed probiotics (Treg activation and immune tolerance) to resolve.
Burton Berkson's "Triple Antioxidant" HCV protocol can be seen as focussing on supporting the TCA cycle and mitochondrial health.

@ George G, Yes, that trial would be worth finding - well spotted.
This review is by the same authors and may mention the trial: http://www.ncbi.nlm.nih.gov/pubmed/21563202/

George Henderson said...

Try this:
http://onlinelibrary.wiley.com/doi/10.1002/hep.24412/pdf

and
http://jn.nutrition.org/content/136/1/295S.long

by the same, or related, authors.

Maybe the woman in the case study was the only person with HCV in the cirrhosis valine trial?

George Henderson said...

This might have been it: the dose is 12g
http://www.ncbi.nlm.nih.gov/pubmed/16737844

Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis.

We conducted a multicenter, randomized, controlled trial to investigate the effect of long-term oral supplementation with branched-chain amino acids (BCAA) on the event-free survival in 622 patients with decompensated cirrhosis. In the present study, the development of liver cancer was analyzed as an endpoint in particular. Subjects received either treatment with BCAA at 12g/day or dietary therapy containing the matched daily energy and protein intake. A Cox regression analysis was carried out to estimate the hazard ratios for different background factors stratified by treatment group. Liver cancer was noted in 89 patients. The risk for liver cancer was significantly higher for males, patients with concurrent diabetes mellitus, patients with an alpha-fetoprotein (AFP) level of 20ng/mL or higher, patients with higher body mass index (BMI), and patients with lower serum albumin levels. When the BCAA group and the diet group were compared for factors that interacted with the treatment arms, the risk for liver cancer was significantly reduced in the BCAA group with a BMI of 25 or higher and with an AFP level of 20ng/mL or higher. Oral supplemental treatment with BCAA may reduce the risk of liver cancer in cirrhotic patients with these specific factors.

George Henderson said...

And here, Table 1 lists 4 studies of BCAA for cirrhosis in Japan.
The case used both valine and BCAA.
http://www.wjgnet.com/1007-9327/pdf/v18/i33/4486.pdf

George G said...

Thanks George.
You're correct the BCAA trials were primarly for cirrhotics, not HCV patients.
I am bit suprised they didn't test Valine on more HCV patients, to see if the VL drop (for the 65year old Japanese woman) happened again.

George Henderson said...

The paper's very recent, so maybe they're doing an HCV l-valine trial as we speak...

George Henderson said...

In fact, it's likely that the case study was published to drum up support for a proper HCV l-valine trial.

George Henderson said...

Happy holidays folks, I'm taking a break, will be mulling this over.

Latest n=1 update - I have a COLD. That's what that was about. Only the second in 2012 and the first was nothing.

Jack Kruse said...

George I use other things with HCV patients. I will be sharing them soon on my Mitochondrial Rx. D Ribose, taurine, HBOT, and methylated B vitamins are some but not all. HCV is becoming a real problem for us clinically and it is clear HCV patients mitochondria are a real issue that clinicians need to pay attn too.

Nick Mac said...

George........

Once one has a sustained response to HCV tx how long will it take for the liver to regenerate and be back to operating at it's maximum potential... taking into account that my liver was dx as F4/6 (Ishak) just prior to tx...?

I can't seem to find any papers written on the subject and would appreciate anything you could point me to.

George Henderson said...

Have a look here Nick
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2008.03840.x/pdf
I haven't had time to read it (on hols, checking in on Macdonalds free WiFi) but it ought to reference what clinical studies there are.
No guarantees of reversal but ought to happen more often when factors that are obviously fibrogenic - seed oils and sugar - or obscurely fibrogenic (gluten, maybe dairy and other allergens) are limited. Zinc seems to be important, for the matrix metalloprotein (MMP) that digests collagen.

Jack, I've heard good things about ribose for CFS/ME. Which is often the HCV dual diagnosis. Look at what HCV does to complement protein C3.

George Henderson said...

HCV mutates, antibodies no longer match properly, bind to HCV core protein which binds to C3, so complement system is dysfunctional and immune complexes are not cleared, resulting in the degenerative diseases. As GB Shaw said in "The Doctor's Dilemma" preface, "Stimulate the phagocytes!"

George Henderson said...

@ Jack,
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302406/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808767/

@ Nick, in the many rat studies fibrosis persists after removal of causative agent (alcohol, toxin, surgery) if dietary fat composition is wrong (seed oils, excess fish oil) but resolves when highly saturated fats are 35% or more of diet and PUFAs are restricted to under 5% of fats.
The Perfect Heath Diet mix of fats, with supplementary zinc, would be ideal. A high intake of glycine is also protective and this would come from the gelatine and bone broth in the PHD.

Nick Mac said...

Cheers George... Interesting paper and qualifies that 'reversal' is the wrong description but rather 'regression' is more appropriate and whatever level of fibrotic regression it can take many years.

It also notes the limitations with liver Bx due to the tiny sample taken especially if that sample is dx with F4 advanced fibrosis like me... apparently, as I'd feared, underdiagnosis of cirrhosis is prevalent.

A 1/50,000th slice of liver can't define the whole picture with any serious accuracy as I'd always believed.

So naturally I agree that one's diet has to play the primary role in regressionary influence... and the PHD is now in full swing for me... the right ratio of SaFA and MUFA.... and highly limited PUFA to max 5%

The immediate problem to address is being away from home cos now I don't want to consume anything I haven't prepared myself so I have to take my own food everywhere I go... lol... I'll get used to it.

Good recipe for bone broth please..?... what bones to ask for at the farmers market...?

Oh yeah how come the PHD doesn't mention eating pigs..?... weren't wild boar a part of caveman diet..? or is there a big difference with farmed pigs..?... and what about fresh rabbits..?.. loads on my property.

Anyway for now it's ruminants only so beef and lamb... and salmon and shellfish... and I absolutely love the coconut oil... delicious.... eating 2 tablespoons a day and cooking with it.

Ciao

George Henderson said...

PHD doesn't recommend pork becauase there is a strong link (for some reason) between eating pork and cirrhosis. Pork and hens don't adapt to modern farming as well as sheep and cattle (which have more bacteria to deal with their fodder).
Note that fish etc. should be the only food high in PUFA. DHA and EPA are exceptions to the rule, in food form anyway.
I use beef "cannon" bones which have plenty of marrow and connective tissue. But probably any bone with lots of tissue attached if you boil it long enough will supply minerals and gelatine.

Cohen Ilan said...

Finally a professionally supported diet. Thanks for sharing, this is the one I'll try as I know the theory behind it.

George Henderson said...

@ Cohen,
Stan on the "Stan (Heretic)" health blog included this in his reply to one of my comments:
"I found your posts in the Hepatitis C blog very interesting! My experience with the High Fat LC diet was started by my friend who used such a diet in 1999 to cure himself of supposedly "incurable" Hepatitis C induced liver cirrhosis."
http://stan-heretic.blogspot.co.nz/2013/01/anti-oxidants-may-promote-rather-than.html?showComment=1358009578634

One day I'll compile all the "testimonial" anecdotes like this I've read from people following similar diets.

Nick Mac said...

@ George
Just got to the chapter which advises that most farm reared pigs are infected with Hep E and it takes cooking at 160 degrees for an hour to kill the virus

I'll stick to Beef Lamb salmon and shellfish....

Really beginning to notice a massive difference on the PHD...

J said...

George,

Out of curiosity can the herpes virus be treated similarly as the recommendations for Hepatitis C?

Thanks.

George Henderson said...

@ J, I'm not sure. It wouldn't hurt but you'd still have to avoid cocoa.
My hypothesis is that cocoa exacerbates HHV not because of l-arginine (it doesn't have much) but because of benzylamine mimicking the love/lust state. Add emotional stress or sleep deprivation and you have a cocktail that mimics the state in which HHV is transferred. HHV is a virus that goes dormant to avoid the immune system when it doesn't have a chance of being passed on.
What could be a better adaptation for HHV than to wake up and become active when it thinks we might be getting amorous? Chocolate and emotional stress - especially with low immunity - might summon it up.
Both lysine and arginine improve immunity. I suspect the arginine theory of HHV is a myth and that lysine plus arginine would be as good or better:
http://www.sciencedirect.com/science/article/pii/S0361923097003493

well, that's my hypothesis. Koloba extract is active against HHV and might be worth applying locally, also vitamin E and selenium.

George Henderson said...

@ Nic, I personally don't know that Hep E has been common enough in the past to fully explain the pork-cirrhosis connection, but it is certainly becoming much more common. I still consider it an unsolved mystery, and possibly a result of a "perfect storm" of many causes.

Great that PHD is making a difference. I consider it the diet most likely to do the most good (and least harm) for the greatest number of people (and easy enough to follow). Which is close to perfect in an imperfect world.

George Henderson said...

that's Kaloba extract: pelargonium sidoides, available as a cold and flu cure in chemists.

http://www.ncbi.nlm.nih.gov/pubmed/18691858

"At maximum noncytotoxic concentrations of the extract, plaque formation was significantly reduced by more than 99.9% for HSV-1 and HSV-2 and a clear concentration-dependent antiviral activity against HSV could be demonstrated for this extract. In order to determine the mode of antiviral action, the extract was added at different times to the cells or viruses during the infection cycle. Both herpesviruses were significantly inhibited when pretreated with the plant extract or when the extract was added during the adsorption phase, whereas acyclovir demonstrated antiviral activity only intracellularly during replication of HSV. These results indicate that P. sidoides extract affected the virus before penetration into the host cell and reveals a different mode of action when compared to the classical drug acyclovir. Hence this extract is capable of exerting an antiviral effect on herpes simplex virus and might be suitable for topical therapeutic use as antiviral drug both in labial and genital herpes infection."

The alcohol-based extract used for colds may not be the ideal form to use locally (some way of working it into a cream might be better), but I'd still consider it worth a try as it's safe and cheap.

http://en.wikipedia.org/wiki/Pelargonium_sidoides

Stanley Hoang said...

Hello George,

If this kind of diet seems to be effective on treating HCV,

what about HBV?

George Henderson said...

on the one hand, HBV doesn't have the same relationship as HCV with VLDL, LDL receptors, etc.

On the other hand, low cholesterol is a risk factor in HBV as well, so is low selenium and vitamin A, and the same things will apply re: PUFA oils, grains, sugar and high-GI and high-carbohydrate diets increasing liver damage.
I expect HBV would benefit from a higher fat, high protein, moderate 'safe starch" diet, with lots of offal and other nutritious and fatty animal foods. I don't know that ketogenic dieting would be useful unless to fix ascites, but you can try anything for a while.

George Henderson said...

I would predict that this type of anti-inflammatory diet would improve health in Hep B,
but I wouldn't necessarily expect the same anti-viral effects.
The virology of HBV seems more obscure to me, despite the virus being known about for longer than HCV, but then I haven't looked at it as much.

Nick Mac said...

I had HBV when I was 20 years old and cleared naturally... got mega jaundice which is how I picked it up... but one thing I recall was being turned off meat and dairy products.. the smell of fat turned my stomach while I was ill with the virus so having a high fat diet might just be difficult for people with long term HBV infection...???... tho of course I have no knowledge of what it's like to have HBV long term

George Henderson said...

That's the effect of jaundice, which inhibits the release of bile, needed to digest most fats. It's a temporary state in liver disease if it isn't due to primary gall bladder/bile duct obstruction.
Hepatitis makes it hard to digest fats like toothache makes it hard to eat solid food.
Eating pureed food won't prevent tooth decay. Digesting fats can be a "use it or lose it" situation, and low-fat diets can cause gall-bladder disease.
Because the fat soluble vitamins are protective against liver disease, fatty foods high in these vitamins (fish, offal, dairy fats and cheese, sauteed greens and tomatoes) should be favoured over purified fats where fat intake is limited. MCT oils from coconut (66% of coconut oil) can be absorbed without bile.

George Henderson said...

As far as I know, chronic HBV is similar to HCV except that HBV flares up periodically to cause damage, and HCV is more likely associated with fatigue and depression.
I think HCV is more damaging to the immune system, HBV is more directly toxic to the liver.

Bill said...

This is kind-of-off topic, but did you come across anything about valine deficiency? I recently found some papers by Toshizo Kimura (circa 1971) which showed 50% fatality rate in rats fed a valine-deficient diet which was completely reversed by eliminating dietary leucine… and some human studies which confirmed the changes in plasma amino acids. Unfortunately the studies were done long ago so no mechanistic details were explored (the cause of mortality wasn’t elucidated, whether it had anything to do with dendritic or hepatic cells, etc.). But it piqued my interest. And indeed, I would be very interested to see an HCV valine trial.

George Henderson said...

That is interesting.
A quick search turned up this:
http://orthomolecular.org/nutrients/valine.html

So even orthomolecular opinion is that valine deficiency is only seen naturally in protein deficiency states.
It's interesting that leucine might antagonise valine, so BCAAs might not be best way to supplement the latter.

The point of entry of a substrate into the TCA cycle may be a critical factor.
Pyruvate switches between acetyl-CoA and oxaloacetate depending on requirements. Succinyl-CoA from valine offers another way to balance or manipulate the cycle by introducing substrate at another phase of the cycle.
That's what I'm thinking.

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George Henderson said...

Some corrections in order here:
1) I found the "succinate" paper and it was actually pyruvate. Soz.
2) I had 3 bad days with hay fever over one spring-to-fall period with my "hygeine hypothesis" protocol. One of these was due to coming down with pertussis, so probably shouldn't count. I required no medication and wasn't driven to desperation as I have been in past years. I'd call that successful enough for now...