Hep C Discussion Forum

There is a lot of misinformation out there regarding antioxidants and how they work. I thought I might present the science of HCV and oxidative stress.

Redox in Normal Metabolism

Inflammation is a separate and distinctly different biochemical process than Oxidative Stress, although they often occur together, especially in HCV. A study showed that in HCV, oxidative stress in the absence of inflammation promotes cancer HCC. This means that even without elevated liver enzymes showing, oxidative stress may be high and undetected and may be promoting carcinogenesis.

So then, what is Oxidative Stress?

In normal metabolism Oxidative Stress is created when free radicals, or Reactive Oxygen Species (ROS) escape from the mitochondria in our cells.

Let me explain that: the mitochondria is where our cells burn (oxidize) glucose and convert it into CO2 and water for energy. As the mitochondria breaks the chemical bonds of the glucose/pyruvate molecule and harnesses the energy in ATP, each successive form of the molecular remnants are called Reactive Oxygen Species (or free radicals) and there are about five distinct species of ROS that are created, and escape from the mitochondria.

When I say escape, I mean that in normal metabolism 2-3% of the ROS species created manage to leak out of the mitochondrial membrane into the cytosol, or cytoplasm inside the cell. The body has created specific antioxidant enzymes to quench these specific oxygen free radicals. These enzymes are reducing agents and our body creates a specific enzyme for each specific ROS species. For instance, the body creates the enzyme Superoxide Dismutase to quench the free radical Superoxide. It creates the enzyme Catalase to quench the free radical Hydrogen Peroxide, and on and on for each of the free radical ROS species.

The balance between our bodys reducing agents (antioxidants) and our boys oxidizing agents (free radicals, or ROS) is called Redox, and our bodies like to keep our Redox levels in normal range, a process called called homeostasis. Many biochemicals in our bodies are reversibly oxidized, and this system is used in normal cell signaling (see disulfide bonds in proteins). When Oxidative Stress becomes extreme, certain mechanisms are triggered - free radical oxidants hitting our DNA trigger a gene switch to create more Glutathione. This is important because Glutathione is the bodys master antioxidant molecule and our bodys natural response to oxidative stress. Glutathione runs many different antioxidant systems in our bodies, recharging vitamins c and maintaining the system of non-enzymatic small molecule antioxidants, controlling the thioredoxin/glutaredoxin antioxidant systems, influencing the methothioadenosine antioxidant system, etc.

Botanical polyphenols (flavonoids, terpenes, etc.) work as single direct reducing agents when they directly quench free radicals. However, their main course of action is to hit the DNA and trigger more Glutathione production (and other reducing antioxidant enzyme production through activation of the Nrf2 gene).

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.