In a previous blog, I discuss the cell danger response and how your cells can get stuck. Dr. Navio termed these complicated biochemical abnormalities seen in inflammatory reactions as a result of cells being threatened by an infectious agent or toxin.  This can often lead to oxidative stress, which has a host of consequences when it comes to your health.  In this blog I want to talk about bilirubin the antioxidant as a potential mechanism that can mediate some of these consequences.

What is Bilirubin?

Bilirubin is the by-product of red blood cell breakdown and a byproduct of heme. Red blood cells have a lifespan of about 120 days and they renew continually. Basically, they are always breaking down.

Here is a summary of how this happens. Resident macrophages eat up old blood cells and recycle them including hemoglobin. Hemoglobin gets broken down to heme and globin. Heme gets converted to biliverdin, which gets converted to bilirubin via hemoxygenase (HO-1), which gets converted to bilirubin via ZINC DEPENDENT enzyme bilirubin reductase.  This forms the unconjugated form of bilirubin. The bilirubin uses albumin to get into the liver, where it is then conjugated.  This is where it becomes water soluble so it can be readily excreted.  Bilirubin gets in liver to go through glucuronidation where glucuronic acid is added so that it leaves the liver in the conjugated form.

Bilirubin the antioxidant then goes into the biliary tree, along with bile, and goes into the intestines and is excreted via stools. Unconjugated bilirubin is toxic, but conjugated is not, as long as nothing interferes with its removal. It is a major component of bile and gives it its green color, but it also gives feces its brown color.

Total bilirubin

Total bilirubin is conjugated + unconjugated bilirubin.

Now when you take your bilirubin measurement in serum, it is a combination of direct (conjugated) and indirect (unconjugated) bilirubin.  Normally indirect bilirubin is approximately 70-85% of total bilirubin. If 50% or more is direct, hepatic/biliary obstruction is suspected. If less than 20% is direct, accelerated hemolysis (RBC) or liver dysfunction is suspected.

Bilirubin the antioxidant

You may have heard that glutathione is a universal antioxidant in the body. But many people do not know about bilirubin the anitoxidant. Both of these substances are prominent endogenous antioxidant cytoprotectants. Despite tissue levels that are thousands of times lower than GSH, bilirubin is actually quite effective. When bilirubin acts as an antioxidant, it is oxidized to biliverdin, which is immediate reduced by biliverdin reductase (BVR) to bilirubin.  Glutathione protects water soluble proteins and bilirubin protects lipids from oxidation.

Unconjugated bilirubin can block the superoxide-producing NADPH oxidase. When NADPH oxidase is upregulated, it can deplete NADPH. Biliverdin is then rapidly reduced by the ubiquitously expressed enzyme biliverdin reductase to yield bilirubin.  Expression of inducible form of heme oxygenase, HO-1, can be boosted by oxidative stress, often derived from NADPH oxidase activity. The promotes the production of bilirubin which feeds back to quell oxidative stress.

Superoxide as public enemy #1

You do not want high levels of superoxide in the body!  It can be damaging. Those of you who have done a genetic test with me know all too well about the damaging effects of the NOX pathway and the upregulation of iNOS.  iNOS, aka inducible nitric oxide, is a form of nitric oxide that often is upregulated when you are sick and fighting an infection.  COVID is notorious for upregulating iNOS.  Another common thing that stimulates NOX are the EMF’s from cell phones. This can lead to NOS uncoupling.  When you get NOS uncoupling, you can have superoxide. Another thing that generates superoxide is oxidized glutathione. That is why taking oral glutathione is not often good for everyone, especially if you are not recycling it properly.

You can also have mutations in superoxide dismutase (SOD) enzymes.  If you are making more superoxide, and don’t have enough enzyme activity to neutralize it, you will have a lot of inflammation.  I really think that a lot of people that seek my help are dealing with upregulation of iNOS.

What are some of the common symptoms of this? 

• Cold hands and feet, brain fog, fatigue, and in men, erectile dysfunction.  If your circulation is weak, you will experience a lot of these symptoms.
• A big problem with iNOS being upregulated is platelet activation, which can cause blood clots. This is another possible pathway in which there may be a rise in blood clots due to pathways activated after COVID infection.
• Another issue is the renin angiotensin (RAAS) pathway.  When this pathway is upregulated with nitric oxide deficiency, you can have problems with water retention, edema and high blood pressure.
• Supporting nitrite to nitrate to nitric oxide pathway inhibits NADPH oxidase, peroxynitrite production, and down regulates IL6, RAAs cycle, Holmes cycle. Bilirubin the antioxidant can support this pathway

Back to Bilirubin the antioxidant

Because bilirubin also functions as an antioxidant, levels may be decreased during oxidative stress.  In fact, bilirubin appears to be the most potent antioxidant against lipid peroxides.  Because of this, low bilirubin has been associated with increased risk of CV disease and all cause mortality.  Bilirubin may also increase insulin sensitivity and protect against future diabetes.

Eliminating endogenous bilirubin renders cells vulnerable to stress.  Bilirubin scavenges superoxide. Neuronal bilirubin prevents NMDA receptor cytotoxicity by scavenging superoxide.

Bilirubin is an antioxidant that can protect cells from 10-fold excess of hydrogen peroxide.  It can inhibit potent pro-inflammatory cytokines such as IL-6, IL-B and TNF-a.  As a result of this mechanism, it can modulate inflammation.

Unconjugated bilirubin modulates iNOS enzyme, reducing iNOS gene expression.  It protects against endothelial dysfunction by modulating nitric oxide concentration, probably through inhibition of NFK-B.

Sirtuins

I often talk about the importance hemoxygense-1 (HO-1).  One mechanism of this enzyme is that supports SIRT1.  If you do not know what sirtuins are, watch this post here I did on Instagram. SIRT 1 is the enzyme that supports endothelial nitric oxide, superoxide dismutase (SOD) and inhibits NFK-b and TNF-a.  SIRT1 supports HO-1. Resveratrol supports SIRT-1, high fructose corn syrup inhibits it.  This is another clue that demonstrates how medical nutrition therapy is helpful with managing disease of inflammation. Anything that stimulates HO-1 supports kidneys and pancreas, etc.

To summarize bilirubin the antioxidant:

• Bilirubin inhibits NADPH oxidase. It inhibits production of peroxynitrite and nitrated molecules
• Bilirubin can lower cardiovascular disease- by inhibiting NADHPH oxidase and superoxide, allowing nitric oxide to be more bioavailable.
• Bilirubin has anti-platelet activation
• Bilirubin scavenges superoxide
• Bilirubin is an antioxidant
• Bilirubin has anti-platelet activation
• Bilirubin protects from cardiovascular disease
• Bilirubin makes nitric oxide be more available

I will repeat- healthy nitric oxide inhibits platelet activation through bilirubin’s mechanism of action:  decreasing Superoxide, inhibiting NADPH oxidase, increasing nitric oxide bioavailability

Oxidative stress is your enemy

Oxidative stress occurs when there is an imbalance of reactive oxygen species and the antioxidants to neutralize it.  Oxidative stress uncouples NOS enzymes, promoting them to becomes a superoxide generator rather than a nitric oxide generator.

What can we do?

We have to downregulate NADPH oxidase so it’s not depleting NADPH so it can be used to make bilirubin.  One way to do that is the lower iNOS activation, by addresses the hidden infections that may be upregulating it. This can be things such as mold, Lyme, Bartonella or any other viral or bacterial infection.  Also, be aware of your EMF exposure, and reduce your exposure by hard wiring your computer, shutting off your Wi-Fi at night, using EMF protective cell phones cases, etc.  Royal Jelly can support this pathway too as source of BH4 which is used as a cofactor in this pathway.  Also, you will want to address if and why there is lipid peroxidation.

Testing and treating

This is a simple blood test your doctor can run for you to test for bilirubin the antioxidant. Optimal ranges for bilirubin is 0.5-0.8mg/dL.

Low bilirubin levels are associated with:

• Oxidative stress- check uric acid and GGT
• Zinc deficiency- biliverdin reductase is zinc dependent and converts biliverdin to bilirubin, thus leading to low levels. Check alkaline phosphatase levels and your hair tissue mineral analysis. Also, you may want to run blood copper and zinc levels to investigate if there is a hidden zinc deficiency due to excessive copper.
• Rheumatoid arthritis
• Renal insufficiency
• NAFLD
• Atherosclerosis
• Calcification
• Blood flow issues
• Less vasodilation
• Carotid atherosclerosis

Elevated levels are associated with:

• Excess hemolysis
• Liver dysfunction – since the liver conjugates bilirubin. Liver dysfunction will increase unconjugated bilirubin
• Bile duct obstruction- bilirubin is cleared from the liver via biliary ducts into the intestines. Thus, if biliary ducts are obstructed, conjugated/direct bilirubin will enter into circulation
• Gilbert’s syndrome- genetic cause of elevated bilirubin.

To increase bilirubin, the following can increase bilirubin (dose unknown)

• Carnosol
• Skullcap
• Curcumin
• Rosemary
• green tea
• garlic
• indole-3 carbinol
• sulforaphane
• vitamin E

In summary, bilirubin is a very important and often overlooked antioxidant.  If your doctor is not running your levels, they really should be.  If you want me to run a complete assessment of you, including a full blood panel and nutrigenomic panel, that can dig deeper into your root cause, visit my Root Cause investigation.

Book a Discovery call to discuss how I can help you!