Bilirubin is a yellow compound generated from destroyed hemoglobin. Its yellow color is responsible for yellow skin in jaundice, and the yellow hue of urine and feces. Bilirubin also has some very beneficial antioxidant properties.
Bilirubin Definition
Bilirubin is a yellow compound that is a breakdown product of heme from hemoglobin in red blood cells.
Bilirubin and its breakdown products give the yellow color in jaundice patients, urine, and feces.
Bilirubin is one of the most toxic natural breakdown products in the body [1].
Bilirubin tests (TBIL and DBIL) are part of blood test panels to assess red blood cell breakdowns and liver function and are usually presented as conjugated and unconjugated bilirubin.
Unconjugated bilirubin is not water-soluble until the liver conjugates it by adding a sugar group. The conjugated bilirubin is then secreted as part of the bile in the stool and urine.
Bilirubin Normal Range
Bilirubin reference or normal range is 0.2 – 1.2 mg/dL for total bilirubin (TBIL), and 0.1 – 0.4 mg/dL for direct or conjugated bilirubin (DBIL) [2].
In the absence of liver disease, higher levels of bilirubin within the reference ranges are beneficial because bilirubin is a potent antioxidant with cell-protective roles in complementary with glutathione [3, 4].
Bilirubin is associated with functional independence in older people.
A cohort study among 4,303 adults 60 years and older found that certain levels of total bilirubin are associated with the all-cause lowest mortality rate [5].
A large cohort study found that higher bilirubin levels generally correlate with lower all-cause mortality [6].
Many correlational studies have shown that elevated levels of bilirubin within the reference range may have some positive effects.
Why Babies Have Higher Bilirubin
50 – 60% of newborns have high bilirubin.
Babies have higher bilirubin because of lower levels of this enzyme. Before birth, this enzyme is actively decreased, since bilirubin needs to remain unconjugated in order to cross the placenta to avoid being accumulated in the fetus. After birth, it takes some time for this enzyme to gain function.
Babies also have a shorter life span of fetal red blood cells.
Last, babies have a relatively low conversion of bilirubin to urobilinogen by the intestinal flora, resulting in relatively high absorption of bilirubin back into the circulation.
They lack the intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin in the feces (this is largely why the feces of a neonate are paler than those of an adult). Instead, the conjugated bilirubin is converted back into the unconjugated form by the enzyme β-glucuronidase (in the gut, this enzyme is located in the brush border of the lining intestinal cells) and a large proportion is reabsorbed through the enterohepatic circulation.
Elevated Bilirubin & Diseases
Many people with chronic health issues have bilirubin levels that are abnormal. The doctors just shrug this off as Gilbert’s syndrome, but other issues could be at play.
If you are struggling with chronic health issues – the way I used to – you probably have piles of lab tests that can potentially tell you a lot about your health. Bilirubin may be one of them. But doctors never had enough time to explain it properly. They will only notice it if the lab flags your test results as outside of normal. But what if all your results are coming back normal, but you know you are feeling nowhere near healthy? They may even tell you there is nothing wrong with you, and that it’s all in your head – I’ve been there.
1) Causes Brain Problems
Newborn jaundice is a common problem because the baby’s liver may take some time to fully function after birth. Without other health problems, this condition typically goes away on its own and is often treated with UV exposure.
Excess bilirubin in a newborn may lead to an accumulation of bilirubin in certain brain regions. This can cause irreversible damage to the brain, causing various brain deficits, seizures, abnormal reflexes, and weird eye movements. This rare type of neurological injury is called kernicterus [7].
Neonatal exposure to high levels of bilirubin can cause severe motor symptoms and cerebral palsy. Exposure to moderate levels of unconjugated bilirubin can also cause damage to the developing central nervous system [8].
2) Associated with Deafness in Newborns
The auditory pathway is the most sensitive part of the central nervous system to bilirubin-induced toxicity. High blood bilirubin levels can cause damage to the auditory system as well as the brainstem [9].
Excessive bilirubin levels are associated with deafness in infants [10].
Only bilirubin levels ≥10 mg/dL above a threshold were associated with a statistically significant increased risk of Sensorineural Hearing Loss [10].
3) May Damage the Liver
High plasma concentrations of bile acids (BA) and bilirubin can cause liver damage [11].
What Increases Bilirubin
1) Alcohol
Moderate alcohol consumption may increase concentrations of blood bilirubin in nonsmokers. Total blood bilirubin concentration increased significantly after drinking [12].
Total serum bilirubin increased significantly after drinking from baseline to 24h in non-smokers (from M = 0.38 to M = 0.51) [12].
2) Exercise
Exercise training significantly increases blood bilirubin levels. However, this effect only occurs with high doses of exercise training [13].
3) Fasting
Fasting can increase bilirubin levels due to reduced intestinal mobility [14].
Short periods of fasting increases unconjugated bilirubin concentration in patients taking atazanavir [15].
The average bilirubin concentration before the fasting diet was 2.31 mg/dl and it was 3.84 mg/dl after [15].
4) High Fat Intake
An increase of intravenous lipid (fat) intake in infants less than 28 weeks old leads to an increase in unbound bilirubin. The higher fat intake leads to more free fatty acids in the blood, which increases bilirubin in the infants [16].
5) EGCG
EGCG increases bilirubin secretion. Hence, green tea consumption will increase bilirubin levels [17].
6) Antituberculosis drugs
The use of antituberculosis drugs increases bilirubin levels [18].
7) Tylenol
Paracetamol (acetaminophen/Tylenol) increases bilirubin levels [19].
8) Antibiotics
Prolonged used of certain antibiotics may lead to increased bilirubin levels in rats [20].
9) Small Intestine Bacterial Overgrowth and Abnormal Gut Movement
Low movement of the intestines and small intestine bacterial overgrowth may contribute to increased levels of unconjugated serum bilirubin, as well as gallstone formation [21].
10) Blood And Liver Diseases
Excessive levels of unconjugated bilirubin may indicate certain problems with the liver, or that there is a high level of red blood cell breakdowns. Whereas, too high levels of conjugated bilirubin might indicate obstruction of bilirubin excretion to the gallbladder.
Why is Your Bilirubin High?
These are not necessarily in the order of likeliness.
If you have high bilirubin, a likely scenario has to do with genetics. It’s important to dig deeper into your genetics so that you can learn how to optimize the genes you have.
The GG genotype in rs4124874 causes less UGT1A1 and showed a significantly higher frequency in patients with Gilbert’s syndrome (58%) than in healthy volunteers (17%) [22].
1) Liver Problems
Excessive levels of unconjugated bilirubin may indicate certain problems with the liver, or that there is a high level of red blood cell breakdowns. Whereas, too high levels of conjugated bilirubin might indicate obstruction of bilirubin excretion to the gallbladder.
2) Lower Bile Excretion
Bilirubin is excreted in the bile, so if you have lower bile excretion, it might increase bilirubin.
3) Less UGT Enzymes
There are a bunch of enzymes in the UGT family (glucuronosyltransferases) that reduce bilirubin, and if you have lower levels of these, it will cause higher bilirubin.
UGTs normally convert unconjugated bilirubin to conjugated bilirubin that can be excreted into the gastrointestinal tract.
In addition to its capability in xenobiotic detoxification, UGT1A1 plays pivotal roles in the clearance of bilirubin [1].
Reduction in UGT1A1 expression is associated with Gilberts’ syndrome characterized by mild, unconjugated hyperbilirubinemia in the absence of liver disease.
The GG genotype in rs4124874 causes less UGT1A1 and showed a significantly higher frequency in patients with Gilbert’s syndrome (58%) than in healthy volunteers (17%) [22].
4) Lower Glucuronidation
Bilirubin is glucuronidated in order to be excreted, so low glucuronidation may increase bilirubin.
5) Gut Dysbiosis
If you have gut dysbiosis, you may have high levels of the enzyme Beta-Glucuronidase, which can decrease glucuronidation.
6) Slowed Gut Flow
Bilirubin levels increase when gut flow (motility) is reduced [14].
7) Lower NRF2
The UDP-glucuronosyltransferase (UGT) family catalyze the conjugation of glucuronic acid to drugs, chemicals, and toxins, making them more water-soluble and readily excreted. Nrf2 has been shown to induce UGT1A1 and UGT1A6.
8) Inflammation and Oxidative Stress
Oxidative stress and inflammation can also increase bilirubin by breaking down red blood cells, which turn into bilirubin (from hemoglobin).
Red blood cells are disposed of in the spleen when they get old or damaged. This releases hemoglobin, which is broken down to heme. The heme is then turned into unconjugated bilirubin in the spleen. This unconjugated bilirubin is then bound to albumin and sent to the liver.
9) Heme Oxygenase – 1
Heme Oxygenase -1 increases bilirubin by breaking it down, and some people might have higher levels of this enzyme. This produces biliverdin, iron, and carbon monoxide.
Induction of heme oxygenase may be a general response to oxidant stress, and increasing bilirubin levels could provide a major cellular defense mechanism against oxidative damage [23].
10) Lower CAR (Constitutive Androstane Receptor)
CAR regulates the genes that transport bilirubin out of the body and is, therefore, regulates the amount of bilirubin, making sure it never gets high enough to become toxic.
People with high bilirubin may have lower levels of CAR activation.
CAR has been shown to induce multiple UGT enzymes and other enzymes that detox bilirubin.
Analysis of the UGT1A1 genes revealed that a SNP located within the CAR-responsive region displayed significantly higher frequency in patients with Gilbert’s syndrome (58%) than in healthy volunteers (17%) [22].
11) Low PXR
PXR helps detox products such as bile and bilirubin [24], so if you have Gilbert’s Syndrome, you may not have enough PXR.
Removing bile can help prevent cholestasis [24].
PXR has been shown to induce the expression of multiple key components in the clearance pathway of bile and bilirubin, including UGT1A1, OATP2, GSTA1 and 2 and MRP2 [25].
Consistent with the pattern of gene regulation, activation of PXR in mice has been shown to prevent experimental hyperbilirubinemia [26].
12) Higher Hemoglobin
Obviously, higher hemoglobin levels can also contribute to increased bilirubin.
13) Light Deficiency
Blue light breaks hemoglobin down and if you aren’t getting enough light, it will increase bilirubin. Light allows the excretion of unconjugated bilirubin in bile because light makes it more soluble.
14) Higher Monocytes in Spleen
High monocytes in the spleen may increase bilirubin because they break down into it.
How to Lower/Reduce Bilirubin
1) Phototherapy
Phototherapy reduces the high levels of bilirubin in infants and helps stop jaundice. However, there are side effects to this therapy, and the bilirubin levels can rebound [27].
2) Anthocyanins
Anthocyanins (pigments) from the Aronia melanocarpa plants can reduce the concentration of bilirubin in the blood [28].
3) Zinc
Zinc salts can bind to bilirubin. In rats, zinc administration greatly lowers bilirubin levels in the blood. This is due to the inhibition of the enterohepatic circulation of bilirubin [29].
4) Taurocholic Acid
Taurocholic acid decreases intracellular bilirubin levels in mice [11].
5) Fish Oil
Additionally, triglyceride (cholesterol) levels can influence bilirubin levels. Fish oil can lower cholesterol levels, which in turn lowers bilirubin levels [30].
6) Estrogen
Estrogen can lower bilirubin levels in women. Oral contraceptives, containing estrogen and progestin, as well as postmenopausal estrogen use, decreased bilirubin levels [31].
7) Aspirin
In rats, aspirin lowers bilirubin levels post-surgery [32].
8) The UGT1A1 gene
The UGT1A1 gene and its variants are associated with lower bilirubin levels [33].
Subjects who ate diets containing vegetables or citrus had significantly lower bilirubin compared to subjects that did not eat any vegetables. In individuals with the UGT1A1 genotype, vegetable and citrus fruit consumption can lower bilirubin levels [34].
9) Stem Cell Therapy
Adult-derived human liver stem/progenitor cells (ADHLSC) can also reduce bilirubin levels in rats with high bilirubin levels [35].
10) Gut Bacteria
Microflora from the human gut can degrade bilirubin.
In cell cultures, Clostridium perfringens reduces bilirubin ditaurate levels [36].
Other species that can reduce bilirubin include Clostridium difficile, Clostridium ramosum and possibly Bacillus fragilis (37).
Health Benefits of Higher Levels of Bilirubin (within range)
1) Associated with Lower Heart Disease Risk
Higher levels of bilirubin in elderly individuals are associated with lower risks of disabling diseases like stroke and heart diseases [38].
High levels of blood bilirubin also reduce the risk of certain heart diseases [39].
Among individuals with high blood pressure, ones with high bilirubin levels were less likely to die from heart diseases [40].
High serum bilirubin may decrease the risk of high blood pressure by working as an antioxidant in the blood vessels [41].
2) Associated with Lower Type 2 Diabetes Risk
Certain genetic mutations in the UGT1A1 gene, encoding a bilirubin metabolizing enzyme, is associated with reduced risks of type 2 diabetes in a diabetic-prone people on Norfolk Island. In addition, the study found that the higher bilirubin levels are among these people, the less likely they are to get diabetes [42].
3) Associated with Lowered Inflammation in COPD and Migraine
COPD is an inflammatory disorder associated with oxidative stress. Blood bilirubin has potent antioxidant actions, and higher concentrations can protect against oxidative stress. In middle-aged smokers, bilirubin lowered COPD disease severity and helps stop its progression [43].
Migraine patients who have higher CRP, an inflammatory marker, have lower total bilirubin [44].
Low serum bilirubin is associated with increased hsCRP in insulin resistant and type 2 diabetic people [45].
4) Reduce Death Rates
People who had higher levels of bilirubin had a lower risk of lung cancer and mortality. Low levels of blood bilirubin correlated with a higher risk of lung cancer and death in male smokers [46].
Compared with male smokers in the highest bilirubin group (>1 mg/dL), those in the lowest bilirubin group (<0.75 mg/dL) had 55% and 66% increase in risks of lung cancer incidence and mortality, respectively [46].
Irregular Bilirubin Levels?
Use Lab Test Analyzer to Find Out How
LabTestAnalyzer helps you make sense of your lab results. It informs you which labs are not in the optimal range and gives you guidance about how to get them to optimal. It also allows you to track your labs over time. No need to do thousands of hours of research on what to make of your lab tests.
SelfDecode Your Genes to Find Out Why
SelfDecode can tell you if your high bilirubin is based on genes you have, and if it is, it can tell you what steps you can take to optimize them.
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