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HCV, Redox under HCV-altered metabolism
Redox under HCV infection – Oxidative Stress triggers Fibrogenesis
HCV creates EXTREME Oxidative Stress. It does this in a number of ways, but the significance of this is that extreme Oxidative Stress triggers normally quiet cells in the liver, called Stellate Cells to change. What they change into is a different type of cell called a Myofibroblast, and these are the critters that secrete collagen, or scar tissue in our HCV-infected livers. These myofibroblasts deposit collagen in all the extracellular spaces in our livers, around the sinusoids and the blood vessels, lymph vessels and bile ducts. These collagen fibers are actually what are called actin fibers, which are contractile proteins – (our muscles are made of the contractile proteins actin and myosin). Well the scar tissue (actin) clamps down on the vessels in our liver, constricting blood flow into the liver and bile flow out.
In normal conditions a third of our blood at any one time is flowing through our hepatic portal vein, the main network of blood vessels that bring blood and food from our digestive tract straight to our liver for digestion, absorption and assimilation. However, when blood flow is constricted in the liver, it causes problems, and a lot of it is simple fluid mechanics. The blood backs up and the serum separates and falls out into the GI cavity, a condition called Ascites. Blood flow backs up from the veins running into the neck as well and cirrhotic patients often bleed from their Esophageal Varices in their necks.
The liver has an enormous capacity to heal, but reproducing liver cells is not the problem, it is finding real estate in the liver that is not taken up by scar tissue that is the problem. Eventually, in End Stage Liver Disease (ESLD) the liver looks “shrunken”, and resembles an old leather shoe sole, with not many living cells in it, but a lot of scar tissue, which has proliferated until it squeezed all the living cells out of the liver.
HCV creates Oxidative Stress by several methods:
· * HCV hijacks about five or six different biosynthetic pathways so that it can create material for its own life-cycle needs, but the most significant HCV-induced metabolic change is to the Glutathione biosynthetic pathway. HCV induces decreased levels of Glutathione production, and that is bad for Redox homeostasis. HCV-infection also affects the Methothioadenosine biosynthetic pathway, which is a separate and distinct antioxidant system.
· * HCV sets up replication “nest” or “rafts” in the mitochondrial envelope where the mitochondrial membrane meets the endoplasmic reticulum. These replication sites, or “rafts” physically tear holes in the mitochondrial membrane, allowing ROS species to leak out. This has a multiplier effect on free radical-generated Oxidative Stress. HCV also works to degrade the mitochondrial membrane. This effort is aided in the fact that HCV also hijacks both Phosphatidylcholine (PC) biosynthetic pathways. Phosphatidylcholine is the phospholipid that makes up 80% of our membrane phospholipids, so decreased production of PC has negative effects on all our cell membranes, including outer cell membranes and intracellular organelle membranes like gogi, mitochondria, endoplasmic reticulum, peroxisomes, etc.
· * HCV infects non-liver white blood cells called macrophages and liver-based kupffer cells which infiltrate the liver in the spaces where necrosis (unprogrammed cell death) occurs. These macrophages are similarly affected by mitochondrial degradation and these white cells spill tremendous amounts of ROS free radicals into the extracellular spaces of the liver. The extreme oxidative stress activates the stellate cells and interacts with the inflammatory process to create a whole messy area called “inflammatory infiltrate”. These are the spaces that fibrosis advances first, and extreme Oxidative Stress, combined with flying cytokines and inflammatory mediators create a boiling stew in these spaces.
· * HCV also induces the impairment of Beta Oxidation of fatty acids in the cells. It does this by reducing the amount of L-carnitine produced. L-carnitine escorts fatty acids to the mitochondrial for burning for energy. When this process is impaired it can lead to a condition called steatosis, or “fatty liver”. Fatty Liver also creates oxidative stress, and this leads to further activation of Stellate Cells.
There is an important point of to be made regarding Oxidative Stress-mediated Fibrogenesis. Fibrogenesis is a separate process and NOT a direct action of the HCV virus. HCV, HBV, alcohol abuse, Steatosis, and hepatotoxic pharmaceutical drugs may all create extreme Oxidative Stress and trigger the process of Fibrogenesis.
That being said, the reasonable method to deal with the pathology of HCV and the metabolic changes induced in the host is to bolster the metabolic pathways that HCV alters. In other words, to try to correct those HCV-induced metabolic alterations by oral supplementation of added nutrient metabolites into the HCV-altered biosynthetic pathways. Since HCV creates oxidative setress through chantges in the metabolome, then it makes sense to bolster those affected biosynthetic pathways in order to re-establish redox homeostasis.
The other thing to mention about botanicals - and prescription drugs as well, is the Cytochrome P450 system. This system was discovered by CS Lieber, I believe, the scientist that did all the anti-fibrotic studies on PC (phosphatidylcholine).
Anyway herbivores like cows are full of cytochrome P450 because they eat all kinds of botanicals that their metabolism has not evolved to deal with. So the Cytochrome P450 system is responsible for binding and escorting those compounds out of our bodies.
It is called generally, detoxification. But many botanicals ties up our cyp450 system, and also many prescription drugs do as well.
That is why interactions are important to watch. Merrybe on this board does a good job explaining the dangers here:
http://www.medhelp.org/user_journals/show/315468/Drug-interactions-in-the-liver-101
http://www.medhelp.org/posts/Hepatitis-C/P450-liver-metabolism-of-drugs-etc/show/792665
The alarming thing is that when you are on those drugs, which are defined as hepatotoxic if they tie up the cytochrome p450 system, then a lot of the plants and fruits and herbs you eat may be affected due to the impaired CYP450 detoxification abilities. In general if your prescription drugs tie up your CYP450 system then everything else will have increased effect to to impaired clearance, so herbs and other prescription drugs might have 2-3 times effectiveness due to impaired clearance.
This is all partly tied into why it is a bad idea to to try to help yourself with botanicals while on treatment.
Anyway herbivores like cows are full of cytochrome P450 because they eat all kinds of botanicals that their metabolism has not evolved to deal with. So the Cytochrome P450 system is responsible for binding and escorting those compounds out of our bodies.
It is called generally, detoxification. But many botanicals ties up our cyp450 system, and also many prescription drugs do as well.
That is why interactions are important to watch. Merrybe on this board does a good job explaining the dangers here:
http://www.medhelp.org/user_journals/show/315468/Drug-interactions-in-the-liver-101
http://www.medhelp.org/posts/Hepatitis-C/P450-liver-metabolism-of-drugs-etc/show/792665
The alarming thing is that when you are on those drugs, which are defined as hepatotoxic if they tie up the cytochrome p450 system, then a lot of the plants and fruits and herbs you eat may be affected due to the impaired CYP450 detoxification abilities. In general if your prescription drugs tie up your CYP450 system then everything else will have increased effect to to impaired clearance, so herbs and other prescription drugs might have 2-3 times effectiveness due to impaired clearance.
This is all partly tied into why it is a bad idea to to try to help yourself with botanicals while on treatment.
The thing about coffee is that it does have reliable science behind its hepato-friendly claims.
But this also speaks to some of the mis-conceptions about antioxidants in general. A lot of that is due to the science being mis-used in commercial marketing, I believe.
In general, all plants all have compounds called polyphenols. They make these compounds in and around the areas of the plant that are exposed to sunlight/ultraviolet light which causes oxidative stress (free radical damage) and these compounds are there to protect from that damage.
A phenol (phenolic ring) is a molecule that consists of a six carbon chain of glucose that has wrapped around to form a ring instead of a chain. The significance of this is that now those electrons form an "electron cloud" that can absorb the hit of a Reactive Oxygen Species (free radical) without incurring damage. If the electron was isolated, as it is in the chain form, the free radical would damage the molecule. Instead the free radical hit is absorbed and "quenched" or stabilized by the electron cloud, and the polyphenol is then converted to its reversibly reduced/oxidized form with no damage to structure.
So, all plants, or botanicals, contain polyphenols and polyphenols protect the surface of the plant from damage caused by sunlight. That is also why fruits with higher skin to total mass ratios have higher ORAC scores - because fruits with more skin have more antioxidants due to protective polyphenols concentrated in the skin.
There are over 50,000 species of polyphenols and humans evolved with these compounds. Polyphenols simply means "more than one phenol", and flavonoids, terpenes, sesquiterpenes and I forget the other one - its on the tip of my tongue, are all subcategories of polyphenols.
But, while each polyphenol has antioxidant capacity, simply due to its ownership of at least one phenolic ring, each polyphenol often has more specific direct acting capabilities such as gene-switching, cell messaging, etc. Polyphenols are known to activate the Nrf2 gene which switches on glutathione production - our body's master antioxidant and our body's natural response to increased oxidative stress.
Most if not all active ingredients in medicinal herbs are polyphenols. Polyphenols also exhibit remarkable synergy in its actions affecting our metabolism, and they are necessary components of our native physiologic/metabolic antioxidant systems.
That being said, each botanical can be overhyped in the marketplace. Adding polyphenols from an herb may add to the strength of your metabolic antioxidant systems, but single botanicals like coffee or milk thistle or single antioxidants like vitamin C or E can not possibly address our body's complete Oxidative Stress equation even in normal healthy circumstances, much less with a condition like HCV, for all reasons listed above.
In other words, antioxidants, free radical ROS, oxidative stress, Redox homeostasis and all that are complicated and interrelated and can't easily be simplified into a simple message or a commercial sound-byte. But in general more botanical antioxidants in your diet are better than less, because it is oxidative stress that switches on Fibrogenesis, or the generation of Fibrosis/scar tissue/collagen.
Limit the fruit for the blood sugars though! Leafy greens are great, turtles live for over a hundred years on that diet!
But this also speaks to some of the mis-conceptions about antioxidants in general. A lot of that is due to the science being mis-used in commercial marketing, I believe.
In general, all plants all have compounds called polyphenols. They make these compounds in and around the areas of the plant that are exposed to sunlight/ultraviolet light which causes oxidative stress (free radical damage) and these compounds are there to protect from that damage.
A phenol (phenolic ring) is a molecule that consists of a six carbon chain of glucose that has wrapped around to form a ring instead of a chain. The significance of this is that now those electrons form an "electron cloud" that can absorb the hit of a Reactive Oxygen Species (free radical) without incurring damage. If the electron was isolated, as it is in the chain form, the free radical would damage the molecule. Instead the free radical hit is absorbed and "quenched" or stabilized by the electron cloud, and the polyphenol is then converted to its reversibly reduced/oxidized form with no damage to structure.
So, all plants, or botanicals, contain polyphenols and polyphenols protect the surface of the plant from damage caused by sunlight. That is also why fruits with higher skin to total mass ratios have higher ORAC scores - because fruits with more skin have more antioxidants due to protective polyphenols concentrated in the skin.
There are over 50,000 species of polyphenols and humans evolved with these compounds. Polyphenols simply means "more than one phenol", and flavonoids, terpenes, sesquiterpenes and I forget the other one - its on the tip of my tongue, are all subcategories of polyphenols.
But, while each polyphenol has antioxidant capacity, simply due to its ownership of at least one phenolic ring, each polyphenol often has more specific direct acting capabilities such as gene-switching, cell messaging, etc. Polyphenols are known to activate the Nrf2 gene which switches on glutathione production - our body's master antioxidant and our body's natural response to increased oxidative stress.
Most if not all active ingredients in medicinal herbs are polyphenols. Polyphenols also exhibit remarkable synergy in its actions affecting our metabolism, and they are necessary components of our native physiologic/metabolic antioxidant systems.
That being said, each botanical can be overhyped in the marketplace. Adding polyphenols from an herb may add to the strength of your metabolic antioxidant systems, but single botanicals like coffee or milk thistle or single antioxidants like vitamin C or E can not possibly address our body's complete Oxidative Stress equation even in normal healthy circumstances, much less with a condition like HCV, for all reasons listed above.
In other words, antioxidants, free radical ROS, oxidative stress, Redox homeostasis and all that are complicated and interrelated and can't easily be simplified into a simple message or a commercial sound-byte. But in general more botanical antioxidants in your diet are better than less, because it is oxidative stress that switches on Fibrogenesis, or the generation of Fibrosis/scar tissue/collagen.
Limit the fruit for the blood sugars though! Leafy greens are great, turtles live for over a hundred years on that diet!
What about those studies that show roasted coffee helps reduce oxidative stress. There used to be lots of posts on here about that. When I try to tell this to others they think I am crazy. And I probably seem that way since I can't cite how it is supposed to work.
http://www.jnatpharm.org/article/102
http://www.dailyrx.com/cirrhosis-liver-patients-who-drank-coffee-were-less-likely-die
http://www.ncbi.nlm.nih.gov/pubmed/17590492
http://www.jnatpharm.org/article/102
http://www.dailyrx.com/cirrhosis-liver-patients-who-drank-coffee-were-less-likely-die
http://www.ncbi.nlm.nih.gov/pubmed/17590492
Its from a lot of different studies - I did the research; I'm a Clinical Laboratory Scientist (Medical Technologist or Hospital Laboratory Scientist), so I am trained to do research. I just did it to get to the bottom of the science and HCV infection as it relates to Clinical Nutrition.
In the Clinical Nutrition model, you identify altered metabolic pathways (usually biosynthetic) caused by infection and supplement those pathways with metabolites and end-products in order to restore normal conditions (homeostasis) in the affected systems in the body. That is how enlightened Clinical Nutritionists and Biochemists approach these types of infectious diseases and the approach is endorsed by some top medical researchers that I work with. They have reviewed the research and endorse it, but it is not research I did, its information thats out there in the literature in the peer-reviewed journals and PubMed.
It helps to understand normal metabolism in order to properly assess the effects of altered metabolism.
The underlying principle, as seen in Clinical Nutrition terms, is that an infection like HCV alters the metabolism in the host. These altered metabolic/biosynthetic pathways create new distinctive nutritional requirements for those patients.
The science is pretty compelling when you research the subject from that frame of reference.
Mike
In the Clinical Nutrition model, you identify altered metabolic pathways (usually biosynthetic) caused by infection and supplement those pathways with metabolites and end-products in order to restore normal conditions (homeostasis) in the affected systems in the body. That is how enlightened Clinical Nutritionists and Biochemists approach these types of infectious diseases and the approach is endorsed by some top medical researchers that I work with. They have reviewed the research and endorse it, but it is not research I did, its information thats out there in the literature in the peer-reviewed journals and PubMed.
It helps to understand normal metabolism in order to properly assess the effects of altered metabolism.
The underlying principle, as seen in Clinical Nutrition terms, is that an infection like HCV alters the metabolism in the host. These altered metabolic/biosynthetic pathways create new distinctive nutritional requirements for those patients.
The science is pretty compelling when you research the subject from that frame of reference.
Mike
I appreciate the very informative post, but it left me wondering where it came from. Are you involved in primary research yourself, or is this info you found printed somewhere? I would love to know the source.
AMA does occur in primary biliary cirrhosis, which is an autoimmune disease. I think oxidative stress might play a role, but as an autoimmune disease it probably has a different cause.
LDN is good for autoimmune diseases, but you should check it out with a doc and get a fibroscan because primary biliary cirrhosis can cause fibrosis.
LDN is good for autoimmune diseases, but you should check it out with a doc and get a fibroscan because primary biliary cirrhosis can cause fibrosis.
Could this cause an elevated AMA ( anti mittachonrial )and eosinophils
Because I have elevations in both, I was told maybe is primary billary cirhosis , but I have no other markers for it
What other disease could it be and is there vitamins or foods I can take to reverse it
Thank you
CH
Because I have elevations in both, I was told maybe is primary billary cirhosis , but I have no other markers for it
What other disease could it be and is there vitamins or foods I can take to reverse it
Thank you
CH
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