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Tuesday, 14 February 2012

Do high-carbohydrate diets and PUFA create a Pro-viral Metabolic Gradient in HCV?

  • Do high-carbohydrate diets, sugars, and “heart-healthy” oils create a pro-viral metabolic gradient in chronic hepatitis C infection?
  • Chronic HCV infection (CHC) has become endemic across most of the world, with rates of infection estimated at 1-2% in New Zealand and 3% world-wide. An increase in liver disease (cirrhosis, and formerly rare primary liver cancers) as cause of death is being seen as a result. Existing antiviral drugs give mixed results, clearing about half of infections after prolonged and often arduous treatment, with a significant risk of hematological, neurological, psychiatric and autoimmune complications, especially in non-responders. In Australia it is estimated that 95% of HCV positive persons will not access antiviral drugs. Contraindications for drug treatment are common among chronically infected people. HCV infection does not become chronic in perhaps half of cases diagnosed early (the difficulties of early diagnosis means the true figure is probably higher) and chronic hepatitis C infection is sometimes associated with no adverse health effects. Alcohol is strongly connected to negative outcomes in CHC.
  • Antiviral response is the rate at which the viral load drops in response to drug treatment. Factors previously shown to reduce the likelihood of response in various populations include: insulin resistance and/or type 2 diabetes; low serum cholesterol or LDL; low serum B12; low vitamin D levels; higher PUFA consumption. The greater the antiviral response, the shorter the duration of treatment (or number of treatments) required, and the lower the exposure to the side-effects and after-effects of antiviral drugs.
  • A few years ago the grapefruit flavanone naringenin was found to decrease HCV virion expression in vitro;
  • "This antiviral effect is mediated in part by the activation of PPARα, leading to a decrease in VLDL production without causing hepatic lipid accumulation in Huh7.5.1 cells and primary human hepatocytes. Long-term treatment with naringenin leads to a rapid 1.4 log reduction in HCV, similar to 1000U of interferon. During the washout period, HCV levels returned to normal, consistent with our proposed mechanism of action."J Hepatol. 2011 Nov;55(5):963-71. Epub 2011 Feb 24
  • "Hepatitis C virus (HCV) infects over 3% of the world population and is the leading cause of chronic liver disease worldwide. HCV has long been known to associate with circulating lipoproteins, and its interactions with the cholesterol and lipid pathways have been recently described. In this work, we demonstrate that HCV is actively secreted by infected cells through a Golgi-dependent mechanism while bound to very low density lipoprotein (vLDL). Silencing apolipoprotein B (ApoB) messenger RNA in infected cells causes a 70% reduction in the secretion of both ApoB-100 and HCV. More importantly, we demonstrate that the grapefruit flavonoid naringenin, previously shown to inhibit vLDL secretion both in vivo and in vitro, inhibits the microsomal triglyceride transfer protein activity as well as the transcription of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and acyl-coenzyme A:cholesterol acyltransferase 2 in infected cells. Stimulation with naringenin reduces HCV secretion in infected cells by 80%." Hepatology. 2008 May;47(5):1437-45
  • In addition to which, it has been known for some time that statin HMG-CoA reductase inhibitors (especially, but not exclusively, fluvastatin) lower HCV viral loads in vivo.
    [HCV and Statins: is there a role? Del Campo, Eslam, Romero Gomez. Statins Review]
  • Findings from HCV virology to date are that assembly of HCV virion is dependent on DGAT1 (and HMG-CoA reductase?), that the completed virion leaves the infected cell via VLDL exocytosis, and that virions infect naïve cells via endocytosis mediated by a number of receptors including LDL-R (which may be more important in the earlier stages of an infection).
  • "TG levels were significantly and directly associated with HCV levels (P = 0.0034) and steatosis (P < 0.0001). Other lipid parameters were significantly lower in those with fibrosis [HDLc (P = 0.001) and TC levels (P = 0.004)] than in those without fibrosis. In patients with HCV genotype 1 infection, more severe liver disease was associated with lower lipid levels, with the exception of TG levels that were directly related to steatosis. The direct relationship between viral load and TG levels is consistent with the proposed mechanisms of very low density lipoprotein/HCV particle secretion." http://www.ncbi.nlm.nih.gov/pubmed/21070504
  • These examples could be multiplied endlessly across PubMed; there are variations between different genotypes and populations, but the direct relationship between TG and viral load, and HOMA and fibrosis, always appears to be present.
  • Now, nothing has yet disabused me of the notion that anything statins can do, a low carb diet can do better. While reading a second-hand copy of Dr Atkin’s New Diet Revolution I was struck by the consistent reductions in TG seen in his patients. Following this up online I found that Jeff Volek et al.’s more recent papers confirm similar drops in both TG and VLDL in very low carbohydrate dieters. Two of the low-carb diet papers discussed in or linked to R. D. Feinman's blog recently have given figures of 40% and 70% reductions in TG respectively. Imagine the average motorist leaves home 40% less often; the roads will soon become less congested. Imagine that that motorist arriving at a destination was causing another motorist (or a thousand) to leave home; a 40% reduction in departures could see the roads virtually empty over time. TG synthesis and VLDL exocytosis, and (perhaps) LDL endocytosis are opportunities for the spread of HCV in the liver and bloodstream of an infected person. Restricting these opportunities significantly by eating a nutrient-dense low-carbohydrate diet seems, on the face of it, a realistic adjunct to drug treatment, as well as a practical way of managing chronic Hep C infection in persons who do not respond to drug treatment, for whom drugs are contraindicated, or who choose not to use SOC drugs because of concerns about their well-documented side effects.
  • This hypothesis remains to be proven in clinical trials, but what seems beyond doubt to this amateur is that current eating patterns - sugar and fruit juice consumption, high-carb junk food cooked in “heart healthy” oils, and high-carbohydrate and low-SFA “healthy eating” guidelines - are likely to establish a pro-viral metabolic gradient against which all antiviral treatments must struggle to make headway.
  • Based on the available evidence, the following dietary parameters seem to be indicated;
  • Miminize fructose, which is a driver of DGAT1, TG and VLDL
  • Restrict total carbohydrate, which also drives DGAT1, TG and VLDL and downregulates PPAR-alpha
  • Consume some dietary cholesterol, which is the natural HMG-CoA reductase inhibitor.
  • Restrict vegetable PUFA, which increases LDL-R numbers and upregulates HMG-CoA reductase
  • Consume some animal PUFAs (EPA, DHA, AA) as these induce PPAR-alpha and inhibit HCV replication and steatosis.
  • Consume most energy from highly saturated and monounsaturated animal fats and fruit oils; saturated fat (but not PUFA) reduces TG and VLDL expression in a low-carb milieu.*
  • Also consume foods, beverages, herbs and spices rich in polyphenols and carotenoids. Many of these have been shown to have antiviral or antifibrotic effects in vitro, which may become more apparent in vivo once the pro-viral metabolic gradient of high-carb eating has been leveled.
* [Dietary Carbohydrate Modifies the Inverse Association Between Saturated Fat Intake and Cholesterol on Very Low-Density Lipoproteins: A.C. Wood et al., Lipid Insights 2011 August 23; 2011(4): 7–15. doi: 10.4137/LPI.S7659]

 These are of course the exact opposite (bar sugar) of the recommendations you will get from both conventionally-trained and naturopathic nutritionists, as well as many GPs, if you consult them on diet for Hepatitis C.
Are there other reasons why this diet would benefit a sick liver, apart from the HCV replication factor?
In fact there are many: reduction of liver fat (due to carbohydrate restriction) and improvement of fibrosis (thanks to dietary SFA and restriction of PUFA) are two reasonable expectations; I will post the evidence for this in the next blog.
A little n=1 experimental data; 4 years ago my viral load was 400,000 units, now after 2 years of low carb dieting and intermittent mild ketosis it is 26,000. This is consistent with the drops seen in the naringenin in vitro experiment being extended over a longer time. Symptoms including digestion have greatly improved, and dependence on supplements has almost vanished.

13 comments:

john said...

Have you looked into vitamin A at all? I believe I have seen several papers showing an antiviral effect (not sure about Hep C specifically).

George Henderson said...

Yup, vit A is very interesting.
It does push down HCV, at least in short courses; it is a potent antifibrotic in animal models of liver disease; it correlates negatively with hepatocellular cancer in two studies, one prospective.
BUT Vit A from diet correlates positively with fibrosis in one study, and alcohol converts retinol to a hepatotoxic polar metabolite which disrupts mitochondrial membrane potential (which probably accounts for the differences in the 3 studies; positive effects were seen in Asia (Shanghia and Taiwan), with lower alcohol consumption, negative effects in Italy).
Can other factors render retinol polar? Maybe iron plus PUFA - this might help account for the pork effect. Surely some drugs.
Definitely worth getting some cod liver oil, unless of course one drinks...
I sometimes use fortified CLO supplements so as to lessen overall PUFAs from fish oil.

john said...

It's interesting how with pretty much any ailment, one can put together a supportive argument that vitamin A would be a good treatment. But, the literature overall isn't that clear. Almost everything I see is positive, but there is an interesting group of papers with overlapping authors about vitamin A and "oxidative insult" in the substantia nigra--and another group about vitamin A and lipofuscin in the RPE. Unfortunately, I never felt like purchasing the full texts.

One factor [regarding the inconsistent epidemiology] could be that in many Asian countries, vitamin A intake/storage is less than in many European countries like France. So maybe we wouldn't expect similar correlations with another variable worldwide. Regarding liver storage, Ghana>>New Zealand>>US>Thailand>Cananda>NYC*.**

*Of course NYC is part of the US.

**This comparison is from a 1974 study that referenced seven studies from 1960s and early 70s; the Ghana study had much lower sample size.

Grace of Animal Pharm told me that she once had a problem with diet high in A and drinking alcohol.

George Henderson said...

If you are retinol-deficient this sets you up for viral illness, and some viruses, like measles, deplete vit A.
Retinol storage is a measure of liver inflammation; HSCs dump retinol when initiating fibrosis.
The anti-inflammatory benefits of retinol are contingent; benevolent microbiota ("pro-biotics"), vitamin D, (and possibly K2 but there's no research yet) seem to be required. This relates to the Th17-Treg shift. Immunology is a real brain-bender in which nothing is what it seems; context changes everything. A pro-inflammatory cytokine in one milieu is anti-inflammatory in another.
Also Vit A is a cell growth factor and this effect will probably be modulated by insulin.
The RDA for retinol is set too low; this is probably due to the toxifying effect of alcohol (and probably some prescription meds that affect the same enzymes) on retinol and the widesperad use of alcohol in our cultures.

George Henderson said...

Anecdotal evidence in support of the hypothesis: Back when I was an IV drug user in Dunedin N.Z., Ritalin (methylphenidate) was the only amphetamine available.
I knew 3 anorexic individuals who used ritalin, contracted HCV, then cleared the virus. Other users whose occasional ritalin use did not result in malnutrition did not clear the virus.
It always seemed anomolous to me that speed and malnutrition should be associated with an antiviral effect. Now it seems consistent with the hypothesis; starvation is a form of carbohydrate restriction.
PPAR-alpha is activated, just as in the naringenin experiments, and as in low-carb ketosis.

max the cat said...

only problem with the high meat diet is that ultimately the cause of liver cancer in HCV is iron accumulation in the liver. the bioavailabilty of iron in meat, plus the increase of non-heme iron caused by the addition of meat or fish, is enormous compared to availability of iron from veg and rice, for instance. the virus suppresses hepcidin-which regulates iron storesin the liver-as does vitamin d, by the way. you can really hurt yourself with high vit d supplementation or dietary sources. repeated phlebotomy(check pubmed hcv phlebotomy, hepatocellular carcinoma phlebotomy,etc.)high dose vit k,are proven cancer preventive in hcv. hcv is quite different from other liver diseases. rat experiments are misleading and useless. in vitro does not tell you what long term human population studies will.

George Henderson said...

There is no iron in tallow or butter, and no need to eat more meat on a high-fat diet than anyone else does on a high-carb diet. You could get protein from eggs and paneer and nuts instead if you like, though it might pay to supplement zinc.

Iron accumulation is a product of inflammation, this is a good schematic of the same factors in AOCD
http://www.fracp.bigpondhosting.com/images/anaemiaofchronicdisease.jpg

It is at the bottom of this page with an explanation
http://www.fracp.bigpondhosting.com/examquestions/2003/2003papertwo31to40.htm

Phlebotomy is a good idea, also use of polyphenolic antioxidants that chelate iron.

we don't have many long-term population studies of HCV and diet, but carbohydrate and polyunsaturated fat (omega 6) tend to show as correlating with cirrhosis, not surprising as that's an inflammatory combination.
Saturated fat, MUFA, and (probably) omega 3 (but no-ones tested that) are safe.
Cholesterol (n the diet) might be problematic for some, but that's what taurine's for.

George Henderson said...

There is a link between vitamin D deficiency and anaemia (and vice versa) but I can't find anything about Vit D promoting iron overload (vit D deficiency anaemia probably isn't protective, too much depends on iron and vit D)

"We found a significant rise in haematocrit and haemoglobin at 3 and 12 months on calcitriol therapy, with no modification of the EPO dose nor ferritin levels."
http://www.ncbi.nlm.nih.gov/pubmed/9453399

More haemoglobin is a good thing as iron there is non-reactive. People take EPO for low platelets, but vit D does the same job here.

James said...

I have been reading this blog and also Peter from Hyperlipid about High Fat - Low Carb diets. I wonder what can be said about another highly prevalent virus, herpes simplex. I am interested in recommendations to deal with it and have opened a blog to share tips I have found relevant based on reading internet content. It is very speculative, but one has to start from somewhere, conventional medicine offers little for this condition.

http://herpesregimen.blogspot.co.uk

George Henderson said...

Thanks James,

you're right, conventional medicine has little to offer. I can think of some herbs (Kaloba) and antioxidants (selenium and vit E) that show promise. Thanks for the link to your blog.

James said...

What do you think of methylene blue for virus and other infections? I've read those clinic trials for Malaria (it goes back hundred years ago). I am not sure how it works but it reminds me of caffeine. Because on one hand, it seems to act as hormesis and killer of weaker cells. This can be seen from the fact it works in combination with other more specific drugs or with red light (cells more photosensitive with MB). On the other hand, it seems as helper, not as a weakener, because it suppresses nitric oxide production which is stressor. The dual role is reminiscent of caffeine, in fact I wonder whether they could have just used caffeine in the clinical trials. However it is not crazy to think MB could be special against infection, for example it's been mentioned as treatment against H Pylori infecting the stomach, where I don't think caffeine is anti-bacterial.

George Henderson said...

As I understand it, methylene blue is a crude but powerful antioxidant/ antiinflammatory
HHV like HCV increases replication by NF-KappaB activation through a pro-oxidant mechanism.
(HCV tweaks mitochondrial respiratory enzymes so excess ROS are generated to nucleus, stimulating NF-KappaB; probably the best damper for this is tocopherol in the form of succinate).
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102-86502011000100010

George Henderson said...

http://www.ncbi.nlm.nih.gov/pubmed/22079390

This sort of thing.