Oct 30, 2013
(***For educational purposes only. Not to be taken as medical advice or used to try to sell anything. My sincere thanks to George Henderson for joining me in attempting the impossible)
Post treatment sides are caused by TLRs (Toll-Like Receptors). TLRs are transmembrane proteins expressed by cells of the innate immune system, which recognize common structures on pathogens, known as pathogen associated molecular patterns (PAMPs), and activate signaling pathways that launch immune and inflammatory responses to destroy the invaders (see attached picture). TLR 2 and 4 interact with viruses and stimulate various pro-inflammatory and antiinflammatory cytokines.
In other words, TLRs recognize the Hepatitis C virus when it first infects you and mobilize different cells (macrophages, NK cells, etc) and pro inflammatory cytokines (like interferon) to defend you against the virus.
Things that activate TLR's.
2. Endotoxin from LEAKY GUT
3. The Hepatitis C virus
Interferon is pro-inflammatory. That's how it elicits a response from the immune system to fight invaders.
2. ENDOTOXIN from LEAKY GUT
When my kids were little, I went to a conference on Hepatitis C and brought back a coloring book with pictures of the liver for my son to color. As he started coloring he asked me, "What's a liver?".
I explained to him that the liver was the organ that got rid of everything we put in our body whether it was drugs, medications, alcohol, creams we rubbed on our skin and the pollution we inhaled. I showed him a picture of a tired liver on the coloring book and told him that's what happened to our liver when we made it work too hard.
The next day I was in the bathroom spraying deodorant under my arms when my son ran in the bathroom, grabbed the can of deodorant and threw it in the trash screaming, "No mommy, you're killing your liver!"I was very proud of him, he had the right idea and I'd never even mentioned deodorant.
So we all know that the liver gets rid of toxic substances we put in our bodies, but how do toxins get to the liver and how does the liver detoxify them? How does it relate to TLRs and the innate immune system?
The liver is the first organ that encounters venous blood from the small and large intestines via the portal vein. So that makes the liver vulnerable to exposure of bacterial products coming from the intestines. Translocation of large amounts of gut-derived products is usually prevented by an intact barrier system made strong by intestinal epithelial cells. So in a healthy organism only minor quantities of bacterial products reach the liver. In general, the liver tolerates small amounts of bacterial products in order to avoid harmful responses, but damage of the intestinal epithelial barrier results in a leaky gut that lets large amounts of bacterial products reach the liver.
Bacterial products, otherwise called Lipopolysaccharide are large molecules consisting of a lipid and a polysaccharide found on the outer membrane of gram negative bacteria. When they reach the liver, they act as ENDOTOXIN and elicit a strong reaction from our immune system. In other words, TLR's recognize bacterial products and activate the immune system cells that reside in the liver (like macrophages and NK cells) to defend you.
Activated TLR signalling induces innate immune responses including cytokine and type I IFN production in the liver. Alarmins, the products released from damaged cells or tissues (like the damaged cells caused by necrosis) also trigger TLR signalling and cause inflammation. Thus, the activation of TLR signalling by microbial products from leaky gut can contribute to the initiation and progression of liver disease.
What can cause a LEAKY GUT?
Dyslipidemia (high cholesterol)
NASH (NonAlcoholic Steatohepatitis)
GI problems (like stomach ulcers, diarrhea, Barrett's esophagus, H,Pylori infection, colitis, etc)
Antibiotics disrupting normal intestinal flora.
3. The HEPATITIS C VIRUS
HCV's core protein interacts with TLR2 and TLR4 and stimulates various pro-inflammatory and antiinflammatory cytokines. NS3/4A disrupts TLR3 and RIG-1 signaling pathways by blocking TRIF and CARDIF and NS5A interacts with TLR4 and impairs NK cell function. Levels of TLRs 2, 6, 7, 8, 9 and 10 are upregulated in both monocytes and T cells in HCV patients. TLR4 is upregulated in T lymphocytes, and TLR5 is increased in monocytes. MD-2, a TLR4 co-receptor, is increased in monocytes and T cells.
TLR2 correlates significantly with the hepatic necroinflammatory activity grade while TLR4 correlates with the fibrosis stage. TLR 4 expression in pancreatic beta cells affects cell viability and insulin homeostasis. Iit contributes to the development of insulin resistance and inflammation through its activation by elevated fatty acids and lipopolysaccharide (metformin is a TLR4 inhibitor, probably the reason it raises SVR). Plus there's TLR7 signaling impairment seen in non-responders.
During interferon treatment, CORTISOL is produced as part of the stress response and both cytokines (interferon) and cortisol enhance TLR 2 expression. Cortisol increases free fatty acids and blood sugar (to increase energy resources) and both those things increase TLR2 expression. High blood sugar, insulin resistance, obesity and lack of sleep cause a low grade chronic inflammation which is associated with expression of TLR4.
Lipopolysaccharide from leaky gut (caused by cirrhosis, IR, dyslipidemia, diarrhea, ulcers, Barrett's esophagus, etc) directly stimulates cortisol secretion. Add to that the other factors that increase cortisol like fear, fever, PTSD, pain, coffee, smoking and you can see how patients can end up with increased levels of cortisol and expression of TLRs.
Continual excess cortisol release eventually causes cortisol receptors to become desensitized leading to increased activity of pro-inflammatory immune mediators and disturbances in neurotransmitter transmission. Unregulated inflammation that can lead to dangerous pathologies long after you finish treatment with interferon.
There is a fine line between "protection from TLRs" and "damage from TLRs". .TLR signaling induces the production of inflammatory mediators and anti-microbial peptides to eradicate invading microorganisms from the host as well as to bridge the acquired immunity to amplify immune responses. However, abnormal activation of innate immune signaling may also cause chronic inflammation, autoimmune diseases, tissue and organ injuries, fibrosis and carcinogenesis. Hepatic inflammation can then cause systemic inflammation followed by the destruction of the intestinal barrier causing leaky gut and bacteria to go from the intestine to the liver. That induces a second activation of TLR signaling in the liver which can cause liver damage long after you finish treatment.
Because one thing is for sure, expression of TLRs doesn't stop the day you finish treatment.