Are Vitamins Killing You? TV3 Inside New Zealand Review

October 28, 2009, 2:59 pm

≫ Next: How a High-fat Paleo diet Protects against HCV replication and Fibrosis of the liver

Review, Inside New Zealand "documentary" Are Vitamins Killing You?

It confirmed what I've always known, that TV cannot report responsibly on inherently complex matters of science or history. Instead of explaining things scientifically in the detail required to give an honest version of events, time is wasted on trivia, soundtracks, action shots that add nothing to the data presented, and the data itself is so often wrong. Thus, last night we were taught that vegetables are a source of vitamin D, that vitamin B is a single vitamin, with the chemical structure of thiamine and a single list of positive and negative effects, that there is no difference between retinol and beta carotene, that vitamin deficiency syndromes in New Zealand are too rare to be worth mentioning, and so on.

Potential pro-oxidants in supplement form are excesses of iron and copper. One of the participants in the program was supplementing iron without a diagnosed deficiency, but her iron levels were not taken, because the show was about vitamins!
Thus a chance to warn the audience about the proven pro-oxidant dangers of high iron levels was missed.

Much was made of a statistical analysis of 60 antioxidant papers (chosen from the many hundreds available) called the 2008 Cochrane Collaboration, yet we were given no detail about what kind of data this actually represented. If we had been told that most of the negative statistics for vitamin E came from a single 28 day, very high-dose trial in terminal cancer patients, and that the doctor conducting this trial has since revised her conclusions (due to important differences between the treatment group and the controls), we might have wondered about the relevance of this to the average vitamin taker. The useful information we might have taken from the CARET study, that it is not wise for smokers to supplement high doses of all-cis beta-carotene, was not shared with us. The positive results for antioxidant supplements from the longest-running large trials to date, the Doctors study and the Nurses study, which were ignored by the Cochrane doctor, were also ignored by the doctors on the Inside New Zealand show.

Arguments were made which cancelled each other out, in a "cake and eat it" style. Thus, supplementing vitamins supposedly gives false security so people do not eat as well, yet positive results of studies using voluntary vitamin takers can be disregarded because studies show that such vitamin takers eat better than anyone else. Okay then...

A sensible view might be that studies using voluntary vitamin takers are far more representative of the real effect that vitamins are having on such populations than the studies used by the Cochrane Collaboration, which favoured people in medical care for various reasons being given high doses of a single vitamin, yet not being told to improve their diets or lifestyles to bring them in line with those of the average vitamin taker. Amongst the many choices made that tended to skew the results of that analysis, the decision was taken to ignore all studies in which no-one died (thus pushing otherwise "insignificant" results towards statistical significance), and to measure "death from all causes" (including accidents), meaning that no useful conclusions could be drawn about the actual health effects of the vitamins.

Because, for example, high doses of vitamin E or beta-carotene can potentially lower intake of one another, and other fat-soluble antioxidants, by competing for absorption, especially in a low-fat diet. This seems to be be a real risk, and it is eaily avoided - mostly by sensible diet. We could have been told about this risk, but that would have meant explaining a scientific principle, the kiss of death for entertainment TV. Because when it comes down to it, entertainment, not information was the point of this program.

Post Script: 2012

You might remember how the Cochrane Collaboration did a meta-analysis of antioxidant supplements some years back and found they increased mortality?
Here, some different authors re-analyse THE EXACT SAME DATA and come to the opposite conclusion.
Huh?
How come the newspapers and TV never reported - this?

Nutrients. 2010 Sep;2(9):929-49. Epub 2010 Aug 30.

Reexamination of a meta-analysis of the effect of antioxidant supplementation on mortality and health in randomized trials

Biesalski HK, Grune T, Tinz J, Zöllner I, Blumberg JB.
SourceDepartment of Biological Chemistry and Nutritional Science, University of Hohenheim, Garbenstrasse 28, D-70593 Stuttgart, Germany. biesal@uni-hohenheim.de

Abstract
A recent meta-analysis of selected randomized clinical trials (RCTs), in which population groups of differing ages and health status were supplemented with various doses of β-carotene, vitamin A, and/or vitamin E, found that these interventions increased all-cause mortality. However, this meta-analysis did not consider the rationale of the constituent RCTs for antioxidant supplementation, none of which included mortality as a primary outcome. As the rationale for these trials was to test the hypothesis of a potential benefit of antioxidant supplementation, an alternative approach to a systematic evaluation of these RCTs would be to evaluate this outcome relative to the putative risk of greater total mortality.
Thus, we examined these data based on the primary outcome of the 66 RCTs included in the meta-analysis via a decision analysis to identify whether the results provided a positive (i.e., benefit), null or negative (i.e., harm) outcome.
Our evaluation indicated that of these RCTs, 24 had a positive outcome, 39 had a null outcome, and 3 had a negative outcome. We further categorized these interventions as primary (risk reduction in healthy populations) or secondary (slowing pathogenesis or preventing recurrent events and/or cause-specific mortality) prevention or therapeutic (treatment to improve quality of life, limit complications, and/or provide rehabilitation) studies, and determined positive outcomes in 8 of 20 primary prevention studies, 10 of 34 secondary prevention studies, and 6 out of 16 therapeutic studies. Seven of the eight RCTs with a positive outcome in primary prevention included participants in a population where malnutrition is frequently described. These results suggest that analyses of potential risks from antioxidant supplementation should be placed in the context of a benefit/risk ratio.
http://www.ncbi.nlm.nih.gov/pubmed/22254063

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How a High-fat Paleo diet Protects against HCV replication and Fibrosis of the liver

December 7, 2011, 12:41 pm

≫ Next: Hepatitis C, Gluten and the Folly of Agriculture

≪ Previous: Are Vitamins Killing You? TV3 Inside New Zealand Review

The Hepatitis C virus replicates and infects cells by hijacking at least two cellular mechanisms, one of which is specific to liver cells; the RNA replication apparatus, which is essential in all cells (and thus is not a realistic target for nutritional therapy), and the mechanism which converts excess carbohydrate to triglycerides (fatty acids) and sends them to the blood stream to be stored in fat cells for later use. The latter mechanism is largely optional, and is sent into overdrive by the high carbohydrate of the current, fashionable, “healthy” diet. The human body has evolved to function on minimal or no carbohydrates, because we evolved under conditions, before the invention of agriculture, where game animals, birds, and fish were plentiful and most available plant sources of nutrition were relatively low in carbohydrates and rich in polyphenols and fibre (bitter or tart, and stringy) compared to those we eat today.

DGAT1 is a liver enzyme essential for HCV replication the production of which is triggered by insulin, which is the hormone the body produces in reaction to glucose, the digestion product of most carbohydrate foods, and more specifically in the liver by fructose, derived from sugar (sucrose) and fruit juice. Blocking DGAT1 is considered to be a realistic target of drug therapies for HCV. However, it is doubtful that any drug it is possible to invent could lower the level of DGAT1 as completely as a diet with no use for it; that is to say, a diet with minimal fructose and no more carbohydrate than can be burned for energy immediately (a very small amount unless you are an athlete in the middle of performance), or could lower DGAT1 without other unwanted effects. Once replicated, HCV escapes from infected hepatocytes via the membrane sites that release VLDL-"cholesterol" into the bloodstream. VLDL carries the triglycerides which have been formed to store the energy from excess carbohydrate (once these are dumped into fat storage VLDL becomes the notorious LDL. The more triglycerides packed into the original VLDL, the more harmful the type of LDL). HCV enters and infects new cells in tandem with LDL, using the LDL receptor. If you use oil or spreads high in "heart healthy" PUFA, including fish oil, the cells express more LDL receptors to pull more LDL from the blood. People with Hep C actually do better if their LDL levels are higher. PUFAs create an increased need for cholesterol; the cell membranes become sloppier and need more cholesterol reinforcement. Liver production of cholesterol, and total body cholesterol content, actually increases on a diet high in PUFA, while the blood level (serum cholesterol) is lowered.

The virus seeks to monopolize cholesterol production in order to reduce serum cholesterol and LDL; low cholesterol and LDL has the effect of increasing LDL receptors; the increased availability of receptors in a low-cholesterol environment maximizes HCV's access to naive cells via its own association with LDL.
Consuming cholesterol-rich foods in the diet also has the effect of reducing LDL receptors, especially in the context of a low-carbohydrate diet, and also reduces hepatic activity of HMG-Co reductase, an enzyme that may be essential in the early stages of HCV infection, and which remains in use by genotype 3.

Thus restricting fructose, total carbohydrate, and PUFA* and eating a cholesterol-rich diet produces three effects on HCV; 1) replication is slowed because less DGAT1 (and less HMG-CoA reductase) is expressed, 2) serum HCV level is lowered because less of the HCV is being secreted from infected hepatocytes. 3) less HCV is being taken up into uninfected hepatocytes. A further benefit is the improved immune function seen on low carb diets, as high insulin and glucose levels compromise immunity. The decreased expression of HCV core proteins also improves immunity, liver function and antioxidant status. Fibrosis is also heavily driven by insulin and all inflammatory processes are slowed or stopped by the serious reduction of carbohydrates. Eating a low carb diet means eating more fats and protein, and these have positive benefits for liver health; protein is a mixture of amino acids, almost all of which have been shown to have anti-inflammatory or antioxidant effects at the concentrations in a high-protein diet, and none of which are harmful (there is no evidence that high protein intake harms the kidneys; the sole experimental finding that began this myth resulted from feeding a diet of meat and soy protein to caged rabbits, an animal which naturally eats very little protein in its diet. If you feed a carnivorous or omnivorous animal a higher-protein diet its kidneys will, if anything, function better than they did before). As for fats, we have been lied to for years ("A lie can travel halfway round the world while the truth is still putting on its shoes" - Mark Twain). Saturated fats do not cause disease, and polyunsaturated fats are not necessarily healthy. A diet including beef tallow, the most saturated of animal fats, protects the liver of rats force-fed alcohol, and such diets are at the heart of the so-called French paradox; populations that drink heavily and eat most saturated fat have the lowest levels of heart disease and cirrhosis. We do not need to invoke resveratrol to explain this result.

(* PUFAs arachadonic acid, EPA, and DHA have antiviral effects on HCV replication, but are profibrotic at higher intakes.)

Dietary Saturated Fatty Acids Reverse Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administration Amin A. Nanji1, Kalle Jokelainen2, George L. Tipoe3, Amir Rahemtulla4 and Andrew J. Dannenberg5 ananji@pathology.hku.hk http://jpet.aspetjournals.org/content/299/2/638.long

Abstract
We investigated the potential of dietary saturated fatty acids to reverse alcoholic liver injury despite continued administration of alcohol. Five groups (six rats/group) of male Wistar rats were studied. Rats in groups 1 and 2 were fed a fish oil-ethanol diet for 8 and 6 weeks, respectively. Rats in groups 3 and 4 were fed fish oil and ethanol for 6 weeks before being switched to isocaloric diets containing ethanol with palm oil (group 3) or medium-chain triglycerides (MCTs, group 4) for 2 weeks. Rats in group 5 were fed fish oil and dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, nuclear factor-κB (NF-κB) activation, and mRNAs for cyclooxygenase-2 (Cox-2) and tumor necrosis factor-α (TNF-α). Endotoxin in plasma was determined. The most severe inflammation and fibrosis were detected in groups 1 and 2, as were the highest levels of endotoxin, lipid peroxidation, activation of NF-κB, and mRNAs for Cox-2 and TNF-α. After the rats were switched to palm oil or MCT, there was marked histological improvement with decreased levels of endotoxin and lipid peroxidation, absence of NF-κB activation, and reduced expression of TNF-α and Cox-2. A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased activation of NF-κB and reduced levels of TNF-α and Cox-2. Long-term treatment of alcoholic liver disease continues to incorporate vitamins, nutrients, and trace elements (Fulton and McCullough, 1998; McCullough et al., 1998). In fact, the role of specific pharmacological agents remains unproven. Clearly, the development of more effective nutritional or pharmacological therapy will depend on further elucidating the mechanisms that contribute to liver injury. Several lines of investigation indicate that dietary fat can modulate the severity of alcoholic liver injury (Mezey, 1998). In experimental animals, for example, diets enriched with saturated fatty acids protect against alcohol-induced liver injury, whereas diets containing polyunsaturated fatty acids promote liver injury (Nanji and French, 1989; Nanji et al., 1989, 1994a). Saturated fatty acids have also been reported to reverse established alcoholic liver injury (Nanji et al., 1995, 1996, 1997b). Importantly, in previous studies, use of alcohol was discontinued at the time that dietary treatment was initiated. This model represented the alcoholic patient who stopped drinking at the time of hospitalization (French, 1995). Discontinuation of alcohol remains pivotal in the treatment of alcoholic liver disease. Although this goal can frequently be achieved in the short-term, the majority of patients resume alcohol consumption, often with sudden deterioration in liver disease (Pares et al., 1986). Hence, it is important to develop therapeutic strategies that simulate the clinical condition in which alcohol use is continued despite the presence of alcoholic liver disease. Previously, we used the intragastric feeding rat model to study the pathogenesis of alcoholic liver disease (Nanji et al., 1999). In addition to being useful for elucidating mechanisms of injury, this model has been used to evaluate various strategies to prevent or reverse alcoholic liver disease (Nanji et al., 1995, 1997b). The results of previous studies suggest that elevated levels of endotoxin and lipid peroxides in alcohol-fed animals activate nuclear factor-κB (NF-κB), leading to enhanced expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (Cox-2), and proinflammatory cytokines (Nanji et al., 1997a, 1999). In the current study, we investigated whether treatment with dietary saturated fatty acids could reverse established alcoholic liver injury despite continued administration of ethanol. We show that diets enriched in saturated fatty acids improved both histological liver injury and biochemical parameters that have been etiologically linked to liver injury.
(The ferretin levels in the livers of the saturated-fat rats were less than half those of the polyunsaturated fat-rats).

Beef Fat Prevents Alcoholic Liver Disease in the Rat Amin A. Nanji MD, FRCP(C), Charles L.

The amount and type of dietary fat is thought to be important in the pathogenesis of alcoholic liver disease (ALD). We investigated the role of different dietary fats in our rat model for ALD. Liver pathology was evaluated in rats fed ethanol and lard or tallow or corn oil over a period of 2 to 6 months. All experimental animals were pair-fed the same diet as controls except that glucose was isocalorically replaced by ethanol. Rats fed tallow and ethanol developed none of the features of ALD, those fed lard and ethanol developed minimal to moderate disease, rats fed corn oil and ethanol developed the most severe pathology. The degree of histopathological abnormality correlated with the linoleic acid content of fat in the diet (tallow 0.7%, lard 2.5%, corn oil 56.6%). We postulate that linoleic acid facilitates development of ALD and provides an explanation for our previous epidemiological observations. Effect of Dietary Fat on Ito Cell Activation by Chronic Ethanol Intake: A Long-Term Serial Morphometric Study on Alcohol-Fed and Control Rats Hisao Takahashi, Kim Wong, Linda Jui, Amin A. Nanji, Charles S. Mendenhall, Samuel W. French (note: Ito Cells are Hepatic Stellate cells in their normal state. This study is saying that rats fed beef tallow had no loss of Ito cells – that is, no conversion to myofibroblasts – whereas rats fed corn oil went into fibrosis) We studied the effects of long-term ethanol ingestion and dietary fat on Ito cell activation morphometrically in rats. Sixteen pairs of Wistar male rats were divided into two groups, one fed tallow and the other fed corn oil as the source of dietary fat. Each group of rats were pair-fed a nutritional adequate liquid diet containing either corn oil (CF) or tallow (TF) as fat as well as protein and carbohydrate. Half of each group received ethanol, the rest were pair-fed isocaloric amounts of dextrose via an implanted gastric tube for up to 5 months. Morphometric analysis of the change in fat and rough endoplasmic reticulum (RER) of Ito cells was performed on electron micrographs obtained from monthly biopsies including baseline. Ito cell activation was assessed by a decrease in the ratio of fat/RER in Ito cells. The ratio of fat/RER in Ito cells of alcoholic rats fed the CF diet (CFA) gradually decreased. The ratio war found to be lower than in the pair-fed control rats (CFC) at 5 months of feeding. CFA 1.74 ± 0.57, vs. 7.46 ± 2.05, respectlvely, p < 0.05, mean ± se). Ito cell fat also significantly decreased at 5 months of feeding (p < 0.05). The fat/ RER ratio In CFA significantly decreased only subsequent to the development of fatty change, necrosis, and inflammation followed by fibrosis of the liver. In contrast, the TFA rats did not show a significant decrease in the fat/RER ratio in the Ito cells throughout the study, while TFC rats showed an increase in the fat/RER ratio. Minimal pathological changes were observed in the livers of CFC, TFA, and TFC rats. These results indicate that activation of Ito cells at a significant level occurred only late in the course of feeding alcohol after moderate to severe abnormalities in liver histology had developed, although activation may have begun at an earlier time of ethanol feeding. The results indicate that dietary fatty acid composition may be an important factor in the pathogenesis of ethanol-induced Ito cell activation.

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Hepatitis C, Gluten and the Folly of Agriculture

December 7, 2011, 12:57 pm

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Gluten and Casein as Factors responsible for the Characteristic Diseases of Chronic Hepatitis C

Not everyone exposed to HCV develops a chronic infection. The rate of natural clearance is unknown, because most people are not aware they are infected until the condition becomes chronic. One known factor in chronic infection with viral hepatitis (A or B) is selenium deficiency in malnourished populations. Celiac disease, the most easily diagnosed form of gluten toxicity, is known to cause selenium deficiency in well-fed populations. Celiac also causes a general deficiency of many antioxidants, protein, and minerals and vitamins. There is a strong association between HCV and celiac disease in many populations tested. There is an even stronger association between interferon-alpha treatment and celiac disease. Interferon-alpha is the cytokine that triggers celiac disease naturally. Celiac disease is only the easiest to diagnose of the gluten sensitivity syndromes. It results in destruction of the intestinal cell vilii, damage which can be detected on biopsy. Even so celiac is seriously underdiagnosed. It is likely that anyone in New Zealand with the symptoms of celiac disease, who is HCV positive, will be told that their symptoms are due to hepatitis C. Testing for Celiac will happen slowly and most likely not at all, unless the patient insists, and testing for other forms of gluten sensitivity is unlikely.

Milder forms of gluten sensitivity might only disrupt those gut receptors responsible for functions such as immune regulation (especially endorphin receptors), mineral transport, or absorption of specific vitamins. Antibodies may form to the proline-rich gluten, gliadin and casein sequences released by peptide digestion which enter the bloodstream, which then attack the proline-rich collagenous tissues, promoting diseases such as liver fibrosis and rheumatoid arthritis. It so happens that the auto-immune symptoms associated with celiac and gluten sensitivity diseases, including liver and gall-bladder disease, and which usually resolve slowly on a strict gluten and dairy-free diet, are essentially identical to the various syndromes seen in chronic Hep C, especially during or after interferon-alpha treatment. Syndromes caused by gluten in celiac disease include: - fibrosis and cirrhosis of the liver - gall bladder obstruction - insulin resistance - thyroiditis - sicca syndrome (dry eyes and mouth) - vasculitis - brain fog (poor memory, confusion) - depression - fibromyalgia - fatigue - optic neuritis - deficiencies of selenium, magnesium, zinc, chromium - deficiencies of fat-soluble vitamins (A, D, E, K) - deficiency of those vitamins converted in the intestines (including folate, B6) - anaemia - thrombocytopenic purpurea (low platelets due to autoimmunity) - GI disturbance; diarrhea, steatorrhea These symptoms are aggravated by the nutrient deficiencies, especially antioxidant, magnesium, and chromium deficiencies, associated with gluten sensitivity. In fact, the symptoms of both Hep C and celiac disease are often partially, but significantly, relived by supplementation of these nutrients, especially when anti-inflammatory botanicals (curcumin, grape seed, ginkgo, milk thistle etc) are added.

Other treatments effective against Hep C have obvious links to gluten sensitivity; for example, low dose naltrexone may exert its beneficial effects on cancer, autoimmune disease, and viral immunity by repairing damage done to endorphin receptors by gluten and casein digests. Similarly, enzyme therapy for cancers may work by promoting the complete digestion of gluten and casein exorphins, and the ketogenic diet for cancer may work by eliminating grains and lowering insulin levels (and hence inflammation), rather than merely by depriving cancer cells of glucose. Exorphins are chemicals found in protein digests (the peptides produced by pepsin digestion of food proteins) which have an affinity for endorphin receptors. Endorphins are the messengers of emotion, and gluten sensitivity is very often found in schizophrenia, autism, ADHD, Aspergers, and the various mood disorders. However, the endorphin system also regulates the immune system, and defects of endorphins and endorphin receptors are associated with cancers and autoimmune disease, as well as AIDS. Endorphins also regulate gut motility; the well-known constipating effect of cheese is an opioid effect. Even people who have no gluten antibodies and no leaky gut (which allows gluten digests to enter the bloodstream in especially large doses) are influenced by the opioid effect of exorphins at the local, gut level.

Diagnosing non-celiac gluten and casein sensitivity without exclusion diets is difficult, if not impossible. Commonly in New Zealand a scratch test for gluten is the doctor’s first choice. This is worse than useless, because we are not talking about an allergy to gluten at all (though these do exist). When gluten, milk and maize are digested in the stomach (by pepsin and hydrochloric acid) a variety of peptides are released. The exact combination of peptides that might appear in the gut varies with the individual, the state of his digestion, and the strain of wheat, milk or maize consumed. Gliadomorphin is a characteristic wheat exorphin; beta-casomorphin-7 is thought to be the most toxic milk exorphin; and the maize exorphins have not yet been identified. Autoimmune reaction to antigenic peptides is not the only way in which exorphins can harm us, so the current insistence on immunological testing seems limited. Also, current tests do not include antibodies to every possible peptide digest of gluten; this would probably be impossible. Further, in many cases symptoms may be due not to gluten but to agglutinating lectins found in the germ, or to phytates withholding nutrients (minerals and vitamin D), or to some synergy of all 3 components.

Luckily, no-one needs to eat grains. Our ancestors got along in better health without them for millions of years. Grain consumption is a comparatively recent phenomenon in human history; very recent indeed in some cases; in Northern Europe and in colonized Oceania it is a habit of mere centuries, if that. In parts of the world where grain-eating goes back longest, for example the eastern Mediterranean, there is a higher rate of adaptation. This does not mean that individuals adapted to grains; individuals died young or became sterile if they lacked the more grain-adapted genes, in order that the race might adapt. But this still does not rule out the diseases of later life. Study of remains of grain-dependent societies, such as Rome and ancient Egypt, show that so-called “modern” diseases such as arthritis and cancer were prolific there. It is trendy to think that such disease results from technology; radiation, pesticides, food processing; and that it can be prevented with an organic vegetarian diet. The sad truth is that in most cases wheat and milk - even organic wheat and milk – products of the older agricultural revolution – are doing more harm than those traces of the modern industrial revolution that we cannot avoid. If our immune systems and our detox enzymes cannot cope with some new agricultural chemical, the most likely reason is the disruption they have received from the old agricultural chemicals – gluten and casein.

It was also agriculture, not food processing, that first placed man in a guilty relationship with his food. Pre-agricultural man killed to eat and took from the forest, and had rituals that made peace with the animals and the plants. He took from these bounteous gods, not from captive creatures. Agricultural man kills for money, pays others to kill for him, and burns down the forest to plant his cash crops. If this was original sin, then the wages of sin have indeed been death.

It is customary to blame lead piping for the decline of Rome. The Roman people were highly wheat-addicted; they would riot for bread; “Bread and Circuses” was the formula for keeping them happy; they were so addicted that the state found it more convenient to supply bread for free (like a methadone clinic for the opiate of the people). Today the state oversees the addition of gluten, milk and maize to an ever-widening range of foods, so that a mere bread shortage is not likely to cause withdrawals. This is probably not intentional; addicts tend to assume that everyone wants to share their habit. In the case of Rome, wheat and lead may have had a synergistic toxicity. Both lead poisoning and wheat consumption tend to reduce iron and zinc absorption. This is why celiac children are often of short stature. The Romans would have become increasingly incapable of sensible planning and come to lack the stern old Roman self-control. We know that a decreasing birthrate of “true born” Romans eventually led to the conscription of barbarian armies and the opening up of Roman citizenship. Today gluten, and the antioxidant deficiency it causes, is a major cause of infertility.

Research has been done into the links between gluten sensitivity and Hep C, showing a strong association (especially after interferon therapy). There is also a strong association between Hep C and lymphoma (a cancer of the lymph glands). Lymphoma is the characteristic cancer caused by gluten; celiacs have a 30x elevated risk of lymphoma. To date no-one seems to have tested a strict gluten- and dairy-free diet for chronic Hep C or post-interferon toxicity, but a great many people with Hep C who take their health seriously have gone gluten free, often without knowing of the links between the two conditions, but motivated by their own well-being when avoiding gluten.

There is no nutritional need that can only be met by grains; nuts and seeds, for example, supply the same amino acids, fats and vitamins in greater concentration (for example, sunflower and sesame seeds are superior sources of methionine and vitamin E), while legumes are rich in complex carbohydrates. Gluten is also a cause of insulin resistance, and everyone who develops liver fibrosis has some degree of insulin resistance. Gluten itself causes a four-fold rise in insulin levels (unusual for a protein). The cure for insulin resistance is two-fold; a high-protein, low-carb diet (the Paleolithic diet is the most natural version of this diet) and replacement of the nutrients depleted by gluten which are essential for the function of insulin receptors; chromium, magnesium and the antioxidant minerals and vitamins. Gluten also seems to cause amino acid deficiencies, including some of the very amino acids which wheat is supposed to supply, methionine and cysteine. Gluten is very much an anti-nutrient once one is sensitive to it.

Recommended reading:
On gluten: Dangerous Grains by James Braly M.D. and Ron Hoggan M.A.
On milk, exorphins, and beta-casomorphin-7 (BCM7): The Devil in the Milk by Keith Woodford
On endorphin receptors and AIDS: Molecules of Emotion by Candace B. Pert
Ron Hoggan’s gluten research http://www.gluten-free.org/hoggan/
A readable introduction to gluten diseases (especially chapter 3) which discusses many syndromes also seen in Hep C http://www.gluten-free.org/hoggan/adhd.txt
Man the Hunter: An Essay on the Paleolithic Diet by Drs Mike and Mary Eades, http://www.ofspirit.com/tw-theproteinpowerlifeplan.htm (Highly recommended, as are all the Eade’s writings, and their Protein Power Blog).

from: Gluten is a Dangerous Luxury of Non-Celiacs http://www.gluten-free.org/hoggan/dubious.txt We hear all the time about pollution in the industrial world being the source for modern man's high incidence of cancer. It is the chemical additives, we are told, in the food we eat, that causes much of the problem. Perhaps. I would like to suggest that the evidence from antiquity, the pattern of the spread of agriculture in Europe coinciding with the patterns of civilizatory illnesses, the levels of SBHG associated with wheat consumption, the high incidence of gliadin antibodies among those with neurological illnesses of unknown origin, the sensitivity to gluten among siblings of celiacs in spite of the absence of genetic indicators associated with celiac disease, and my own investigation of the literature regarding lymphoma, all point to the strong possibility that gluten is a dangerous substance to many more people than just celiacs. - Ron Hoggan, 1997

To which I might add: the parallel associations between gluten sensitivity and the various syndromes traditionally attributed to HCV infection all point to the even stronger possibility that gluten is a very dangerous luxury for people with hepatitis C.

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Hep C Treatments in 5 Words

December 7, 2011, 1:29 pm

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

≪ Previous: Hepatitis C, Gluten and the Folly of Agriculture

People are always asking me to put my Hep C findings into simple language and keep it short. It's hard to do this without cutting corners. But increasingly I find things falling into simple categories, each of which can be explored seperately.

Hepatitis C in 5 words or less A Hep C protocol should protect against the following aspects of HCV infection:

Oxidative stress (liver damage, diabetes, inflammation) – Hep C depletes antioxidants, low antioxidant levels are associated with poor outcomes. The combination of oxidative stress and hypomethylation is the preventable cause of hepatitis, fibrosis, and cirrhosis. Some genotypes also promote the accumulation of iron, which increases oxidative stress exponentially. Genetics, iron fortified foods, and poor liver function can also add to iron loads.

Treatment – mixed antioxidants (selenium ACE type), Co-enzyme Q10, silymarin, polyphenols, OPCs.

Hypomethylation (steatosis, fatigue, depression) – Hep C depresses methylation, which allows fats to accumulate and decreases energy output. Methylation is the process needed to supply creatine, phosphatidylcholine, carnitine, co-enzyme Q10, glycine, melatonin, adrenaline, cholesterol and steroids; methylation also inactivates histamine and niacinamide, and helps with detoxification. Methylation also plays a role in DNA synthesis and in regulating the expression of genes and the activity of proteins. All methylation in the body is carried out by the SAMe form of methionine, except for the methylation of methionine itself, which requires B12, folic acid, and/or betaine. Hypomethylation (deficient methylation) in Hep C is largely due to inhibition of vitamin B12 by oxidative stress, the poor absorption of B12 and folate when stomach acid is inadequate, and anorexia and nausea limiting intake of foods rich in methionine. So-called low fat foods that are low in high-quality protein and essential fats and high in carbohydrates are especially problematic - the liver synthesises fats from carbohydrates in any case. Overcooked fats and refined oils and spreads should be avoided, vegetable oils minimized, some PUFA from fatty fish (omega 3 EFAs) and extra virgin olive oil is acceptable but most fats should come from red meat, cream and butter, dripping, and coconut.

Treatment – l-methionine or SAMe, B12, folic acid, phosphatidylcholine (lecithin), carnitine, betaine.

Immunosuppression (HCV replication, co-infections, allergies) – Hep C interferes, both directly, and via oxidative stress, with immune function, allowing co-infections and autoimmune syndromes to develop. Increased levels of interferons during illness can bring about gluten and other allergies in previously tolerant individuals.

Treatment – selenium, probiotics, zinc, vitamin A, vitamin D, vitamin C, cordyceps, astragalus, garlic, echinacea.

Note on antiviral herbs: Ginger, silymarin, grape seed OPCs, green tea extract, blueberry leaf extract, Rosa Rugosa flowers, various iridiods, stevia all directly inhibit HCV cell entry or replication; resveratrol enhances HCV replication.

Inflammation (other inflammatory conditions, liver damage, mood disorders) – Hep C increases production of pro-inflammatory cytokines, which can promote fibrosis, and prostaglandins, which strip essential fatty acids from cell membranes, causing pain and mood changes. Inflammation and oxidative stress are closely related. Similar processes are involved in PMS, bipolar disorders, psychosis etc. so it is not surprising that moods, emotions and perceptions can be affected by Hep C. Inflammatory cytokines can also trigger sensitivity to complex proteins such as gluten (wheat, rye, barley) and casien (cow's milk), which then become an additional cause of inflammatory disease.

Treatment – magnesium, vitamin D, ginkgo, EPA and DHA (krill oil is the best source), niacinamide, N-acetyl-glucosamine (glucosamine can be an effective substitute for NSAIDs). Gluten free, low carbohydrate diet high in saturated fat.

Detoxification (liver damage) - Exotoxins and endotoxins requiring phase 1 and phase 2 detox – drugs, toxins, pollutants, cholesterol and steroids - must be processed by liver and kidneys. Many of the phase 2 reactions use glutathione, glycine and taurine, levels of which are reduced in Hep C, and pantothenic acid (B5). Glycine production is inhibited by hypomethylation. Improperly metabolized toxins can add to oxidative stress, damaging the liver, or inhibit enzymes, impairing liver function.

Treatment – sulfur amino acids, B vitamins, broccoli sprouts, whey protein

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

February 14, 2012, 12:14 pm

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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 DAGT1 (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 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 major driver of DAGT1, TG and VLDL

Restrict total carbohydrate, which also drives DAGT1, TG and VLDL

Consume dietary cholesterol, which is the natural HMG-CoA reductase inhibitor.

Restrict vegetable PUFA, which increases LDL-R numbers and de novo cholesterol synthesis.

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.

↧

HCV, Fructose and Fox01

June 14, 2012, 2:13 pm

≫ Next: Is a Diet High in Saturated Fat Good for the Liver?

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

Here's a bit of corroborating evidence on the wisdom of restricting fructose in Hep C, and the possibility that HCV might create a fructose sensitivity predisposing towards insulin resistance and type 2 diabetes.

Fox01 is a transcription factor involved in the response to insulin; it governs both lipogenesis (the conversion of carbohydrate to fats) and gluconeogenesis (the production of glucose) in the liver. These are both ways in which excess energy can be sent out from the liver, or stored there in a stable form.

HCV core protein increases Fox01 activity via oxidative stress, which causes the transcription factor to be retained in the nucleus;

http://www.ncbi.nlm.nih.gov/pubmed/22291689
http://www.ncbi.nlm.nih.gov/pubmed/20357092

Fructose increases Fox01 activity by increasing its production;

http://www.ncbi.nlm.nih.gov/pubmed/16985262

Thus there is potential for a synergistic effect of HCV plus fructose to disregulate insulin response, triglycerides, and blood sugar, beyond that of either acting independently.
Further, as HCV core protein causes Fox01 retention as a result of mitochondrial superoxide production (HCV core protein inhibits complex 1 in the mitochondrial respiratory chain), this can also be ameliorated by supplementation of mitochondrial antioxidants; Co-enzyme q10 (or ubiquinol), manganese, tocopherol and selenium; zinc, copper, carnitine, and phospholipids.

This is consistent with the trials of MitoQ as a hepatoprotectant in Hep C.

Furthermore, as can be seen from the fructose reference above, PPAR-alpha can antagonise Fox01: PPAR-alpha is upregulated in carbohydrate, or calorie, restriction.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC408372/

"The data indicate that PPARα plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARα stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues."

This suggests ketogenic dieting and/or intermittent fasting as strategies that can be used to clear liver fat and normalise blood sugar regulation.

For example:
http://www.salk.edu/news/pressrelease_details.php?press_id=560

"The Salk study found the body stores fat while eating and starts to burn fat and breakdown cholesterol into beneficial bile acids only after a few hours of fasting. When eating frequently, the body continues to make and store fat, ballooning fat cells and liver cells, which can result in liver damage. Under such conditions the liver also continues to make glucose, which raises blood sugar levels. Time-restricted feeding, on the other hand, reduces production of free fat, glucose and cholesterol and makes better use of them. It cuts down fat storage and turns on fat burning mechanisms when the animals undergo daily fasting, thereby keeping the liver cells healthy and reducing overall body fat.

The daily feeding-fasting cycle activates liver enzymes that breakdown cholesterol into bile acids, spurring the metabolism of brown fat - a type of "good fat" in our body that converts extra calories to heat. Thus the body literally burns fat during fasting. The liver also shuts down glucose production for several hours, which helps lower blood glucose. The extra glucose that would have ended up in the blood - high blood sugar is a hallmark of diabetes - is instead used to build molecules that repair damaged cells and make new DNA. This helps prevent chronic inflammation, which has been implicated in the development of a number of diseases, including heart disease, cancer, stroke and Alzheimer's. Under the time-restricted feeding schedule studied by Panda's lab, such low-grade inflammation was also reduced. "

When we say restrict fructose - which is surely the simplest way to avoid over-activating Fox01 - what is meant?

Dietary sources that are highest in fructose are sugar, high-fructose corn syrup, and fruit juice (especially apple or grape juice concentrate). Agave, honey, and dried or tinned fruit are also high in fructose. Drink and snack sweeteners are especially problematic because they tend to be consumed between meals; thus they not only increase fructose exposure, but also support the "constant feeding" model that is the opposite of intermittent fasting (or traditional, scheduled eating), and that leads to fatty liver, high triglycerides, and blood sugar disregulation.
Fruit, while an important source of fructose, is less problematic because the amount in a serving is small and the presence of fibre, minerals, vitamin C and polyphenols provides benefits (for example, naringenin in grapefruit and other citrus fruits activates PPAR-alpha). It is recommended that two servings of fresh, unsweetened fruit be eaten daily.
Sugar in small amounts as a normal culinary ingredient, eaten only at meal times (for example in sauce or relish, or dried fruit in curries) is probably not an issue; but the use of sweetened drinks and snacks, including commercial fruit juices, icecream, and meusli bars, between meals is the sort of thing that should be discouraged...

Your grandparents were right.

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Is a Diet High in Saturated Fat Good for the Liver?

July 18, 2012, 4:18 pm

≫ Next: Fructose, Calories, Carbohydrate and de novo lipogenesis: What does "Hypercaloric" mean?

≪ Previous: HCV, Fructose and Fox01

If we follow the advice laid out in a previous post and increase fat while restricting PUFA, will the extra saturated fat be good or bad for our liver, HCV aside?

That depends, I suppose on whether you think alcohol and drugs and NAFLD are good models for virus-related liver damage. At present they are the only models we have. And we know that alcohol, acetaminophen, and fructose don't help people with Hep C. So I think they are very good models; all the mediators of liver damage from those causes are also present in the livers of people with Hep C (high ferritin, stellate cell activation, LPS sensitivity, lipid peroxidation, oxidative stress, and so on).
So personally I don't see it as any kind of leap to accept the relevance of papers like these. Besides, the proof of the suet pudding will appear in the eating thereof.

Hepatic Stellate Cells are the cells that make collagen in fibrosis. They are also called Ito cells, which explains why I missed all these Ito cell studies before (when I was collecting data on factors, including SFAs, that reduced hepatic stellate cell activity).
This is another line of evidence supporting the view that saturated fat in the diet is antifibrotic.
"When tallow was substituted for corn oil the Ito cells were not activated and the liver histology was normal".

Is it the PUFA restriction alone, or the addition of SFA?
My reading of these papers is that both play a role. Even 5% calories as PUFA causes some fibrosis on a low-fat diet, but none when corn oil is added to beef fat or coconut MCT to give a similar ratio.

These may only be animal tests, but I assure you, if a supplement performed half as well as saturated fat in animals, it would out-sell Silymarin.
Besides, we are talking about something everyone eats already.

We used the intragastric feeding rat model for alcoholic liver disease to investigate the relationship between transforming growth factor (TGF)-beta 1 and inhibition of endothelial cell proliferation. Twelve groups of male Wistar rats (four to five rats per group) were fed ethanol or dextrose with either corn oil or saturated fat for 1-, 2-, and 4-week periods. All control animals were pair fed the same diets as ethanol-fed rats except that ethanol was isocalorically replaced by dextrose. In the ethanol-fed groups, nonparenchymal cells were isolated and TGF-beta 1 was measured in the nonparenchymal cell supernatant. Liver pathology and endothelial cell proliferation with an antibody to proliferating cell nuclear antigen were studied in all groups. Plasma TGF-beta 1 was measured in all rats. Pathological changes (fatty liver, necrosis, and inflammation) were observed only in the corn oil/ethanol-fed rats at 4 weeks. Significantly higher levels of TGF-beta 1 were seen in both plasma and nonparenchymal cell supernatant in rats fed corn oil and ethanol; plasma levels of TGF-beta 1 were not significantly different between the dextrose-fed controls and saturated fat/ethanol-fed rats. A significant inverse correlation (r = -0.89, P < 0.01) was seen between plasma TGF-beta 1 and the number of endothelial cells arrested at G1/S. Immunohistochemistry revealed the presence of TGF-beta 1 staining in interstitial macrophages only in rats fed corn oil and ethanol. The present study provides evidence for a role for TGF-beta 1 in inhibiting endothelial cell proliferation in experimental alcoholic liver disease. Arrest of endothelial cells may lead to their differentiation and/or to produce mediators that could stimulate other cells such as Ito cells. Sustained TGF-beta 1 may also lead to Ito cell production of extracellular matrix.

Alcohol Clin Exp Res. 1991 Dec;15(6):1060-6.
Effect of dietary fat on Ito cell activation by chronic ethanol intake: a long-term serial morphometric study on alcohol-fed and control rats.
Takahashi H, Wong K, Jui L, Nanji AA, Mendenhall CS, French SW.
Source

Department of Internal Medicine, National Kurihama Hospital, National Institute on Alcoholism of Japan, Kanagawa.

Abstract
We studied the effects of long-term ethanol ingestion and dietary fat on Ito cell activation morphometrically in rats. Sixteen pairs of Wistar male rats were divided into two groups, one fed tallow and the other fed corn oil as the source of dietary fat. Each group of rats were pair-fed a nutritional adequate liquid diet containing either corn oil (CF) or tallow (TF) as fat as well as protein and carbohydrate. Half of each group received ethanol, the rest were pair-fed isocaloric amounts of dextrose via an implanted gastric tube for up to 5 months. Morphometric analysis of the change in fat and rough endoplasmic reticulum (RER) of Ito cells was performed on electron micrographs obtained from monthly biopsies including baseline. Ito cell activation was assessed by a decrease in the ratio of fat/RER in Ito cells. The ratio of fat/RER in Ito cells of alcoholic rats fed the CF diet (CFA) gradually decreased. The ratio was found to be lower than in the pair-fed control rats (CFC) at 5 months of feeding. CFA: 1.74 +/- 0.57, vs. 7.46 +/- 2.05, respectively, p less than 0.05, mean +/- SE). Ito cell fat also significantly decreased at 5 months of feeding (p less than 0.05). The fat/RER ratio in CFA significantly decreased only subsequent to the development of fatty change, necrosis, and inflammation followed by fibrosis of the liver. In contrast, the TFA rats did not show a significant decrease in the fat/RER ratio in the Ito cells throughout the study, while TFC rats showed an increase in the fat/RER ratio.(ABSTRACT TRUNCATED AT 250 WORDS)
http://www.ncbi.nlm.nih.gov/pubmed/1789382

Alcohol Alcohol Suppl. 1991;1:357-61.
Ito cell activation induced by chronic ethanol feeding in the presence of different dietary fats.
French SW, Takahashi H, Wong K, Mendenhall CL.
Source

Department of Pathology, Faculty of Medicine, University of Ottawa, Ontario, Canada.
Abstract

Bronfenmajer et al. (1966) first studied Ito cells in alcoholic hepatitis (AH) by light microscopy (LM). The number of Ito cells and the number of fat droplets were increased. Okanoue et al. (1983) found that Ito cells were reduced by LM but increased by electron microscopy (EM) in scars in AH. Ito cells were activated in scars (increased RER and decreased fat in Ito cells with transition to fibroblasts). Minato et al. (1983) showed that increased RER in Ito cells correlated with increased collagen synthesis of liver biopsies in vitro. Mak et al. showed increased RER correlated with the degree of fibrosis in alcoholic baboons (1984) and alcoholic cirrhosis in man (1988). French et al. (1988b) showed morphometrically that Ito cell fat was decreased and RER was increased only in scars but not in normal sinusoids so that Ito cell activation was restricted to the scars. There was no correlation of sinusoidally located Ito cell fat or RER with the amount of perisinusoidal collagen. In rats fed ethanol and a nutritionally adequate diet including corn oil (25% of calories) by intragastric cannula for five months the fatty liver progressed to focal central fibrosis, and Ito cell activation (fat/RER) was increased. When tallow was substituted for corn oil the Ito cells were not activated and the liver histology was normal. Thus, the type of dietary fat and the local environment (scars) are important factors in the activation of Ito cells by alcohol in vivo.
http://www.ncbi.nlm.nih.gov/pubmed/1845563

This paper suggests that flaxseed oil may not be the best omega-3 supplement for alcoholics: linolenic acid is the vegetable form of omega-3.

Besides, the benefits from PUFAs in Hep C (antiviral and metabolic) are only seen with DHA, arachadonic acid, and EPA (in descending order of potency), and these are only found in animal fats; oily fish, fatty red meat, organ meat, dairy fats, and egg yolks.

Life Sci. 2003 Jul 18;73(9):1083-96.
The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells.
Li J, Hu W, Baldassare JJ, Bora PS, Chen S, Poulos JE, O'Neill R, Britton RS, Bacon BR.
Source

Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27858-4354, USA. lichixin@yahoo.com
Abstract

Chronic ethanol consumption can result in hepatic fibrosis and cirrhosis. In addition to oxidative metabolism, ethanol can be metabolized by esterification with fatty acids to form fatty acid ethyl esters (FAEE) such as linolenic acid ethyl ester (LAEE). We have previously demonstrated that LAEE has promitogeinc and activating effects on hepatic stellate cells (HSC), but the mechanisms of these actions are not known. Intracellular signaling through MAP kinase pathways, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) can influence the activity of the transcription factor AP-1, while cell-cycle regulatory proteins such as cyclin E and cyclin-dependent kinase (CDK), play an important role in cell proliferation. In this study, we demonstrate that treatment of HSC with LAEE increases cyclin E expression and cyclin E/CDK2 activity, which may underlie the promitogenic effects of this compound. In addition, LAEE increases ERK and JNK activity, and these pathways play an important role in the activation of AP-1-dependent gene expression by LAEE. The stimulation of intracellular signaling pathways in HSC by this well-characterized ethanol metabolite may contribute to ethanol-induced hepatic fibrogenesis.
http://www.ncbi.nlm.nih.gov/pubmed/12818718

Dietary Saturated Fat Reduces Alcoholic Hepatotoxicity in Rats by Altering Fatty Acid Metabolism and Membrane Composition

Rats fed a saturated fat diet are protected from experimentally induced alcoholic liver disease, but the molecular mechanisms underlying this phenomenon remain in dispute. We fed male Sprague-Dawley rats intragastrically by total enteral nutrition using diets with or without ethanol. In 1 control and 1 ethanol group, the dietary fat was corn oil at a level of 45% of total energy. In other groups, saturated fat [18:82 ratio of beef tallow:medium-chain triglyceride (MCT) oil] was substituted for corn oil at levels of 10, 20, and 30% of total energy, while keeping the total energy from fat at 45%. After 70 d, liver pathology, serum alanine aminotransferase (ALT), biochemical markers of oxidative stress, liver fatty acid composition, cytochrome P450 2E1 (CYP2E1) expression and activity and cytochrome P450 4A (CYP4A) expression were assessed. In rats fed the corn oil plus ethanol diet, hepatotoxicity was accompanied by oxidative stress. As dietary saturated fat content increased, all measures of hepatic pathology and oxidative stress were progressively reduced, including steatosis (P < 0.05). Thus, saturated fat protected rats from alcoholic liver disease in a dose-responsive fashion. Changes in dietary fat composition did not alter ethanol metabolism or CYP2E1 induction, but hepatic CYP4A levels increased markedly in rats fed the saturated fat diet. Dietary saturated fat also decreased liver triglyceride, PUFA, and total FFA concentrations (P < 0.05). Increases in dietary saturated fat increased liver membrane resistance to oxidative stress. In addition, reduced alcoholic steatosis was associated with reduced fatty acid synthesis in combination with increased CYP4A-catalyzed fatty acid oxidation and effects on lipid export. These findings may be important in the nutritional management and treatment of alcoholic liver disease.

LOOK AT THIS TABLE: http://jn.nutrition.org/content/134/4/9 ... nsion.html

In fact, this paper should be read in full and all the figures and tables studied, because there are 4 groups of control rats fed various fats without alcohol, and what happens to them is as interesting as the effects with alcohol.

The control rats fed most saturated fats gained the least weight. Corn oil (high PUFA) was significantly more fattening than a mixture of beef fat and coconut MCTs, in a breed of rat designed to get fat on a "high fat" diet.

And here's one for the vegetarians: Olive oil is quite good at suppressing fibrosis, though perhaps not as brilliant as beef fat. (note that mutton, goat, venison, cocoa, and dairy fats ought to be similar to beef and coconut).

When I say "saturated fat" I really include monounsaturated fat, as it behaves chemically in pretty much the same way; it takes more than one unsaturated bond in close proximity (there are two such bonds near to one another in omega-6 lineolic acid) to promote lipid peroxidation.

J Gastroenterol. 2009;44(9):983-90. Epub 2009 Jun 9.
Dietary olive oil prevents carbon tetrachloride-induced hepatic fibrosis in mice.
Tanaka N, Kono H, Ishii K, Hosomura N, Fujii H.
Source

First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
Abstract
AIM:

The specific purpose of this study was to investigate the effects of dietary olive oil on hepatic fibrosis induced by chronic administration of carbon tetrachloride (CCl(4)) in the mouse. In addition, the effects of oleic acid, a major component of olive oil, on activation of hepatic stellate cells (HSCs) were investigated in vitro.
METHODS:

Mice were fed liquid diets containing either corn oil (control, AIN-93) or olive oil (6.25 g/L) throughout experiments. Animals were treated with CCl(4) for 4 weeks intraperitoneally. The mRNA expression of TGF-beta1 and collagen 1alpha2 (col1alpha2) in the liver was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). The HSCs were isolated from mice, and co-cultured with either oleic acid (100 microM) or linoleic acid (100 microM) for 2 days. The expression of alpha-smooth muscle actin (alpha-SMA) was assessed by immunohistochemistry. In addition, the production of hydroxyproline was determined.
RESULTS:

Serum alanine aminotransferase levels and the mRNA expression of TGF-beta and collalpha2 were significantly reduced by treatment of olive oil. Dietary olive oil blunted the expression of alpha-SMA in the liverand liver injury and hepatic fibrosis were prevented by treatment of olive oil. The number of alpha-SMA positive cells was significantly lower in HSCs co-cultured with oleic acid than in those co-cultured with linoleic acid. Concentration of hydroxyproline in culture medium was significantly lower in cells co-cultured with oleic acid than in the control.
CONCLUSIONS:

Dietary olive oil prevents CCl(4)-induced tissue injury and fibrosis in the liver. Since oleic acid inhibited activation of HSCs, oleic acid may play a key role on this mechanism.

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Fructose, Calories, Carbohydrate and de novo lipogenesis: What does "Hypercaloric" mean?

July 26, 2012, 3:47 pm

≫ Next: The Metabolic Push-Me-Pull-You: HCV core protein, and the even-handed generosity of DM2: Gluconeogenesis and De Novo Lipogenesis, Oh My!

≪ Previous: Is a Diet High in Saturated Fat Good for the Liver?

What does “hypercaloric” actually mean?

One possible objection to the prediction that fructose (and glucose from higher carbohydrate intakes) will enhance HCV replication by inducing DAGT1 and VLDL expression is the claim that is sometimes made that fructose only exerts strong effects on de novo lipogenesis in hypercaloric states.
Otherwise, it will be used to replenish glycogen stores or converted to energy.
The chemistry textbooks put this another way; glucose is converted to fat when it cannot be used to replenish glycogen or generate ATP. No mention of calories. The possibility is left open that other factors - micronutrient deficiencies, toxins, mitochondria defects, hormonal sensitivities - could influence the process.
(Note: I will skip between glucose and fructose in this essay; I think that anyone familiar with this topic will recognize that there is no sleight of hand going on. Fructose is a subset of carbohydrate, of which glucose is the main representative.)
The whole calories in, calories out controversy would take too long to review here. Suffice it to say that, in my opinion, counting calories in provides a both over-complicated and over-simplified way to do something that is more quickly and usefully done by counting (or estimating, rather) grams of fat, carbohydrate, and protein in a meal.
And counting calories out with any hope of accuracy is pretty much impossible unless you spend time in a laboratory or a high-tech gym, and the results there won’t tell you much about calorie expenditure in other conditions. That’s what your appetite ought to be doing…
The most sensible definition of a hypercaloric state is provided by Chris Kresser at Healthy Skeptic; basically, if you are gaining weight, your diet is hypercaloric. (Dr Kresser summarizes the case against fructose as a driver of DNL )

Unfortunately the loss and gain of body weight is a very protracted process and the weight of most people fluctuates from hour to hour and day to day.
Is there such a thing as a hypercaloric meal?
If I were to graph calories out in the course of a day, the baseline of expenditure (basal metabolic rate) would be quite high, with many peaks above it where I exerted my body or my mind; any troughs where the BMR dropped would be shallow.
If I were to graph calories in, you would see two huge curves around my two meals; the graph would be at zero at least half the time. There would only be four “isocaloric” points on the graph, two hypercaloric peaks (of perhaps 4 hours duration each) and the rest of the time, calories in would be less than calories out.
To confuse things even more, if you fast for a week no single day's eating can restore you to a "hypercaloric" state, but carbohydrate will be converted to fat as soon as glycogen stores are full...
Simply because that is how your body stores most of the energy it gets from carbohydrate. Glycogen stores cannot be expanded beyond about 150% of normal (and even that takes some doing - see the next link), whereas fat stores, as everyone knows by now, are pretty much capable of expanding indefinitely.

This makes it very hard to rely on the result of any particular piece of research unless we know a great deal about the surrounding conditions.
Lucas Tafur has done a worthwhile analysis of one DNL study.
Showing how things may not always be as they appear.

A further point is that fructose studies often use pure fructose, when what we should be concerned about is a) the combined effect of fructose and glucose, at the ratios similar to those found in sugar, HFCS, and fruit juice; and b) the combined effects of sugar and dietary carbohydrate from starch.
Recently Dr Peter Attia has published
some tables showing the difference in triglycerides after feeding of glucose, fructose, and HFCS.

A further complication is, that in the case of type 2 diabetes (a common complication of Hepatitis C), there is already a high blood glucose level due to increased hepatic glucose production.
Does this elevated blood sugar then mimic a “hypercaloric” state whenever additional sugars are fed? Any fed sugars have to compete with blood glucose for conversion to glycogen or ATP.
And DNL, according to the textbooks, occurs when sugars are surplus to amounts that can be converted to glycogen or ATP (and if DNL cannot take care of the sugars, they will be dumped through the kidneys, a convenience which is not conducive to good kidney function in the long haul, hence the connection between diabetes and kidney disease).
Calories, of course, can also come from fat or protein. Is a meal of fat likely to prevent replenishment of glycogen?
R. D. Feinman points out that fructose is easily converted to glycogen when total dietary carbohydrate is restricted.

That’s where we want to be. That’s the sweet spot, if you’ll pardon the expression. Restriction of carbohydrate means we don’t need to worry about the occasional fruit we eat, or the sugar in the pickle we put on our bacon and eggs, or the sugar in our dark chocolate, within reason. There’s fructose in beetroot, carrot, potato, and onion that no-one ever mentions.
Of course, carbohydrate can, at least in theory, cause fatty liver and high TG without any DNL whatsoever; if the liver is preoccupied with burning carbohydrate, it may be unable to convert all the fat you eat into ATP; in which case the fat will be recycled into triglycerides, to be stored in the liver or released as VLDL (or IDL).
You really do want to be primarily a fat-burner, either way.

The problem with the “hypercaloric” version of fructose-driven DNL is that it promises that “if you don’t eat too much, it doesn’t matter”. But the science doesn’t tell us how much to eat and when to achieve this miracle.
And restricting calories overall tends to increase appetite and mess with our best intentions.

Whereas R. D. Feinman’s prescription “if you don’t eat carbs (much) it doesn’t matter (much)” is more practical.
Or, in Professor Feinman's own words, "as carbohydrate and calories are reduced, any effect of fructose will be minimized. In the extreme, if you are on a very low carbohydrate diet, any fructose you do eat is likely to be turned into glucose".

Glucose, for glycogen storage or conversion to ATP, rather than fat.

A philosophical digression

There is a critical philosophical distinction between the type of notions that calories (from physics) and macronutrients (from chemistry) represent.

A sugar molecule is real, a gram is abstract, but you can look at, handle and taste a gram of sugar.
A calorie is abstract and amorphous (it could be applied to food, petrol, wood, coal, uranium, movement, noise, heat, radiation and so on).
There are glucose receptors, metabolites and so on. There is no receptor or enzyme that deals with calories. Saying "calories (in)" is often just a lazy and potentially misleading way of saying "so many grams (or ounces etc.) of macronutrients in such and such a ratio" (just as carbohydrate is a lazy way of saying "starch and/or sugar" which is itself a lazy way of saying something even more informative).
(If I say "a whale 100metres long" I am giving you extra information about the whale. You are not meant to be focusing on the implication that a metre is 1/100th the length of my whale.)

A calorie does not have a "nature". There is no natural history of the calorie as there is a natural history of every nutrient.
So why bother? Calories (or joules) are the only way to measure calories out for comparison with nutrition taken in. This is useful for calculations of work and food allowance - as in rationing, for example, or for planning calorie restricted or overfeeding diets.
But it does lead to a false assumption - that what is the only useful measurement of metabolic output must therefore be the only measurement of input worth considering.

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The Metabolic Push-Me-Pull-You: HCV core protein, and the even-handed generosity of DM2: Gluconeogenesis and De Novo Lipogenesis, Oh My!

July 31, 2012, 3:37 pm

≫ Next: Why Might Statins Cause Memory Loss and Arterial Calcification? Vitamin K2, and HMG-CoA Reductase

≪ Previous: Fructose, Calories, Carbohydrate and de novo lipogenesis: What does "Hypercaloric" mean?

One of the features of HCV which I will probably return to again and again in this work-in-progress is that it represents a useful model of metabolic syndrome and DM2. HCV-infected hepatocytes run simultaneous gluconeogenesis and de novo lipogenesis, showing disordered insulin signalling (not just insulin resistance, which would decrease lipogenesis). The mechanisms involved (metabolic and immunologic) are being studied in detail and seem to have a lot to tell us about non-viral DM2. I would suggest that they are more relevant than drug-damage models of insulin deficiency or resistance; the interference is more subtle, the adjustments are clearly the results of adaptive processes, are highly effective, and are only mildly cytotoxic.

At the very least, HCV presents another angle from which to look at these problems.

Steatosis and insulin resistance in hepatitis C: a way out for the virus?

The hepatitis C virus (HCV) induces lipid accumulation in vitro and in vivo. The pathogenesis of steatosis is due to both viral and host factors. Viral steatosis is mostly reported in patients with genotype 3a, whereas metabolic steatosis is often associated with genotype 1 and metabolic syndrome. Several molecular mechanisms responsible for steatosis have been associated with the HCV core protein, which is able to induce gene expression and activity of sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor γ (PPARγ), increasing the transcription of genes involved in hepatic fatty acid synthesis. Steatosis has been also implicated in viral replication. In infected cells, HCV core protein is targeted to lipid droplets which serve as intracellular storage organelles. These studies have shown that lipid droplets are essential for virus assembly. Thus, HCV promotes steatosis as an efficient mechanism for stable viral replication. Chronic HCV infection can also induce insulin resistance.

(The hepatitis C virus has evolved to be transmitted from infected cells on the lipid transport system; therefore it “wants” infected cells to maximise triglycerides and release of (HCV-carrying) VLDL; the higher the TAG, the more HCV virions in serum and the greater the chance of infection from blood-to-blood encounters with the host; also, the virus can ensure that it stays a step ahead of the host’s immune defences by regularly infecting naïve cells.)

Del Campo and Romero Gomez, the authors of this paper, are experimenting with the statins (mainly fluvastatin) as anti-HCV agents. A sensible deduction from the evidence, but quite possibly not as sensible as carbohydrate restriction and intermittent fasting. However I don’t doubt that it is easier to get funding for a drug trial than for a trial of an antiviral Atkins-type diet. Yup, I can see how that suggestion might go down at the funding board.

A suggestion might be that the virus is inducing IR at the gluconeogenesis end, while promoting those genes that normally respond to insulin at the lipogenesis end of hepatocyte metabolism.

But what is the advantage of promoting gluconeogenesis and elevated blood glucose?

HCV can perhaps replicate more effectively if TAGs are not being used as a fuel, i.e., if carbohydrate is the cell’s main energy substrate. If viral manipulation of cell processes to promote gluconeogenesis results in elevated blood glucose, this will tend to prevent lipids “sponsored” by the virus being oxidised to fuel cell processes. Gluconeogenesis is underwriting lipogenesis.
(correction: officially, at least, hepatocytes only run on ketoacids (pyruvate and oxaloacetate) from amino acid catabolism. However, another reference (Best and Taylor) implies that these are fasting-state gluconeogenesis substrates, and states that the newborn liver is wholly dependent on sugars and lipids. It seems more likely that any cell uses a mix of energy substrates and that in the case of hepatocytes the preferential usage is ketoacids, if only because other cells cannot metabolize gluconeogenic amino acids. Anyhow, this suggestion can be left in the air for now.)

How do infected hepatocytes (about 2-25% of the total, greater in non-responders, in one study) manage to produce this two-way excess? We are used to cells that convert glucose (or fructose) or lipids to triglycerides, or glycogen and amino acids (or fructose) to glucose, but how does a cell do both at once? Does the cell take in more substrate than it normally would – a pate de foie gras forced feeding under viral prompting – or does it neglect the many other duties of a hepatocyte and squander the ATP produced through its mitochondrial density on its guest, or both?

This even-handed generosity is explained in diabetic research by concurrent insulin sensitivity and insulin resistance.

“[Although] an impairment of insulin receptor signaling to Foxo1 can explain insulin's inability to restrain HGP, one would predict that, if the liver were wholly insulin resistant, triglyceride (TG) synthesis and assembly into ApoB-containing lipoproteins would also be impaired. But the opposite is true in the diabetic liver.

In recent years, the idea that the diabetic liver may harbor a noxious brew of insulin resistance and excessive insulin sensitivity has gained a second wind.”

The HCV toxin that manipulates cell processes is called core protein and yields a number of fractions.

Confusingly, HCV core protein is also an integral part of the viral coat or capsid. Like Batman’s utility belt, it performs an amazing array of functions in its interactions with lipoproteins, mitochondria, immune system pathways, cell surface receptors, and RNA copying mechanisms. Like a pushy talent agent it ruthlessly promotes the interests of its RNA wherever it goes.

HCV core protein (like that of the more benign Hepatitis G virus, GVB-V) shares genomic features with plant oleosins. These proteins are found associated with fatty droplets in grains and seeds, and sesame oleosin is a type1 (IgE) allergen. Presumably oleosin-like properties (unique to these two related viruses) allow the close association with VLDL-LDL that is characteristic of the HCV lifestyle.

Some of the transcription pathways involved are (as we might expect, and to return to our muttons) very close to those implicated in non-viral DM2. HCV core protein promotes gluconeogenesis by increasing activity of nuclear Fox01 transcription factor (Fox01 is to glucose what NF-KappaB is to cytokines) through inhibition of phosphorylation by mitochondrial ROS (inhibition of Mito Complex 1 by HCV core protein).

In Robert Lustig et.al.’s DM2 hyperglycaemia scenario, fructose plays the same role (perhaps decreased phosphorylation is the result of fructose depleting [P1] as in the text book extract I will end with).

“Hepatic insulin resistance, made worse by elevated fructose concentrations, prevents the phosphorylation of FoXo1, which allows this protein to enter the nucleus and induce the transcription of enzymes that promote gluconeogenesis. “

This is the one paper than anyone curious about Robert Lustig’s ideas should read, especially the sections on dietary fat vs dietary carbohydrate as factors in DM2.

N=1

in 2007 my HCV viral load was 400,000

Earlier this year, after a few months of more-or-less ketogenic diet (25-75g carbs), VL was 26,000

After a month or so of higher carbs (but still low-carb – 50-150g) latest VL was 60,000

Summary

Trying to get these concepts and references into one smooth flow has been like herding cats, so I will summarize in plain language:

HCV (through its core protein) can promote both insulin resistance (elevating blood glucose) and/or insulin sensitivity (elevating fasting triglycerides). This both mimics and adds to dietary metabolic syndrome, and increases the risk of Type 2 Diabetes. And a diet and lifestyle that encourages DM2 will promote increases in viral load, disease pathology, and resistance to treatment.

Because HCV down-regulates GLUT2 to produce the gluconeogenic effect, reducing glucose uptake of infected hepatocytes, fructose becomes an ideal substrate for both gluconeogenesis and lipogenesis. Fructose consumption is predicted to optimize viral replication.

A carbohydrate-restricted version of the Paleo diet – Paleo-Atkins is a convenient shorthand for this – preferably with time-restricted feeding (16 hour daily fasts and 8 hour feeding windows, or at least no carbohydrate or protein outside of regular mealtimes), is – or ought to be – the default diet for DM2 and fatty liver.

This diet ought to reduce the HCV viral load (as in my case), improve Hep C pathology (ditto), and improve the response to treatment (we'll see one day, maybe).

Research into HCV core protein effects on gluconeogenic and lipogenic regulation can provide insights into the mysterious aetiology of diabesity. For example, tending to corroborate the theory that high-fructose diets play an important causative role in metabolic disease.

More on Fructose:

Not everyone metabolizes fructose the usual way, and not everyone who does clears it easily.

Everyone needs to metabolise glucose, and the genes for this have been conserved, but our ancestors sometimes survived for long periods without much fructose exposure, and these genes show more variety.

For example, the higher rate of gout in some South Pacific populations may be the result of adaptation to an ancestral diet low in fructose.

Metabolism of Fructose

Although fructose can be phosphorylated in the 6 position at a slow rate by non-specific kinases, most of ingested fructose is phosphorylated in the liver by a fructokinase that specifically directs phosphorylation at the C-1 position of this ketose. No mutase is known that can catalyse conversion of fructose 1-phosphate to fructose 6-phosphate, nor can phosphofructokinase effect synthesis of fructose diphosphate from fructose 1-phosphate. The only pathway available to the latter is made possible by a specific aldose that catalyses the following reaction:

Fructose 1-phosphate ó dihydroxyacetone phosphate + glyceraldehyde

The further metabolism of glyceraldehyde requires reduction by NADH to glycerol, which is then phosphorylated by glycerol kinase, using ATP, and reoxidized by NAD+ to dihydroxyacetone phosphate. The latter then enters the usual glycolytic sequence.

Individuals who lack fructokinase excrete the major portion of ingested fructose in the urine. “Fructose intolerance” is a more serious illness, characterized by genetic lack of the aldose specific for fructose 1-phosphate, which accumulates after fructose ingestion and inhibits diverse enzyme systems. Even normal individuals may experience difficulty with large fructose intake. Although both the kinase and the special aldolase are present in large and equivalent activities, fructose 1-phosphate may accumulate in the liver for some time after a large fructose flux, e.g., after ingestion of a large quantity of sucrose.

The explanation offered is as follows: Because of the effectiveness of the kinase, both [ATP] and hence [P1] are lowered in liver cells. The P1 inhibition of adenylate deaminase is thus released and inosinic acid [IMP] accumulates; in intact, perfused liver [IMP] increases seven-fold in ten minutes under such circumstances. However, IMP is a powerful inhibitor of the fructose 1-phosphate aldolase (K1 = O.1 mM and Km F-1-P = 0.18 mM), thus delaying further metabolism of this compound.

The presence of fructose and galactose in the intestine, with the amino acids, inhibits intestinal absorption of the latter.

Metabolic effects of androgenic compounds on the sex organs and tissues...include increased fructose production by seminal vesicles and utilization of this sugar by seminal plasma, with concomitant enhancement of the activity of both aldose reductase and ketose reductase.

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Why Might Statins Cause Memory Loss and Arterial Calcification? Vitamin K2, and HMG-CoA Reductase

August 5, 2012, 3:27 pm

≫ Next: The Role of Vitamin Fortification in the Obesity Epidemic

≪ Previous: The Metabolic Push-Me-Pull-You: HCV core protein, and the even-handed generosity of DM2: Gluconeogenesis and De Novo Lipogenesis, Oh My!

In a recent trial of statin use in diabetes, greater compliance was associated with coronary calcium progression.
Statin doctors were quick to discount the findings. But aren't statins supposed to stop atherosclerosis? In this case, whether or not the statins caused the problem, they certainly didn't prevent it.
Is there a mechanism whereby statins may increase calcium deposits in arteries?
Let's look first at another side effect of statins; "certain cognitive effects such as memory loss and confusion".

Is there one effect of statins that could account for both these results?

Statins are HMG-CoA reductase inhibitors. HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis. Cholesterol, like most lipophilic hormones and vitamins, is a terpene derivative, or isoprenoid.
Some of the essential isoprenoid structures, such as those found in vitamins E and A, are formed in plants, but others, including Co-enzyme Q10 (ubiqionone) are formed in the cytosol from a product of the HMG-CoA reductase pathway, mevalonate.
That statins can lower ubiquinone levels is well-known and accounts for occasional serious adverse reactions.
However, ubiquinone and cholesterol are not the only HMG-CoA reductase dependent compounds essential for health.

a) ubiquinone
b) menaquinone
the repeating isoprene group derived via HMG-CoA reductase is bracketed.

Vitamin K is present in green vegetables and vegetable oils as phyloquinone, and in fatty animal foods as menaquinone-4 (MK4), while bacteria produce menaquinone-7 (MK7).
Vitamin K1 is converted to vitamin K2 by removal of the phytyl side-chain and replacement with an isoprenoid side-chain.
When this occurs in the brain the MK4 produced is an essential co-enzyme for the synthesis of special sulfur-containing lipids called sulfatides. Low CNS sulfatide levels are associated with congnitive decline and seen in the early stages of Alzheimer's disease.

Low sulfatide content in brain myelin has been recently linked with the disruption of myelin integrity [14, 21], whereas the disruption of myelin integrity was implicated as an essential contributor to cognitive deficit [6, 7, 43, 44]. Although our findings of dietary-associated decreases in myelin sulfatides suggest a potential disruption in myelin integrity in evaluated brain regions, it is currently unknown whether such disruption would be sufficient to modify motor and cognitive functions controlled by these brain regions.

In the present study both dietary forms of vitamin K1 were converted to menaquinone-4 (MK-4) in the brain.

Doug Bremner states that congnitive impairment is more commonly reported with the more lipid-soluble statins, such as Zocor (simvastatin) and Lipitor (atorvastatin), which cross the blood-brain barrier, and is rarer (but still seen) with water-soluble statins such as Pravachol (pravastatin).

Vitamin K2 as menaquinone-4 (MK4) also prevents arterial calcification.

Warfarin-treated rats were fed diets containing K1, MK-4, or both. Both K1 and MK-4 are cofactors for the endoplasmic reticulum enzyme γ-glutamyl carboxylase but have a structurally different aliphatic side chain. Despite their similar in vitro cofactor activity we show that MK-4 and not K1 inhibits warfarin-induced arterial calcification.

Chris Masterjohn has long been writing about the importance of vitamin K2 on his blog at Weston A. Price.

Thus there may be a common mechanism for both calcification and memory loss; decreased conversion of vitamin K1 to MK4.

Now it may be that a diet high in animal fat and fermented dairy products will supply all the MK4 you need. But is a person being prescribed statins to lower cholesterol going to be advised to consume such a diet?
Only if the doctor knows that the saturated fat lipid hypothesis is nonsense (the sugar-and-starch lipid hypothesis is another matter entirely).

An article postulating that statins might affect bone density by lowering K2 synthesis was published by Linda L. Demer in the journal Arteriosclerosis, Thrombosis, and Vascular Biology in 2001.

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The Role of Vitamin Fortification in the Obesity Epidemic

August 14, 2012, 3:23 pm

≫ Next: Footnotes in Support of the Thiamine Hypothesis of Obesity

≪ Previous: Why Might Statins Cause Memory Loss and Arterial Calcification? Vitamin K2, and HMG-CoA Reductase

The beriberi weight loss diet; fortification for the "fattening carbohydrate" theory of obesity.

The obesity epidemic is more advanced in wheat-eating countries and countries with a high intake of processed carbohydrates, and less advanced in countries with a high intake of carbohydrate from polished rice.

It has been noticed for more than a hundred and fifty years that animals accumulate fat on a low-fat, high-carbohydrate diet. Metabolism favours lipogenosis; the steady state (isocaloric) metabolic flux is carbohydrate => fatty acids => CO2 + H2O.

There are exceptions to this rule; lipogenesis is decreased to 5% of normal when caloric intake is inadequate to maintain weight. And lipogenesis is decreased when the B vitamin thiamine is deficient in the diet.

The metabolism of carbohydrate greatly increases the requirement for thiamine (anuerine, vitamin B1). Thiamine is the required co-enzyme for the first step in the conversion of pyruvate to acetyl-CoA, which is how energy from glucose enters the Citric Acid, Krebs, or TCA cycle.
http://en.wikipedia.org/wiki/Pyruvate_dehydrogenase

Conversion of pyruvate to acetyl-CoA is required for conversion of glucose to ATP and also for conversion of excess glucose to fatty acids (which requires ATP).

Thiamine is one of the B vitamins and plays an important role in energy metabolism and tissue building. It combines with phosphate to form the coenzyme thiamine pyrophosphate (TPP), which is essential in reactions that produce energy from glucose or that convert glucose to fat for storage in the tissues. When there is not enough thiamine in the diet, these basic energy functions are disturbed, leading to problems throughout the body.
http://medical-dictionary.thefreedictionary.com/Thiamine+deficiency

In a situation where the ability to convert pyruvate to acetyl-CoA is not restricted by the availability of thiamine, some individuals will experience increased appetite and fat storage. This is a normal adaptation to store energy against future lean periods (fat being the body’s default fuel).

When thiamine is severely depleted, as in alcoholism, energy cannot be stored as fat and even the normal fat deposits of lean individuals shrink.

The exception is beer drinkers, who can gain fat (”beer belly"). Beer is a better source of thiamine than other alcoholic drinks.

In most western countries white flour is fortified with vitamins including thiamine. In America, white rice is also fortified. 75% of white bread was fortified by 1942 in the USA. Since then fortification and supplementation has spread through the food supply. Vitamins are popular and thiamine is known to be non-toxic.

The thiamine content of a modern multivitamin is about 10 times the amount issued to prevent beri beri in troops serving in WW2.

This is the oldest formulation I can find data on:

http://www.medsafe.govt.nz/profs/datasheet/a/Apo-BComplextab.pdf

Vitamin waters and energy drinks are popular sources of extra thiamine (and carbohydrate). In New Zealand thiamine is added to breakfast cereals, yeast extract spreads, Milo and other popular chocolate drinks; fortification is pervasive in the food supply.

What happens if thiamine intake is marginal on a high-carbohydrate diet? Surely the conversion of carbohydrate for immediate energy needs would be favoured, and the consumption of extra carbohydrate to be stored as fat would be suppressed. And we do in fact find that deficiency of thiamine causes anorexia. Imagine a diet where carbohydrate is not fortified, and thiamine comes from pork, fish, dairy etc. eaten with polished grains (these foods are of course also eaten in the USA and Europe with fortified grains), or with root vegetables which supply more thiamine than polished grains but less than fortified foods.

Thiamine on such a diet would be adequate for good health but would not favour extreme accumulation of fat; accumulation of pyruvate would work to suppress appetite if excess carbohydrate was consumed.

The non-glucose related TPP-dependent enzyme, branched-chain ketoacid dehydrogenase, catalyses the production of acyl-CoA derivatives from branched-chain amino acids in liver and muscle.

Professor Bruce Ames has published a number of reviews on the Micronutrient Triage theory; that micronutrients are apportioned differently when scarce. Mild deficiency of selenium, for example, spares the systems affected by severe deficiency. Short-term survival takes precedence over long-term survival. In the case of thiamine, fat storage is a long-term survival project.

In a country such as New Zealand, with a large impoverished underclass (“let them eat carbs!”), and a high rate of alcoholism due in part to tradition, in part to pro-alcohol governments washing their hands of responsibility for issues of pricing and availability, thiamine over-abundance undoubtedly prevents much harm. We are not discussing a toxic effect of thiamine, nor a benefit from deficiency, but the likelihood that marginal thiamine status, and the metabolic adjustments this requires on a high-carbohydrate diet, was preventive of obesity in past populations eating white bread, white sugar, polished rice, boiled potato, and so on.

This is not meant to imply that these populations were healthy as a result.

The association between vitamin fortification and obesity has been well studied. There is indeed a strong association (with a 10-year delay). http://www.ncbi.nlm.nih.gov/pubmed/21126339

In this paper, obese individuals store and recycle thiamine more than controls.http://www.ncbi.nlm.nih.gov/pubmed/15098017

The bottom line: even if this hypothesis is correct, no responsible person would advocate thiamine restriction as a response to the obesity epidemic or a treatment for obesity. Thiamine-replete populations are healthier, even if they are fatter, and the fat storage process that thiamine catalyses is not pathological in itself. Carbohydrate restriction, on the other hand, is a practical way out of any dilemma, as it reduces the requirement for thiamine at the same time as exposure to fortified foods and fattening carbohydrates is reduced.
In fact, high-fat diets can be used to prevent thiamine deficiency: http://www.jbc.org/content/206/2/725.full.pdf

Thiamine is also essential for production of acetylcholine and GABA. These are vital neurotransmitters and deficiency of thiamine causes severe neurological and psychological symptoms and, if prolonged, nerve and brain damage, due in part to disordered glutamate and GABA signalling and oxidative stress. In alcoholism or severe malnutrition this is called Korsakoff’s syndrome.
http://pubs.niaaa.nih.gov/publications/arh27-2/134-142.htm
pentose phosphate pathway

A classic symptom of early thiamine deficiency is a “sense of impending doom”. This is like something from the weird tales of H. P. Lovecraft. You feel in your soul that your doom is near; exactly when, how, or why you have no idea. This literally dreadful sensation might be familiar to anyone with experience of amphetamine or cocaine abuse. It is probably related to low GABA status.

Raw fish can contain a thiamine-destroying enzyme, thiaminase. Perhaps this also helps to explain the popularity of sushi among dieters, and the low incidence of obesity in high-carb cultures like Japan and Okinawa.
Thiaminase can also be produced by some gut bacteria, perhaps as a way of competing with other commensal species for carbohydrate released from resistant starch.

Thiamine is released by the action of phosphatase and pyrophosphatase in the upper small intestine. At low concentrations, the process is carrier-mediated, and, at higher concentrations, absorption occurs via passive diffusion. Active transport is greatest in the jejunum and ileum (it is inhibited by alcohol consumption and by folic deficiency). Decline in thiamine absorption occurs at intakes above 5 mg. _ Wikipedia

The presence of anti-thiamin factors (ATF) in foods also contributes to the risk of thiamin deficiency. Certain plants contain ATF, which react with thiamin to form an oxidized, inactive product. Consuming large amounts of tea and coffee (including decaffeinated), as well as chewing tea leaves and betel nuts, have been associated with thiamin depletion in humans due to the presence of ATF. Thiaminases are enzymes that break down thiamin in food. Individuals who habitually eat certain raw freshwater fish, raw shellfish, and ferns are at higher risk of thiamin deficiency because these foods contain thiaminase that normally is inactivated by heat in cooking.

http://lpi.oregonstate.edu/infocenter/vitamins/thiamin/

In fact, it looks as though anti-thiamine factors of all classes might be prevalent in precisely those diets most often called in evidence to falsify the carbohydrate-insulin hypothesis of obesity: for example,

In the Philippines, the Tagalog word for beriberi is 'bangungut' which means nightmare and classically death occurs in sleep after a heavy meal consisting of rice and fish (Lonsdale, 1990). The thiaminase in the fish may compound an initial marginal dietary thiamine deficiency and can be fatal.

Some bacteria (e.g. Bacillus thiamineolyticus) are also capable of destroying thiamine. It has been reported that 3% of Japanese show a thiamine deficiency due to this cause. Thiaminase bacteria have been frequently isolated from human stools in Japan and it was reported that the thiamine levels in the blood of these patients was low in spite of adequate intake largely due to the destruction of thiamine in the intestines (Bhuvaneswaran and Sreenivasan, 1962).

http://helid.digicollection.org/en/d/Js2900e/8.2.html

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Footnotes in Support of the Thiamine Hypothesis of Obesity

August 15, 2012, 1:16 pm

≫ Next: Viral Manipulation of Host Behaviour by HCV?

≪ Previous: The Role of Vitamin Fortification in the Obesity Epidemic

Some footnotes in support of the Thiamine Hypothesis:

From The Penguin Encyclopaedia of Nutrition, by John Yudkin:

"The reduction in the prevalence of beri-beri in some countries, such as Japan, has come about by a general improvement in living standards, which as always has been accompanied by a reduced proportion of cereal in the diet, and an increased proportion of other foods. In addition, some governments have introduced legislation requiring a lesser degree of milling of the rice, but this is not always enforced, and the people still prefer the whiter polished rice they have been used to. Nor has there been much success in persuading people to parboil rice if they have not traditionally used it in this form. The addition of thiamine to rice has also been attempted by some countries, but this too is difficult to enforce in the poorer countries.

[The imported rice which we buy in New Zealand is not fortified, and vitamins are sprayed on fortified rice and easily lost in washing and cooking. Only in the USA and Canada does the fortification of rice appear to be, though not mandatory, very pervasive]

Although beri-beri is usually found in people whose staple food is polished rice, it does occur, although rarely, in other circumstances. It has been seen, for example, in areas where there has been a high dependence on bread made with highly-milled and unfortified wheat flour."

From Principles of Biochemistry 1954 (1973 edition)

"The sparing action of lipid was thought to reflect a lesser metabolic demand for thiamine, but since the thiamine pyrophosphate (TPP) content of the tissues of animals fed a high-lipid diet is considerably higher than that of animals on a high-carbohydrate diet, the lipid may in some manner protect thiamine from destruction.

Nutritional surveys indicate that for much of the American population the thiamine intake is marginal; few adults consume more than 0.8 mg/day, and many eat appreciably less. Thiamine intake can be augmented relatively cheaply by increased use of peas, beans, and enriched or whole-wheat bread, as well as by improved cooking practices. Prolonged cooking of peas and beans with soda results in destruction of as much as 60% of the original thiamine content, and excessive cooking leaches the water-soluble thiamine from many foodstuffs."

In a 1994-1995 survey, the mean intake of thiamine by American adults had more than doubled, to about 2 mg/day, with the lowest percentile near the older figure of 0.8 mg/day, and the highest at around 4 mg/day (this was from food alone, vitamin supplements were not included; today, energy drinks, vitamin enriched chewing gum, and vitamin water would also be boosting the intake): http://www.nap.edu/openbook.php?record_id=6015&page=466

Conclusion:

There is a difference in thiamine status between East and West, and a difference between the Western past, even the recent past, and the Western present, which is consistent with optimal thiamine status being a factor in the "obesity epidemic".
Marginal thiamine status has the potential to be an important confounder when evaluating associations between the proportional carbohydrate content of different diets and obesity rates.

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Viral Manipulation of Host Behaviour by HCV?

August 23, 2012, 7:16 pm

≫ Next: Recent Blood tests: HCV Genotype 3 and Cholesterol

≪ Previous: Footnotes in Support of the Thiamine Hypothesis of Obesity

It's well known that some viruses and other parasites can influence host behaviour and physiology to maximize their spread.
Respiratory viruses make you cough and sneeze. Rabies makes you aggressive (it is spread by biting) and hydrophobic (dehydration concentrates the virus in your saliva). Toxoplasmosis replaces a mouse's instinctive fear of cats with an attraction to them (Toxo has a two-phase, mouse-cat-mouse life cycle).
A blood borne virus like HCV falls somewhere between a 'flu virus and rabies in its ease of spread. It relies mainly on injections and transfusions, being dependent on blood to blood transmission.
What adaptations and manipulations of host physiology and behaviour would promote the spread of a virus that can today only be spread effectively by licit and illicit medical procedures?

Dysphoria comes to mind. Feelings of depression and pain for no good reason; slow recovery from other insults, bad hangovers from alcohol that cannot be relieved by more alcohol. Hypochondria that exposes one to both medical procedures (means of transmission in past decades, and in 3rd world nations today) and to oral medications that can decrease ones sense of caution. Tending to lead to, and reinforce, less hygiene and more sharing among addicts. Poverty that makes blood donation a necessity (a good means of spread in past decades).
In the modern world, a blood-borne disease that makes you feel bad in every way, but leaves you well enough to find a means to ease this temporarily, has a good chance of moving from host to host. The after-effects of the drug-seeking behaviour itself will soon perpetuate the state that benefits the virus.

Interestingly, some nutriceuticals that ease HCV pathology have also been shown to decrease drug seeking behaviour and related pathologies:

NAC prevents cocaine relapse:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661026/

Glutamate and compulsion in addictions:
http://psychiatryonline.org/article.aspx?articleid=17769

Acetyl-carnitine in methadone withdrawal (ALCAR is a GABA agonist)
http://journals.lww.com/clinicalneuropharm/Abstract/2009/01000/Acetyl_L_Carnitine_in_the_Management_of_Pain.8.aspx

Milk Thistle as effective as fluoxetine for OCD:
http://www.naturafoundation.co.uk/?objectID=4031&page=1

Niacinamide/nicotinamide a GABA (or benzodiazepine) receptor enhancer:
http://www.sciencedirect.com/science/article/pii/0091305780902361

NAC reduces cannabis use:
http://ajp.psychiatryonline.org/article.aspx?articleid=1184217

Does the virus modulate behaviour? Does it need to? And did it do so differently in its evolutionary past?
Before the 20th century, medicine was of less use to blood-borne viruses like HCV. (see the second part of this article, HCV and the History of the Human Race). Warfare would have been a better way to get out and about, to jump from one tribal group or one city-state to another.
Could a virus make us more aggressive or xenophobic?
Would it need to? Or were we already warlike enough to make the perfect host?

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Recent Blood tests: HCV Genotype 3 and Cholesterol

August 26, 2012, 2:45 pm

≫ Next: The Origins of the High-Fat Hep C Diet

≪ Previous: Viral Manipulation of Host Behaviour by HCV?

Some results of recent blood testing from Auckland Hospital. Getting enough blood to run the tests was, as always, difficult, but at least was possible on this occasion. It’s worth mentioning this because anything I report about my status should be seen in context. I’m 54 years old, I’ve been diagnosed HCV+ since 1991 (this was the first year testing became available here, I likely was infected much earlier), I was an IVDU, polydrug user from the 1980s till well into this century, an alcoholic and solvent abuser as well for much of the last. I gave up methadone, my last drug of addiction, about a year ago.

My fibroscan (elastography) result was 6.8. This is very light scarring (healthy livers go up to 5, cirrhosis starts at 12).

My ALT is 67 U/L; all the other LFT scores are normal (WNL).
Albumin is 52; this is the maximum normal, and I think a pretty reliable sign of a functioning liver.

Iron saturation was high at 0.55, and ferritin high at 251. This is definitely something I’ll be looking at. However, I don’t have the signs of inflammation that I used to attribute in part to high iron. I'm fit, sleeping well, and pain-free.

Hemoglobin was 154 g/L. MCV and MCH were maximum normal.
WBC count was low at 3.86 (4.0-11.0 is normal). Individual WBC counts were all low but WNL.
This is interesting because I haven’t had any infections all year (it’s almost spring) beyond one light cold. Are my WBCs low because some other aspect of innate immunity is taking care of business? Because my diet is low in allergens, pathogens and toxins, and the probiotics I take are working?

IgG was 14.3, IgM 0.89, both WNL.
Platelets were WNL at 237, haemostatis PR = 0.9, HbA1c = 36
Negative for coeliac markers, but then I never touch grains, so I would be.
Vitamin B12 = 495 pmol/L (ref. 170-800)
Folate = 28 nmol/L (ref. 9-45)

HIV negative, HBV antibody positive, HBs Ag negative. As I haven’t had an HBV vaccine, this means I’ve been exposed to hepatitis B and cleared it at some stage. I’m pretty sure I know when that was; everyone else in that room got sick.

The most interesting news for me; my HCV genotype is 3. If you’re wondering why it took so long to find this out, you don’t understand the New Zealand health service.

HCV Genotype 3 and Cholesterol.

Genotype 3 is the form of HCV most specifically associated with fatty liver (steatosis) and hypocholesterolaemia. Steatosis can be a negative factor in any case of HCV infection but in G3 it is promoted by viral mechanisms as well as host dietary factors. One of the mechanisms is the suppression of distal sterol synthesis beyond the proto-sterol lanosterol.

HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms.http://www.ncbi.nlm.nih.gov/pubmed/22318926

G3 wants HMG-CoA reductase to keep ticking over; as completed cholesterol accumulates it suppresses HMG-CoA reductase. By lowering conversion of lanosterol to cholesterol, the virus keeps the enzyme active – and cholesterol low.

(The reduction in cholesterol - distal sterol - synthesis seems to be achieved by lowering expression of the cytochromes CYP51 and CYP11A - see table II).

Without the cholesterol, fats can’t leave the cells of the liver easily. They stay there till the virus is completed and ride out whenever triglycerides (and the HCV virions) are released as VLDL. This should mean a relatively high TG/LDL ratio.

There's another benefit to the virus, perhaps the main one; with serum cholesterol levels low, LDL-receptors are increased to compensate, and the LDL-receptors mediate the entry of HCV virions into uninfected cells.
Less cholesterol equals more LDL-R; more LDL-R equals greater ease of entry for HCV.
This is why we should limit PUFA (cut out vegetable oils), this plus the damage from the oxidation of highly polyunsaturated membrane lipids. Animal PUFAs - AA, DHA, EPA - have antiviral benefits and we want to be eating these, but probably not supplementing them that much (Krill oil is better than fish oil).

Put another way, the viral strategy is to corner the market in cholesterol and restrict the supply. This increases demand in uninfected cells, increasing their exposure to the virus, which enters using LDLR associated receptors like CD81 and NPC1L-1.

What happens if you just eat a lot of eggs? The cholesterol from the diet suppresses HMG-CoA reductase (http://www.lipidworld.com/content/6/1/34/), as well as eventually decreasing LDL-R expression (http://ajcn.nutrition.org/content/39/3/360). The viral strategy is stymied from both ends.

Not everyone with HCV G3 develops steatosis or hypocholesterolaemia. Could the difference be something as simple as having adequate cholesterol in the diet and limiting carbohydrate?

Higher LDL is a good indication that someone with HCV will respond to antiviral drugs, and is associated with lower rates of fibrosis.
However, clinical experience (thanks, Silvia) is that high LDL doesn’t always mean good response, low LDL doesn’t always mean non-response.

It’s worth remembering that a crappy diet of cake and biscuits can elevate LDL (at least, it usually does this in people without HCV) as surely as a good grain-free diet of eggs, meat and vegetables. We’re not really talking about the same phenomenon at all. Just as, in physics, the phenomenon we call weight can be produced by gravity (on the surface of the earth) or by acceleration (in a centrifuge or rocket), and its meaning and implications may be quite different. Shooting across space in an accelerating rocket ship may well have different long-term consequences compared to standing on the Earth’s surface, even if both sets of scales are reading the same weight at present.

Think about it: saturated fat supposedly elevates serum cholesterol, which is a risk factor for heart disease (I tried to find a scientific reference for this simple statement, without added nuances about particle size, ApoE, and BMI, but it has proved surprisingly difficult. However, most governments, and quite a few doctors, still say it; for example, the Australians here: http://www.aihw.gov.au/high-blood-cholesterol/).
Increasing consumption of saturated fats doesn't correlate with CVD risk, but obesity does.
So either fat doesn't make you fat (which is the case in some scenarios, but surely not all), or something else that also makes you fat gives you heart disease.

My GP is still encouraging me to lower my cholesterol, and the hospital didn’t take a reading. Me, I feel thankful it’s still “a bit high”. If I was in the cholesterol range that the NZ government thinks is optimal, I’d start to get a bit worried.

One size fits all? Wasn’t there a chap called Procrustes once who believed that? Whatever became of him?

Appendix:

Current lipid panel (fasting): mmol/L converted to (mg/dL). Ok, only when the frickin' HTML will allow it. Note how no reading except HDL can be "too low".

Total Cholesterol: 6.7 H
Triglyceride: 0.8
HDL: 1.63 (63.57)
LDL (calc.) 4.7 H
Chol/HDL ratio: 4.1

HCV viral load on this day (21st May 2012): 60,690 IU/mL (4.78 log)

Lipid panel from 07 Feb 2012, during ketogenic diet phase:

Total Cholesterol: 8.9 HH (347.1)
Triglyceride: 1.3 (115.7)
HDL: 1.65 (64.35)
LDL (calc): 6.7 H (261.3)
Chol/HDL ratio: 5.4 H

HCV viral load on this day: 25,704 IU/mL (4.41 log)

"Total blood cholesterol levels above 5.5 mmol/L are an indication

of a greatly increased risk of developing coronary heart disease.

Levels above 6.5 mmol/L are considered to indicate extremely high

risk.".

5.5 mmol/L = 214.5 mg/dL, 6.5 mmol/L = 263.5 mg/dL.

This is interesting: http://renegadewellness.files.wordpress.com/2011/02/cholesterol-mortality-chart.pdf

And this:

"In 1987, in the Journal of the American Medical Association Framingham Study investigators reported these two important findings: 1) Over age 50 there is no increased overall mortality with either high or low serum cholesterol levels, and 2) In people with a falling cholesterol level (over the first 14 years of the study), for each 1% mg/dl drop in cholesterol there was an 11 percent increase in all-cause mortality over the next 18 years. (JAMA 1987;257:2176-2180)"

Hey, I'm over age 50! Better keep my cholesterol up.

More on the adverse consequences of low cholesterol from Chris Masterjohn.

It gets worse:

"There were 27 deaths due to suicide. Adjusting for age and sex, we found that those in the lowest quartile of serum total cholesterol concentration (less than 4.27 mmol/liter) had more than six times the risk of committing suicide (rate ratio = 6.39; 95% confidence interval = 1.27-32.1) as did subjects in the highest quartile (over 5.77 mmol/liter). Increased rate ratios of 2.95 and 1.94 were observed for the second and third quartiles, respectively. The effect persisted after the exclusion from the analysis of the first 5 years of follow-up and after the removal of those who were unemployed or who had been treated for depression. These data indicate that low serum total cholesterol level is associated with an increased risk of suicide."

Zoe Harcombe lists the conflicts of interests of the scientists who set UK cholesterol guidelines; every single one of them receives money from companies that market "cholesterol lowering" statin drugs. Hmmn.

Well I guess they can always start prescribing antidepressants once they get your cholesterol down.

↧

The Origins of the High-Fat Hep C Diet

August 28, 2012, 3:30 pm

≫ Next: A Hard Day's Night - Cholesterol, Cancer and Selenium

≪ Previous: Recent Blood tests: HCV Genotype 3 and Cholesterol

The other day I rediscovered one of my early posts about my concept of a high fat diet for Hep C.
It was posted on the Life Extension Foundation forum on 27 Feb 2011.

I started restricting carbs after reading "Protein Power" by Michael and Mary Eades, where the rationale for reducing inflammation by restricting carbs and eating more fats is spelled out.
This was good, but it wasn't till I read "Dr Atkin's New Diet Revolution" that I saw the link between what happens to VLDL/TG on ketogenic diets, and what HCV does to exploit lipids.
Next, I found out about the Nanji-French research that demostrates a liver-protective role for saturated fat, and tried limiting PUFA.
Then (about October 2010) I started to get the results I wanted and was ready to write about it, so I posted about it on MySpace (remember MySpace? Tom you bastard, I want my customized settings back!) then posted this at LEF (to date there have been no responses).

http://ask.lef.org/1620/Atkins-Paleo-Diet-for-treatment-of-Hepatitis-C?keywords=DIET&pageindex=1

the HCV virus
is linked exclusively to lipid metabolism (blood fats, commonly but
erroneously called "cholesterol").

- HCV virion is completed by enzyme DGAT, which also packages fats
(triglycerides) prepared by the liver.

- HCV virion escapes infected liver cells via VLDL-c expression.
VLDL-c (very low density lipoprotein cholesterol) carries fats made by
the liver to cells that need them, also carries cholesterol and
lecithins made by the liver.

- HCV virion enters uninfected liver cells via LDL-c receptor. LDL-c
is remains of VLDL-c after fats have been delivered. The fewer
triglycerides, the larger the VLDL-c and LDL-c, hence the fewer interactions there will be with receptors.

This is why HCV only infects the liver - only hepatocytes have all of
these enzymes and receptors.

Now, where do triglycerides and VLDL-c come from? Over half comes from
the carbohydrate in the modern high-carbohydrate diet, converted to
fats for storage or energy, and this half is not produced at all on
high-fat diets.
In other words, on a high-fat, very-low-carb diet, serum levels of
triglycerides (FAT = Fatty Acid Triglycerides) and VLDL-c are
approximately 50% of the levels seen on a low-fat diet.
This diet should automatically reduce the HCV viral load by a similar
amount and the reduction should continue over time. Because the LDL-c
receptor is upregulated on the high-fat diet, probably increasing
uptake of HCV (yet the LDL-c are larger, so there are even fewer of them) the effect is not quite as clear-cut as that, but the trend is definitely downward (we need someone with math skills to
design a mathematical model for this).
[note: I don't think today that the LDL-C receptor will be upregulated so much, if at all, if the diet is high in cholesterol and restricted in PUFA]
Further, on a high-fat diet there is also a very significant drop in
pro-inflammatory cytokines involved in liver fibrosis and autoimmunity
(which are connected to and driven by insulin) - see Volek et.al.
There are other benefits too: the food being nutrient dense puts less
work on the gut, and extracting energy from fats requires fewer
vitamins and minerals compared to carbohydrate metabolism. Oxidising a
long-chain saturated fat to ATP involves the same reaction over and
over, which is economical, whereas oxidising glucose involves a
different reaction at each step. This is why refined carbohydrates and
foods high in sugar and starch cause vitamin and mineral deficiencies,
while meat contains all the nutrients needed to process the fats it
contains.

Further, diets high in highly saturated fats such as coconut oil, palm oil, and beef tallow are able to reverse liver fibrosis (Mezey, also Nanji et.al.), while high-PUFA vegetable oils promote liver damage in inflammatory conditions. DHA and lecithin are exceptions to this rule.

The ideal diet for Hep C, according to this hypothesis (and borne out by my experience over the past year) is a diet rich in animal protein and animal fat, with some fish but mostly red meat and eggs, in which most carbs come from green, leafy vegetables. Coconut and coconut cream are used with fish, and grains are completely avoided, as are all sugars except dark honey, fruit juice except small amounts of pomegranate, legumes are restricted to small infrequent servings, all potato is replaced with small servings of sweet potato and pumpkin. Food that needs fat is cooked in beef tallow or butter. Cold pressed virgin olive oil and sm all amounts of sesame seed oil are the only liquid oils used. Nuts and seeds are eaten occasionally. Berries are the main fruit, with small amounts of apple, mango, and apricot [I have no idea now why these particular fruits were my exceptions to the no-fructose rule. Today I'd prefer citrus, and the occasional banana]. Spices are used often; cheese and yoghurt are preffered to milk and milk solids.

As for the objection that this diet may elevate cholesterol, high cholesterol levels in Hep C are associated with less fibrosis and a better response to interferon-ribavirin. This is a diet that elevates HDL-c and lowers triglycerides, which are better proxy markers than cholesterol alone.

Antioxidant supplements including Co-Q10, selenium, tocopherols, zinc, ascorbate, grape seed extract, plus krill oil or cod liver oil and vitamin D3 are taken.

Also, supplements supplying 400mg calcium and 150mg magnesium are taken with each meal of meat or high-iron vegetables to significantly reduce iron uptake.

Glucosamine and niacinamide, plus B12 and folate are used to promote normal iron metabolism and erythropoesis if necessary.

This hypothesis first published (c) 2010 by George D. Henderson, Huia, Auckland, New Zealand

While looking for this, I also found the Atkins website recommendations for Hepatitis. These are pretty much the supplements I used to take, some of which I still use.
FYI, here is my current supplement regime:

100mg co-enzyme Q10

120mg Enzogenol pine bark extract (or 200mg grape seed extract)

4mg astaxanthin

Lactobaccilus rhamnosus and bifidus probiotic

Magnesium (as CMD) with salt

Vitamin D (10,000 iu 2x weekly)

Vitamin K2 (MK7) 90mcg daily

vitamin E 130iu (in above supps, or I probably wouldn't bother)

vitamin C 60mg (ditto, but I'd take 500mg 2x daily if I had it)

I also eat some brazil nuts every day for extra selenium, and eat liver regularly for retinol, copper, etc.

What do I do in my spare time? This.

Thanks for reading this blog so patiently and critically, now it's time to relax and enjoy a song: "Secret Holiday" by The Puddle. http://thepuddle.bandcamp.com/releases

↧

A Hard Day's Night - Cholesterol, Cancer and Selenium

September 1, 2012, 2:50 pm

≫ Next: Preventing and Reversing Hepatic Fibrosis - Herbs and Supplements

≪ Previous: The Origins of the High-Fat Hep C Diet

Note: this is a long post, but stay with me; it has some surprising twists. Tell your friends, but don't spoil the ending for them!

Low cholesterol is a risk factor for liver cancer in HBV infection; I wouldn't be surprised if it's the same for HCV, as low cholesterol is a risk factor for fibrosis and non-response.

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http://www.ncbi.nlm.nih.gov/pubmed/8490412

BMJ. 1993 Apr 3;306(6882):890-4.

Prolonged infection with hepatitis B virus and association between low blood cholesterol concentration and liver cancer.

Chen Z, Keech A, Collins R, Slavin B, Chen J, Campbell TC, Peto R.

OBJECTIVE: To determine whether prolonged infection with hepatitis B virus is associated with a lower blood cholesterol concentration.

DESIGN: Cross sectional study.

SETTING: 81 villages in rural China with a high prevalence of chronic infection with hepatitis B virus.

SUBJECTS: 1556 apparently healthy men aged 35-64 years, randomly selected.

MAIN OUTCOME MEASURES: Hepatitis B virus carrier state; plasma concentrations of cholesterol, apolipoprotein B, and apolipoprotein A I.

RESULTS: 238 (15%) of the men were positive for hepatitis B surface antigen, indicating that they were chronic carriers. Plasma concentration of cholesterol was 4.2% (0.11 mmol/l) lower among carriers (that is, positive for hepatitis B surface antigen) than among non-carriers (95% confidence interval 0.6% to 8.0% (0.01 to 0.21 mmol/l), p < 0.05), and apolipoprotein B concentration was 7.0% (0.036 g/l) lower (2.8% to 11.2% (0.014 to 0.058 g/l), p < 0.001). In contrast, no association was observed between plasma concentrations of cholesterol or apolipoprotein and hepatitis B that had been eradicated (that is, patient positive for hepatitis B core antibody but negative for hepatitis B surface antigen).

CONCLUSIONS: Chronic hepatitis B virus infection, which usually starts in early childhood in China, seems to lead not only to a greatly increased risk of death from liver disease but also to a somewhat lower cholesterol concentration in adulthood. This common cause produces an inverse association between cholesterol concentration and risk of death from liver cancer or from other chronic liver diseases.

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Much the same thing happens with Hep C, where low cholesterol is definitely a part of the viral strategy, not just a consequence of liver damage:

J Viral Hepat. 2006 Jan;13(1):56-61.

Serum lipid pattern in chronic hepatitis C: histological and virological correlations.

Siagris D, Christofidou M, Theocharis GJ, Pagoni N, Papadimitriou C, Lekkou A, Thomopoulos K, Starakis I, Tsamandas AC, Labropoulou-Karatza C.

Lipoproteins are closely connected to the process of hepatitis C virus (HCV) infection. The aim of this study was to evaluate the lipaemic profile in patients with chronic HCV infection, and to identify any association between serum lipid levels and viral load, HCV genotype or liver histology. Total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and triglycerides (TG) were measured in the sera of 155 patients with chronic HCV infection and 138 normal subjects, matched for age and sex. Viral parameters and liver histology were evaluated in HCV-infected patients.

Serum TC (P < 0.0005), HDL-C (P < 0.0005) and LDL-C (P < 0.0005) were lower in chronic hepatitis C patients compared with controls. Grading score was positively correlated with TC and LDL-C. Patients with HCV genotype 3a had significantly lower levels of TC, HDL-C, LDL-C, higher viral load and higher frequency of hepatic steatosis than those with other genotypes. Logistic regression analysis identified genotype 3a (OR, 6.96; 95% CI, 2.17-22.32, P = 0.0011) as the only significant predictive variable associated with low serum cholesterol concentration.

HCV infection is associated with clinically significant lower cholesterol levels (TC, LDL and HDL) when compared with those of normal subjects. This finding is more pronounced in patients infected with HCV genotype 3a.[/b] Further studies are necessary to define the pathophysiology of the relationship between lipid metabolism and HCV infection.

*********************************************************************************

And low cholesterol in Hep C is also associated with an increased risk of liver cancer:

HPB (Oxford). 2010 Nov;12(9):625-36. doi: 10.1111/j.1477-2574.2010.00207.x.

Evidence of aberrant lipid metabolism in hepatitis C and hepatocellular carcinoma.

Wu JM, Skill NJ, Maluccio MA.

OBJECTIVES: Lipids are linked to many pathological processes including hepatic steatosis and liver malignancy. This study aimed to explore lipid metabolism in hepatitis C virus (HCV) and HCV-related hepatocellular carcinoma (HCC).

METHODS: Serum lipids were measured in normal, HCV and HCV-HCC patients. Whole-genome microarray was performed to identify potential signature genes involved in lipid metabolism characterizing normal vs. HCV vs. HCV-HCC conditions.

RESULTS: Serum cholesterol was significantly reduced in HCV and HCV-HCC patients compared with normal controls, whereas there was no difference in glucose and triglycerides. Microarray analysis identified 224 probe sets with known functional roles in lipid metabolism (anova, 1.5-fold, P ≤ 0.001). Gene-mediated fatty acid (FA) de novo synthesis and uptake were upregulated in HCV and this upregulation was further enhanced in HCC. Genes involved in FA oxidation were downregulated in both the HCV and HCC groups**. The abnormality of cholesterol metabolism in HCV was associated with downregulation of genes involved in cholesterol biosynthesis, absorption and transportation and bile acid synthesis; this abnormality was further intensified in HCC.

CONCLUSIONS: Our data support the notion that HCV-related lipid metabolic abnormalities may contribute to hepatic steatosis and the development of cancer. Identification of these aberrations would stratify patients and improve treatment algorithms.

*******************************************************************************

My conclusions;

dietary cholesterol ought to reverse some of these abnormalities; this would explain the strong protective effect of eggs against viral hepatitis mortality seen in the China Study (note that T C Campbell, author of the controversial China Study*, was one of the authors of the first paper).

Replacing seed oils with animal fats, polyunsaturated fats (other than those in animal fats - AA, EPA and DHA) with monounsaturated and saturated fats, and restricting carbohydrate, especially sugar and grains, will tend to correct HCV-related lipid abnormalities.

[* Controversial because T C Campbell is a vegetarian and misinterpreted some of the China study data selectively to support a vegan bias. Amongst other things, he misinterpreted the effects of a diet of pure casein - which is a selenium-deficient purified milk protein used to produce liver cancer experimentally in rats - to claim that all animal protein is somehow harmful, and vegetable protein is beneficial. For example, soy, gluten and peanuts - yeah right, I don't think so. We'll come back to selenium in a minute.]

**"Genes involved in FA oxidation were downregulated in both the HCV and HCC groups". Very low carbohydrate dieting (and/or fasting) reactivates these fat burning genes, such as PPAR-alpha, which also inhibits HCV replication (the naringenin gene).

Perhaps vitamin E is not very effective (below) because it fails to elevate cholesterol in HCV (it is usually supposed to "improve" lipids somewhat):

*******************************************************************************

Int J Vitam Nutr Res. 2003 Nov;73(6):411-5.

Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.

Takagi H, Kakizaki S, Sohara N, Sato K, Tsukioka G, Tago Y, Konaka K, Kabeya K, Kaneko M, Takayama H, Hashimoto Y, Yamada T, Takahashi H, Shimojo H, Nagamine T, Mori M.

Patients with chronic hepatitis C virus (HCV) infection often develop liver cirrhosis and hepatocellular carcinoma (HCC). The purpose of this study was to test the chemopreventive effect of alpha-tocopherol on hepatocarcinogenesis in patients with liver cirrhosis and a history of HCV infection.

Eighty-three patients with liver cirrhosis and with positive history of HCV infection were divided at random into two groups. Forty-four patients were treated with alpha-tocopherol (Vit E group) while the other 39 were followed as controls. The clinical background (gender, age, and laboratory data) was similar in the two groups. Serum levels of alpha-tocopherol, albumin, alanine aminotransferase (ALT), and total cholesterol and platelet count were measured serially over a period of five years.

The mean serum concentration of alpha-tocopherol was low in both groups at entry and was significantly higher in the Vit E group than in the control group one month after treatment. Platelet count, serum albumin, ALT, and total cholesterol were not different between the two groups during the five-year period. Cumulative tumor-free survival and cumulative survival rate tended to be higher in the Vit E group than in controls, albeit statistically insignificant. The serum level of alpha-tocopherol was low in patients with liver cirrhosis and positive for HCV. Although the administration of alpha-tocopherol normalized the level one month later, it could neither improve liver function, suppress hepatocarcinogenesis, nor improve cumulative survival.

Patients treated with alpha-tocopherol tended to live longer without development of HCC but the difference was not statistically significant.

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You might remember how the Cochrane Collaboration did a meta-analysis of clinical trials of antioxidant supplements some years back and found most of them increased mortalitity? Apart from selenium and vitamin C, that is.

One finding of the Cochrane Collaboration was that selenium supplements (and only selenium supplements) significantly reduced the occurence of gastrointestinal cancers in all of five trials - an average relative risk of 0.59 (0.46-0.75).

I wonder, was liver cancer considered a GI cancer for the purposes of that analysis?

********************************************************************************

Nutrients. 2010 Sep;2(9):929-49. Epub 2010

http://www.ncbi.nlm.nih.gov/pubmed/21699491

Has Selenium a Chemopreventive Effect on Hepatocellular Carcinoma?

http://aje.oxfordjournals.org/content/150/4/367.short

Both experimental and epidemiologic studies have linked a low dietary intake of selenium with an increased risk of cancer. The authors examined the association between plasma selenium levels and risk of hepatocellular carcionoma (HCC) among chronic carriers of hepatitis B and/or C virus in a cohort of 7, 342 men in Taiwan who were recruited by personal interview and blood draw during 1988–1992. After these men were followed up for an average of 5.3 years, selenium levels in the stored plasma were measured by using hydride atomic absorption spectrometry for 69 incident HCC cases who were positive for hepatitis B surface antigen (HBsAg) and/or antibodies against hepatitis C virus (mostly HBsAg positive) and 139 matched, healthy controls who were HBsAg positive. Mean selenium levels were significantly lower in the HCC cases than in the HBsAg-positive controls (p =0.01). Adjusted odds ratios of HCC for subjects in increasing quintiles of plasma selenium were 1.00, 0.52, 0.32, 0.19, and 0.62, respectively. The inverse association between plasma selenium levels and HCC was most striking among cigarette smokers and among subjects with low plasma levels of retinol or various carotenoids. There was no clear evidence for an interaction between selenium and α-tocopherol in relation to HCC risk.
Am J Epidemiol 1999; 150; 367–74.

Anticancer Agents Med Chem. 2010 May;10(4):338-45.

Selenium in the prevention and treatment of hepatocellular carcinoma.
Darvesh AS, Bishayee A.

http://www.ncbi.nlm.nih.gov/pubmed/20380634

Hepatocellular carcinoma (HCC) happens to be one of the most lethal cancers in the world. Even though most cases occur in the developing world, reported cases in Western Europe as well as North America are on a steep rise. Human HCC etiology includes chronic liver disease, viral hepatitis, alcoholism, iron overload as well as dietary carcinogens such as aflatoxins and nitrosoamines. Surgical resection as well as liver transplants, which are currently used to treat HCC, is mostly ineffective. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. Both oxidative stress and inflammatory mechanisms have been implicated in the pathophysiology of HCC. The use of dietary antioxidants and micronutrients has been proposed as an effective means for successful management of human HCC. Trace elements such as vanadium and selenium are involved in several major metabolic pathways as well as antioxidant defense systems. Selenium has been shown to be involved in the prevention of numerous chronic illnesses such as several specific cancers and neurodegenerative diseases. This review examines the potential role of selenium in the prevention and treatment of HCC. The in vivo and in vitro effects of selenium and the mechanisms involved in preclinical models of liver cancer are critically reviewed in this article. The chemopreventive and therapeutic effects of selenium are reviewed especially in relation to its antioxidant property. Future directions and potential challenges involved in the advance of selenium use in the prevention and treatment of liver cancer are also discussed.

*********************************************************************************

And now, for those who've made it this far, a real treat:

http://cancerres.aacrjournals.org/content/63/20/6707.full

Our findings indicate that selenium deficiency induces apoptosis in some “hepatocyte-like” cells. However, most HCC cells, particularly HBV-related ones, tolerate selenium deficiency and escape its deadly consequences. Thus, as demonstrated by the gain of survival capacity of apoptosis-sensitive cell lines with Vitamin E, such malignant cells have acquired a selective survival advantage that is prominent under selenium-deficient and oxidative-stress conditions.

*********************************************************************************

Hepatocellular cancer cell lines containing HBV virus genes are more resistant to selenium deficiency than other hepatocytes.

I'll bet that exactly the same thing applies to HCV. You won't get it in the genome like HBV as it's an RNA not a DNA virus, but there's the same relationship with selenium deficiency and cancer, so it seems likely.

Brazil nuts = 19mcg selenium each on average.

(Note: most if not all hepatocytes used in HCV cell culture studies are actually hepatoma - i.e. liver cancer - cell lines. Maybe that's why the antiviral drugs they develop don't always work in real livers! And maybe some of what we think we know about HCV is wrong.)

And the final twist, worthy of Roald Dahl:

First, some news from the UK;

Too Much Selenium Can Increase Your Cholesterol

The researchers found in those participants with higher plasma selenium (more than 1.20 µmol/L) there was an average total cholesterol level increase of 8% (0.39 mmol/L (i.e. 15.1 mg/dL). Researchers also noted a 10% increase in non-HDL cholesterol levels (lipoproteins within your total cholesterol that can help predict the risk of someone suffering a heart attack or chest pain). Also, of the participants with the highest selenium levels, 48.2% admitted they regularly took dietary supplements.

A 10% increase in what we might here term "good" cholesterol might be just enough to offset the drop in cholesterol caused by HCV.

(I like the way that 48.2% of these subjects "admitted" to taking supplements that may have elevated their non-HDL cholesterol. Not "reported", "admitted". No doubt they cracked under interrogation, while the other 51.8% successfully denied the allegation.)

US research shows the same trend;

http://www.ncbi.nlm.nih.gov/pubmed/1990681

Atherosclerosis. 2010 Jun;210(2):643-8. Epub 2010 Jan 11.

Serum selenium and serum lipids in US adults: National Health and Nutrition Examination Survey (NHANES) 2003-2004.

Laclaustra M, Stranges S, Navas-Acien A, Ordovas JM, Guallar E.

OBJECTIVE: High selenium has been recently associated with several cardiovascular and metabolic risk factors including diabetes, blood pressure and lipid levels. We evaluated the association of serum selenium with fasting serum lipid levels in the National Health and Nutrition Examination Survey (NHANES) 2003-2004, the most recently available representative sample of the US population that measured selenium levels.

METHODS: Cross-sectional analysis of 1159 adults>or=40 years old from NHANES 2003-2004. Serum selenium was measured by inductively coupled plasma-dynamic reaction cell-mass spectrometry. Fasting serum total cholesterol, triglycerides, and HDL cholesterol were measured enzymatically and LDL cholesterol was calculated.

RESULTS: Mean serum selenium was 136.7 microg/L.
[HTML's inconvenient but understandable dislike of epidemiological data presentations means that you'll have to look at the fulltext for details, sorry]

CONCLUSION: In US adults, high serum selenium concentrations were associated with increased serum concentrations of total and LDL cholesterol. Selenium was associated with increasing HDL cholesterol only at low selenium levels. Given increasing trends in dietary selenium intake and supplementation, the causal mechanisms underlying these associations need to be fully characterized.

full text here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878899/

********************************************************************************

Of course, fatty animal foods - such as pork and bacon - are the best source of selenium besides brazil nuts and supplements, so some of these statistics could be due to the cholesterol-elevating effects of animal fats.

"of the participants with the highest selenium levels, 48.2% admitted they regularly took dietary supplements" in the UK study; it was 75.1% in the US, but surely not all supplements supplied selenium and even fewer supplied a high dose of selenium.

From table 1 the difference in saturated fat intake between quartiles is small but the trend matches selenium.

But still - there's a pattern here.

Enter the virus, cholesterol goes down, cancer goes up;

enter selenium, cholesterol goes up, cancer goes down.

Oh, by the way, lower cholesterol is associated with higher cancer death rates across the board...

This paper summarizes the state of research into selenium and seum lipids and glucose:

http://www.nutritionandmetabolism.com/content/7/1/38

"Interestingly, the effects of selenium supplementation on blood lipids are contradictory in animal and human studies. In rats, selenium supplementation increases LDL receptor activity [28,29] but decreases 3-hydroxy 3-methylglutaryl co-enzyme A (HMG-CoA) reductase expression [30], leading to decreased plasma LDL cholesterol and total cholesterol levels. However, one animal study in mice showed a significant increase in plasma cholesterol with the loss of housekeeping selenoprotein expression [31]. In human, selenium supplementation was found to increase total cholesterol and triglyceride levels in French adults [27]. Total cholesterol and LDL cholesterol levels also increased after selenium supplementation in the Chinese population [32]. Another study showed no further decrease in triglyceride or LDL cholesterol concentration but a blunted increment of HDL with selenium supplementation in participants with coronary heart disease receiving simvastatin-niacin treatment [33]. Therefore, the role of selenium supplementation on lipid metabolism in humans deserves further research. Recently, the apoE δ4 gene was found to play a central role between selenium levels and lipid metabolism in rural elderly Chinese [34]. The underlying interactive mechanism between susceptible gene, selenium, and lipids needs further investigation."

It seems the rodent is not such a good model for the interactions we are interested in here, not suprisingly as their lipoprotein regulation diverges from that of humans in many ways.

*********************************************************************************

Thanks for having followed this investigation to its startling conclusion. Here's a reward: "12,000 Miles", from the beautiful album The Overflow by Humphreys and Keen. If you like this, you can download the entire 13-song album here for only $5US http://humphreysandkeen.bandcamp.com/

↧

Preventing and Reversing Hepatic Fibrosis - Herbs and Supplements

September 7, 2012, 2:32 pm

≫ Next: How To Come Off Methadone Without Really Trying

≪ Previous: A Hard Day's Night - Cholesterol, Cancer and Selenium

Limitations of the paper: This was written a few years ago and does not incorporate everything I have learned since. Nor does it contain many references and live links, though I have added some, and some references do appear at the end. It is obviously unfinished - a work in progress posted to inspire other researchers - and should be treated as such.
On the other hand it compiles much valuable information that does not appear elsewhere.

A reference first to set the scene:

Hepatology. 2006 Feb;43(2 Suppl 1):S82-8.

Reversal of hepatic fibrosis -- fact or fantasy?

Friedman SL, Bansal MB.

Realistic expectations for successful anti-fibrotic therapies reflect solid evidence of fibrosis

regression in patients treated effectively for viral liver disease, as well as growing clarity in

the understanding of mechanisms of extracellular matrix production and degradation.

The paradigms of stellate cell activation and apoptosis remain valuable frameworks for

understanding pathways of hepatic fibrogenesis and fibrosis regression, respectively.

http://www.ncbi.nlm.nih.gov/pubmed/16447275

Liver Fibrosis - Prevention and Reversal

Hepatic stellate cell activation and proliferation; HSC inhibition, apoptosis, and reversion induced by natural compounds.

The Hepatitis C Handbook by Matthew Dolan is one of the best resources in the subject of Hep C. I was amazed to find, looking up fibrosis in the index, that there is no reference at all to it in the 1997 edition.

Until the last 10 years or so fibrosis was seen purely as an aspect of liver damage that was not really distinct from damage to hepatocytes. In fact, fibrosis, and therefore cirrhosis is an aspect of liver repair mechanisms, albeit one that can lead towards increased damage and loss of function if it is not switched off. The good news is that many strategies have been developed to switch off fibrosis and resorb scarring (for example, in Modern Chinese Medicine the herbal preparation Cpd 861 was able to reverse 4 stages of fibrosis and 2 of cirrhosis in clinical trials) and it seems relatively easy to prevent fibrosis from snowballing in the first place. To understand how this is possible, we must first look at fibrosis as a natural event.

Hepatic Stellate Cells

Damage to the liver, whether by drugs, virus, radiation, or trauma (for example, a biopsy needle) must involve damage to the microcirculation, the tiny blood vessels essential to liver function, as well as to hepatocytes. The microcirculation consists of endothelial cells, called sinusoidal because there are windows in them. This tiny tube, only 2-3 cells in diameter, is surrounded by a space (the Space of Disse) separating it from the hepatocytes. The Space of Disse is inhabited by main two cell types; Kuppfer cells, the macrophage white blood cells that keep it clean, and Hepatic Stellate Cells (HSCs or Ito cells). In health, HSCs have three main functions; they store fats and vitamin A; they produce and degrade matrix (collagen and similar protein fibres), both to restrict the size of particles able to pass in and out of the microcirculation, and perhaps to keep open the Space of Disse; and, HSC also serve as glial cells, similar to the neuroglial caretaker cells in the brain; that is, they respond to many neurotransmitters and neural hormones, and can both break down and produce many such chemicals, interacting with the nerves that transit the liver. This is particularly important as it gives a mechanism as to how moods and emotions can impact on liver function, and vice versa, as well as some psychoactive drugs.

HSC activation

In the case of traumatic or chemical liver damage, the function of HSCs changes. They lose their vitamin A stores and convert to a type of cell called a myofibroblast. Fibroblasts are seen in scar formation in other tissues, and are part of the immune response to injury. The primary function of the HSC fibroblast is to remodel the damaged intracellular matrix (collagen), by breaking it down with zinc-containing metalloproteins (in healthy HSCs, zinc is used in the storage and transport of vitamin A instead) and creating more. HSC myofibroblasts also conscript other HSCs to their aid, by producing chemicals that spread the process of conversion (HSC activation) and reproduction (HSC proliferation). This process ought to be switched off once the liver has repaired itself, but in some cases does not stop, and this ongoing remodeling of matrix collagen results in the later stages of fibrosis, and cirrhosis; the HSC fibroblasts produce tangles of collagen and also contract around the endothelial cells, closing down the (already microscopically narrow) blood vessels of the microcirculation and causing toxins to accumulate, and the hepatocytes in the area lose their function, eventually dying and setting off another cycle of fibrosis.

Nitric Oxide

An important chemical messenger for keeping HSCs in line and maintaining the tone of the microcirculation is endothelial nitric oxide (NO.-). Nitric oxide is a free radical that functions, in the liver, as an antioxidant; other free radicals, such as superoxide, can destroy it. For this reason antioxidants help to maintain nitric oxide levels, for example Ginkgo. Preparations of antifibrotic herbs based on Ginkgo extracts have successfully prevented fibrosis in clinical trials. I will discus the mechanism and success rates of other antifibrotic herbs later. Nitric oxide is produced from the interaction of l-arginine and oxygen, catalysed by NADPH, a vitamin B3 co-enzyme. Vitamin B3 (as niacinamide) also has important antifibrotic effects in its own right.

Inflammatory Cytokines and Niacinamide/Nicotinamide
The primary cytokines (protein messengers) involved in activating HSCs are Transforming Growth Factor Beta (TGF–beta) and TNF-alpha, which activates the pro-inflammatory transcription factor NF-kappaB. Vitamin B3 as nicotinamide inhibits both TGF-beta and TNF-alpha. Vitamin E, especially in the form of alpha-tocopherol succinate, also inhibits TNF-alpha and NF-kappa B. We know that these vitamins are effective at normal supplement doses because vitamin B3 is effective against arthritis, which is another disease in which TNF-alpha and NF-kappa B play a major role, at doses which (at the upper end) can affect liver function in other ways, by competing for SAMe, thus inhibiting the transport of fats from hepatocytes (potentially leading to jaundice in poorly nourished individuals with hypomethylation – easily prevented by taking B12 and folate, and by taking divided doses, rather than taking one large dose. However in clinical use manifestation of these potential risks is minimal). B3 also elevates HDL cholesterol, and higher levels of HDL cholesterol are associated with healthy nitric oxide levels.

The most important effect of B3 is, that it induces the apoptosis (programmed cell death) of activated HSCs. B3 is the only vitamin that does this. Apoptosis of HSCs, as well as quiescence, is probably essential if the liver is to recover from fibrosis. Other supplements that promote HSC apoptosis are CLA (conjugated lineolic acid) especially the c-9, t-11 isomer found in ruminant and dairy fat, resveratrol (which likely promotes HCV replication in high doses), green tea extract, apricot kernels, and berberine (an alkaloid found in many yellow herbs, including golden seal, coptis, and Oregon grape root).

Neurotransmitters

HSCs are also activated by some neurotransmitters at high concentrations, including serotonin, epinephrine (adrenaline), and adenosine. Caffeine inhibits adenosine receptors; it also increases synthesis of nitric oxide and lessens synthesis of collagen precursors from l-arginine, while the antioxidant polyphenols in coffee chelate iron and protect nitric oxide and collagen; this is probably related to the anti-fibrotic effects seen in some coffee drinkers (antioxidants that protect collagen, such as OPCs, tend to be anti-fibrotic; it makes sense that damage to matrix should trigger HSC activation). A neurotransmitter which inhibits HSC activation is gamma butyric acid, GABA. Vitamin B3 enhances sensitivity of GABA receptors – in fact, this gives it an anti-anxiety effect equal to that of valium, as GABA is an inhibitory neurotransmitter, opposed to adrenaline which is stimulatory, and valium has an antianxiety effect in part because it attaches itself to GABA receptors. This is another antifibrotic mechanism of niacinamide. It would be interesting to see whether this GABA-ligand effect translates into any antifibrotic influence for benzodiazepine drug use. However, the antifibrotic effects of B3 which I have researched are multiple, and do not depend on any single mechanism. They include:
synthesis of nitric oxide - increase of nitric oxide by inhibition of ADMA - increase of HDL cholesterol - reduction (recycling) of glutathione - modulation of GABA receptors - inhibition of TNF-alpha and NF-kappaB - inhibition of TGF-beta - inhibition of HSC activation and proliferation - promotion of HSC apoptosis http://www.ncbi.nlm.nih.gov/pubmed/16165703- prevention of excess catecholamine synthesis - lowered synthesis of acetaldehyde from alcohol, therefore less toxicity.
Benefits of B3 supplementation in fibrosis, not limited to those above, strongly suggest that commonly repeated advice to avoid this vitamin in cases of hepatitis is misguided. Jaundice and acute hepatitis are contraindications, and daily dose then should be limited to 200mg in multivitamins, but in stable, chronic cases of hepatitis C a dose of 500mg niacinamide 3x daily seems well tolerated. The only toxicity of B3 relates to its methyl-acceptor role; as long as one supplements B12 and folate, or SAMe, or lecithin, and eats a reasonable amount of protein, this will not cause hypomethylation. Niacinamide (with other vitamins) has been used for decades in the orthomloecular treatment of alcoholism, with prevention of cirrhosis as an incidental benefit, without serious complications, despite the prevelance of liver damage in alcoholics.

Estrogen, antifibrotic foods

Estrogen is also antifibrotic, and pre-menopausal women have a lower rate of fibrosis than males. However, this protection can be lost at menopause. However, phytoestrogens, especially genistein from soy, also inhibit HSC activation and proliferation by acting on estrogen-B receptors. On the n=1, I am allergic to unfermented soy, and I don’t consider it a fit food for humans, but I have no problems with isoflavones, which are found in a variety of legumes. Fermented soy products are a better source of isoflavones than unfermented. Resveratrol is another phytoestrogen effective at dietary levels; grape juice and raisins supply as much resveratrol as red wine.

Another food that is antifibrotic at normal dietary levels is curry. Both curcumin (from turmeric) and extract of fenugreek (methi) inhibit HSC activation. India has a high rate of hepatitis C infection yet a low rate of liver cancer (a rare sequella of fibrosis), and this has been attributed to the consumption of curries. Other ingredients in curry, including saffron, have been studied for their antifibrotic effect. The use of ghee, high in saturated fat and CLA, in the traditional Indian diet is also likely to provide antifibrotic benefits.

Iron

Iron, unless it is strongly bound in proteins or chelated with polyphenolic phytochemicals, is strongly pro-fibrotic and all antifibrotic herbal extracts and phytochemicals seem to have some iron-chelating ability. Iron interacts with superoxide (Haber-Weiss reaction) and peroxide radicals (Fenton reaction) to produce the more reactive hydroxyl radical (also the product of ionizing radiation – both nuclear and electromagnetic). Iron can also interact with antioxidant vitamins, especially vitamin C, in place of superoxide, and iron-vitamin C combinations are used to induce fibrosis (activate HSCs) experimentally. Thus, taking vitamin supplements that combine vitamin C and inorganic iron in one pill is rather unwise – but avoiding vitamin C will not help. Firstly, the same kind of reaction takes place with superoxide radical, which is more reactive than any antioxidant (and more penetrative), as well as with glucose and homocysteine (pro-fibrotic in its own right), and superoxide (as well as glucose and homocysteine) levels will be higher if antioxidants are low; secondly, vitamin C deficiency causes the formation of low-quality collagen, which might be a factor in the constant matrix remodelling seen in fibrosis; thirdly, ascorbate-iron catalyzed hydroxylation reactions play an important role in metabolism and detoxification; the synthesis of carnitine, tyrosine and serotonin, for example, depends on this type of reaction.

Copper can also function in the same way. Zinc, which is important for the breakdown of matrix collagen, competes for absorption with iron and copper (especially as inorganic zinc sulphate – note that organic mineral chelates may not compete asa directly). Calcium also competes with iron, as do many phytochemicals, including coffee and green and black teas.

Antioxidant Enzymes

But iron can become very strongly antioxidant if it is part of the catalase enzyme, which converts peroxide to water (similar to the selenium-containing enzyme glutathione peroxidase). Catalase works together with SOD (copper and zinc, or manganese) to remove superoxide and peroxide before they can react with reduced iron (Fe2+). Adaptogenic medicinal herbs like ginseng and astragalus and medicinal mushrooms are able to increase production of these enzymes (assuming the minerals – especially selenium, zinc, and manganese, as iron and copper are usually found elevated in Hep C - are there), as do the isothiocyanates and glucosinolates found in cruciferous vegetables (broccoli, cabbage, kale, watercress, mustard etc.).

Vitamin A
Because HSCs naturally store vitamin A, it might be expected that vitamin A would have some action for or against fibrosis. It turns out that vitamin A as retinyl palmitate (the form of vitamin A in cod liver oil) is potently antifibrotic (as are various carotenoids in their own right), but a very interesting feature of this in animal trials is that liver pretreated with vitamin A and exposed to toxicity produces less collagen and fewer activated HSCs than liver not so pretreated, yet the vitamin A pretreated liver has a significantly higher level of AST and ALT liver enzymes after the toxic exposure. In other words, an elevated liver enzyme count can be consistent with the prevention of fibrosis.

No doubt damaged hepatocytes can be replaced more easily than excess collagen can be cleared away. In the MCM medicines below, hepatoprotective herbs (such as schizandra) are sometimes added to antifibrotic mixtures.

Vitamin D is also anti-fibrotic http://www.ncbi.nlm.nih.gov/pubmed/21816960
The non-scientific literature on Hep C is full of warnings against supplementing nicotinamide, retinol, and vitamin D3.
These warnings, based on the effects of extreme overdose, have no relevance to normal diet or supplementation at clinical dosages. Restricting these vitamins in the belief that they are dangerous is infinitely more risky than supplementing them. Retinol status, for example, is inversely associated with hepatocellular cancer in prospective studies of populations with chronic viral hepatitis.

Modern Chinese Medicine

Modern Chinese Medicine has made a special study of fibrosis, identifying both the processes involved and a number of traditional herbs that address various aspects of fibrosis, especially when associated with viral hepatitis. Herbal mixtures have been designed to address various aspects of fibrosis prevention in one formula. Thus apricot kernels (armand de nord, north almonds, bitter almonds), which promote HSC apoptosis, may be combined with pine pollen, which protects collagen and microcirculation, cordyceps, a medicinal mushroom with antiviral properties which corrects immune suppression, ligusticum, which reduces platelet stickiness (PAF, platelet aggregating factor, is a factor in fibrosis), notoginseng, which is a potent antioxidant with traditional use in protecting the cardiac circulation, and schizandra, which protects hepatocytes and increases bile flow. The star of antifibrotic herbs in MCM seems to be the very well researched radix salvia miltiorrhiza (red sage, dan shen), a cheap herb with multiple antifibrotic actions. Salvia out-performs other herbs and polyphenols with antifibrotic actions, at levels easily attained by supplementation with extracts, and is used in most MCM antifibrotic mixtures.

Reversal of fibrosis and even early-stage cirrhosis is often seen in clinical trials of these new Chinese medicines. I predict that the rate of reversal will increase when the herbs are combined with appropriate amounts of antioxidant and antifibrotic nutrients; a-tocopherol succinate, selenium, zinc, manganese, niacinamide, NAC, lecithin, cod liver oil, OPCs, as well as antifibrotic foods; curries, grapes and raisins, mango, berries, soy and other legumes. The neuroglial function of HSCs provides scientific validation for stress-relieving practices such as breathing excercises, yoga, tai chi, and cognitive therapy in the management of fibrosis.

REFERENCES (to be expanded. In the meantime, to find a reference i.e. to the antifibrotic effect of curcumin, just google "curcumin hepatic stellate", and so forth. Medline references will then be found at the top of the next page.)

1 Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem
2000; 275:2247-2250

2 Iredale JP. Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis 2001; 21: 427-436

3 Bataller R, Brenner DA. Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis
2001; 21: 437-451

4 Reeves HL, Friedman SL. Activation of hepatic stellate cells -a key issue in liver fibrosis. Front Biosci 2002; 7: d808-826

5 Wang BE, Wang TL, Jia JD, Ma H, Duan ZP, Li XM, Li J, Wang AM, Qian LX. Experiment and clinical study on inhibition
and reversion of liver fibrosis with integrated Chinese and Western Medicine. CJIM 1999; 5: 6-11

6 Yin SS, Wang BE, Wang TL. The effect of Cpd 861 on chronic hepatitis B related fibrosis and early cirrhosis: A
randomized, double blind, placebo controlled clinical trial. Zhonghua Ganzangbing Zazhi 2004; 12: 467-470

7 Wang TL, Wang BE, Zhang HH, Liu X, Duan ZP, Zhang J, Ma H, Li XM, Li NZ. Pathological study of the therapeutic effect
on HBV -related liver fibrosis with herbal compound 861. Weichangbingxue He Ganbingxue Zazhi 1998; 7: 148-153

↧

How To Come Off Methadone Without Really Trying

September 10, 2012, 5:15 pm

≫ Next: Vitamin D3 could save your life, pretty much.

≪ Previous: Preventing and Reversing Hepatic Fibrosis - Herbs and Supplements

Over a year ago - I think it was in August - I finally came off methadone, which drug I'd been taking since the late 1980s, including every day, barring accidents, since 1990. I started reducing gradually from 120mg in 2004, after I started taking antioxidants (see the recent post on Viral Manipulation of Host Behaviour). There are two rules about this kind of slow reduction:

The first: whatever happens, NEVER ask for the dose to be put back up. There's always something else you could be doing instead.

The second rule is related to the first: use the discomfort from reductions to experiment, to sort out the changes in diet and lifestyle and the supplements that will actually help you once drug-free. At this stage there will always be another dose tomorrow, so mistakes are less important.

By the end I had a pretty perfect protocol worked out. Diet really helped. Gluten, dairy, carbs, even too much fruit or vege made things much harder. This is the letter I wrote to my case manager when I quit. I was on about 7.5 mg/day and could have drawn it out longer. Some people say the last drop is the hardest, but this wasn't the case with me. Every drop got easier and easier. The less methadone I took, the better I felt. I still have my last doses of methadone in the house. In the past year I've never considered I've had any use for it, nor have I felt any kind of desire for it. Feelin' fine...

15 August 2011

Hi Mark,
I won't require another pickup, I'm due for one tomorrow, but don't need it, having had no dose since Friday. Saturday I was weak and slept very badly, Sunday I was weaker but slept well, today I feel virtually normal if a bit convalescent. Unless my body has found and released a stored well of methadone, I think I'm over the worst.

As I have got lower adjustement has tended to get faster.

My tips for withdrawal;

1) low carb diet. Cravings for unhealthy (sweet or high-carb) food and cravings for drugs are related, so a diet that reduces cravings of all sorts is best. Plus, I think it easier and more reliable to burn fat than carbohydrate during withdrawal. And extra protein is required - make room for it.

2) hormonal regulation - supplement vitamin D, use DLPA pre-treatment to elevate endorphins during withdrawal, tribulus increases hardihood and resistance to pain and stress.

3) l-carnitine or acetylcarnitine is clinically proven to significantly reduce methadone withdrawal; 500mg 3-4x daily improves energy and mental focus by promoting burning of fats and GABA sensitivity.
http://www.ncbi.nlm.nih.gov/pubmed/18978503

4) niacin (as niacin 100-200mg PRN or no-flush niacin 500mg 3-4xdaily) supresses craving and physical discomfort, especially combined with vitamin C.

5) magnesium chelate in high doses, plus salt, prevents cramps

6) high-dose probiotic prevents diarrhoea

7) multivitamin/mineral because metabolism is sped up, diuresis etc. will deplete some other nutrients. Not so much on a nutrient-dense low-carb diet though.

I was following this regime through the lower stages, below 10mg.
And there you have it. Feelin' fine, and no struggle over willpower (whatever that is) was ever required, methadone (and other drugs) held no appeal, but an inspiring dream on Friday night definitely helped.

In my dream I was looking at pictures of cities;
one was: Dunedin: the Edinburgh of the Antarctic. the other: Edinburgh: the Edinburgh of the World.

Then I was on a skyscraper over Edinburgh (the city where I was born) looking down on huge cathedrals and mausoleums, around to skyscrapers, then up and around to structures built by Gods or Giants, in a kind of Art Deco style, topped by square white pillars with a rounded edge at the front topped by statues of winged Egyptian animal-headed Gods which I could see all around the skyline, all visible in a bright, pastel light like the light of sunrise, or a Maxfield Parrish sky. Then I realised how high up I was, how dangerous it was to get back inside, and woke up. The awe-struck emotion from the dream and the imagery remained with me vividly all day. An experience of grandeur as an intense emotion. What it meant I can't say but it sure was a good thing.

Footnote: at a time of stress you need lots of energy, but you also don't want too much food that needs digesting sitting your stomach. A diet that helps you burn any stored fat (i.e. a diet that doesn't raise insulin) and that also supplies concentrated energy - i.e. is "energy dense" in the language of the Food Police - is one that adds less stress to an already stressful situation.

See this very different yet weirdly analogous story about running an ultra marathon on a low-carb diet:

http://www.meandmydiabetes.com/2012/08/11/western-states-100-low-carber-wins-ultramarathon-steve-phinney-and-jeff-volek-study/

You can learn a lot about low-carb vs. high carb from a careful perusal of this story, even if you're not interested in athletics. For example, it becomes obvious why people who are dieting tend to eat fewer calories on high-fat diets. It has nothing to do with flavour.

He’s got very little body fat, but if let’s say he’s 7% by weight body fat that means he still has at least 30,000 calories of fat in his body when he starts the race.

A 30,000 calorie tank of fuel? On his body?
STEVE PHINNEY: When the starting gun goes off, 30,000 calories of body fat. Now, if you run this race typically your body will burn 10,000 calories over the 100-mile course, so he’s got enough to run the race three times over before runs out of fat fuel. But that’s because he’s a fat-burner. For the carb loaded runners, who are less adapted to burning fat, at the same starting line, even if they’d done their carb loading to the maximum, the most carb calories they’d have in their bodies is 2,000. Now, if you’re running on a carb fuel strategy, and you’ll need 10,000 calories to complete the 100-mile race, that 2,000 calories of carb stored in your body at the start of the race is only 1/5 of the fuel that you need to complete the race.

High-carbers have to fuel up more often?

STEVE PHINNEY: That’s correct. In contrast, if you’re running on a fat fuel strategy, you’ve got three times as much fuel in the tank as you need to complete the race and that’s the beauty, literally the metabolic beauty of the low-carb adapted athlete in an ultra-performance event.

That leads to another important distinction between the high carb diet high-fat diet and that is for many runners when they use the high carbohydrate fuel strategy many runners found that by mile 50 and certainly by mile 75 that they started having major gastrointestinal upset. The upset would get to the point that not only could they not hold food down, but they had a hard time holding liquids down.

Some high-carb runners had trouble with digestion? But not on low-carb/high fat?

STEVE PHINNEY: Yes, and that’s disastrous in a race where the sweat losses and the evaporative losses are so great that if you can’t keep fluids coming in, you’re out of the race. Many of the high-carbohydrate runners experienced frequent and severe gastrointestinal problems. In fact, what has induced many of them to do this bold thing and switch to get being low-carb is that they’ve heard from other people who do this race that when they went from high carb to a low-carb, high-fat diet those gastrointestinal problems went away.

Now, if you were just detoxing off opiates, instead of running an ultra-marathon, that would still be a highly desirable advantage, wouldn't it?

↧

Vitamin D3 could save your life, pretty much.

September 18, 2012, 5:23 pm

≫ Next: More Cholesterol Madness; Malcolm Kendrick on Viral Hepatitis. Plus, What would Jesus eat?

≪ Previous: How To Come Off Methadone Without Really Trying

http://hepatitiscresearchandnewsupdates.blogspot.co.nz/2012/09/d-livering-message-importance-of.html#.UFoZ4bJlTzw

What we have here is the full-text of a very good review paper on vitamin D and liver disease, including chronic Hep C, on the Hepatitis C Research and News blog.
The review is from the latest Journal of Hepatology.
This is good stuff, very thorough, and lacking the usual "vitamin D can be toxic, so you should be too scared to take our advice" hand-wringing that usually weakens the message when it trickles down to the Hep C community through the usual suspects.
All the fat-soluble vitamins are critical for surviving viral hepatitis, especially retinol, D3 and K2 (sourcing extra vitamin E in the diet is less important if the dietary fats are relatively saturated, but tocopherols and tocotrienols may be useful as part of an antioxidant regime). Selenium - a mineral needed to prevent peroxidation of fats - and carotenoids, which require fats for absorption, are also protective factors, but carotenoids are not a substitute for retinol.

See Plasma Selenium Levels and Risk of Hepatocellular Carcinoma among Men with Chronic Hepatitis Virus Infection for some population data on selenium, retinol and carotenoids. Although tocopherol - vitamin E - made no impression in these stats, the best dietary sources of tocopherol are exactly the oils high in linoleic acid - vegetable omega 6 - that promote liver fibrosis; so there may yet be a protective effect of tocopherol that is cancelled out by the context of the foods that are supplying it in this study. Vitamin E is necessary for maximizing the conversion of carotenoids to retinol. http://www.sciencedirect.com/science/article/pii/S0891584900002963
Vitamin K2: http://www.ncbi.nlm.nih.gov/pubmed/17541221

↧

More Cholesterol Madness; Malcolm Kendrick on Viral Hepatitis. Plus, What would Jesus eat?

September 22, 2012, 1:55 am

≫ Next: Dining In The Fourth Dimension

≪ Previous: Vitamin D3 could save your life, pretty much.

The following is from an article by Malcolm Kendrick, author of The Great Cholesterol Myth.
http://www.spiked-online.com/articles/0000000CAE78.htm

And so the latest argument is that nobody in modern society has a normal cholesterol level.

An article in the Journal of the American College of Cardiologybest sums up this line of thinking. Under the heading 'Why average is not normal', O'Keefe, the lead author, makes the claim that: 'Atherosclerosis is endemic in our population, in part because the average LDL ("bad" cholesterol) level is approximately twice the normal physiologic level.' In short, according to O'Keefe, our cholesterol level should be about 2.5mmol/l, not 5.2mmol/l.

This argument, if true, does neatly demolish the question 'How can people with normal, or low, cholesterol levels be protected against heart disease?'. O'Keefe and others would argue that we all have a high cholesterol level. Everyone is ill, and all shall have statins.

One regularly quoted fact, which superficially seems supportive of O'Keefe's hypothesis, is that peasant farmers in China have very low cholesterol levels and a very low rate of heart disease (although their average cholesterol levels are actually about four, not two-and-a-half).

But when you study the figures with more care, they reveal something else. As usual, those with low cholesterol levels have by far the highest mortality rates. Liver failure and liver cancer are common causes of death. However, there is a simple explanation for this association. Many Chinese peasant farmers have chronic hepatitis, which creates low cholesterol levels, and also leads to liver failure and liver cancer. This is why people with low cholesterol levels die young.

Does this mean that a low cholesterol level protects against heart disease? No: what the Chinese data tell us is that those with higher cholesterol levels are not chronic hepatitis carriers, so they live longer and have more chance of developing heart disease in old age. On the other hand, those with low cholesterol levels cannot die of heart disease, because they are already dead.

Without chasing too many mad arguments around, the simple fact is that everyone in the West does not have a raised cholesterol level. Repeated studies have shown that a perfectly normal, or healthy, cholesterol level lies between about four and six, and lowering it cannot protect against heart disease, otherwise we will have introduced a new concept into medical science: normal is unhealthy and must be treated.

******

Message; cholesterol that is normal or "high" (the old "normal") is a good thing if you have chronic viral hepatitis. And cholesterol in your diet will provide some of the protection you're lacking if serum cholesterol is low; but it probably won't elevate serum cholesterol. This is more likely with saturated fat in the diet. Polyunsaturated oils and spreads are likely to depress it further.
Dr. Robert Atkins noted (in "Dr Atkin's New Diet Revolution") that his diet - high in fat, very low in carbohydrate - tended to lower cholesterol in patients when it was very high (the "normal" range was more realistic in his day) and raise cholesterol towards the normal range when it was unusually low.

What to eat? Although I revere Dr Atkins, the diets in his books use far too much oil and processed food.
These are two versions of what I think is just about ideal.
http://www.archevore.com/get-started/
by Dr Kurt Harris, and
http://perfecthealthdiet.com/the-diet/
by Paul and Shou-Ching Jaminet.
I recommend trying the lower end of carbohydrate consumption in either diet; but I also think it's OK to experiment with both higher carb and ketogenic dieting to find out what's ideal for you.The supplements/ special nutrient suggestions in the Perfect Health Diet are valuable too, and if you want recipes The Perfect Health diet blog provides many examples.
Niether diet mentions Hep C, but that's OK; we're not metabolic freaks, and in this case what's good for so many other people out there with type 2 diabetes, fatty liver, autoimmune problems, and malnutrition seems to be made for us.

In terms of a fasting lipid profile, there are some variables that may matter with regard to Hep C; you want TG (fasting tryglycerides) to be low (lower than HDL, or much the same, is perfect), and you do not want LDL or total cholesterol to be low.
High TG means that more HCV virions can leave the infected cells (estimated to average 50 per cell per day), low LDL means that they have more chance of getting into uninfected cells (because there are more receptors). Lower TG with any given LDL count means that the LDL particles are larger and there are fewer of them, which also reduces HCV virion opportunity. Low LDL may to some extent be compensated by a cholesterol-rich diet, which also reduces LDL receptor numbers.

"in experimental animals such as the hamster and the rabbit, dietary cholesterol increases liver cellular cholesterol and suppresses both hepatic cholesterol synthesis and LDL-receptor expression. In the rat, dietary cholesterol also increases liver cellular cholesterol, but its effect on the LDL-receptor is variable and species-dependent."
http://onlinelibrary.wiley.com/doi/10.1002/hep.510260112/pdf

referenced in "Dietary Fats and Alcoholic Liver Disease" by Esteban Mezey:
http://onlinelibrary.wiley.com/doi/10.1002/hep.510280401/pdf

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