Search This Blog

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."
  • 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.