Gilbert’s syndrome is a condition involving a defect in a phase 2 glucuronidation gene known as UGT1a1. The result of this causes elevations in the levels of unconjugated bilirubin. The current scientific consensus is that Gilbert’s is a relatively benign condition. I disagree with that contention. I believe that UGT1A1 genetic polymorphisms are prone towards producing a wide array of problems that are associated with:
- Reduced hepatic glucuronidation and clearance of steroid hormones such as estrogen
- Impaired metabolism and clearance of thyroid hormones, such as Thyroxine and Reverse T3
- Impaired xenobiotic detoxification and clearance
- Impaired biosynthesis of heme and altered porphyrin metabolism
- Digestive symptoms that are associated with SIBO, bloating and constipation
- Mood-related symptoms, such as anxiety
Overview of Bilirubin Metabolism, Hepatic Function & Bile Synthesis
The breakdown of red blood cells takes place in the spleen, where the constituent hemoglobin is degraded into heme and biliverdin. The result of this is the formation of unconjugated bilirubin. Unconjugated bilirubin makes its way to the liver, where the phase 2 glucuronidation pathway conjugates bilirubin through the action of the enzyme UGT1a1. Individuals with Gilbert’s syndrome have inherited a polymorphism within the UGT1a1 gene, reducing their capacity to conjugate bilirubin sufficiently.
Because UGT1a1 is integral in the breakdown of numerous molecules, genetic polymorphisms may have a significant influence on: toxin load, hormone levels, digestive functions, mood and energy.
UGT1A1 & Thyroid Hormone Metabolism
Numerous anecdotal observations from my clients with UGT1a1 genetic polymorphisms suggest a wide spectrum of related symptoms. A common finding is the association between total bilirubin levels and thyroid hormones, T4 and RT3. I’ve observed a trend towards a positive association between them. In other words, when bilirubin levels are higher, T4 and RT3 levels also move higher. What’s the possible reason for this? UGT1a1 is one of several glucuronidation genes that control levels of T4 (R), and RT3 is also controlled by UGT glucuronidation (R). You must remember that the liver is integral in the metabolism and breakdown of hormones. This is absolutely true of thyroid hormones. For individuals who have gone down the Reverse T3 rabbit hole trying to figure out why values are elevated, if you see that total bilirubin is simultaneously high, consider looking at your UGT1a1 genetics as the primary cause. The same may be true if your Free or Total T4 levels are trending on the higher side.
UGT1A1 & Steroid Hormones: Estrogen
UGT1A1 is integral in the metabolism and biotransformation of the steroid hormone 17-ß-estradiol (R). Defects in UGT1a1 may impair the breakdown of estrogen, and this relationship has been studied in relationship to breast cancer risk (R). This information may be useful for women who carry the UGT1a1 gene, who also have estrogen dominance-related symptoms, such as:
- Bloating and water retention
- Breast tenderness
- Fibrocystic breasts
- Mood swings
It’s important to consider that impaired clearance of estrogen may affect other steroid hormones, such as testosterone and cortisol. Future scientific research should be able to clarify how UGT1a1 is affecting other steroid hormones.
Porphyria, UGT1A1 & Heme Biosynthesis: Nausea, Anxiety, Constipation, Abdominal Pain
Porphyria and secondary porphyria are conditions involving an abnormal synthesis of heme. This typically results in increased excretion of urinary porphyrins, and a laundry list of complex symptoms. There may be an intrinsic relationship between Gilbert’s, abnormal heme synthesis and porphyria. A single study from 1987 identified the presence of heme biosynthesis abnormalities in 14 patients with Gilbert’s and associated hyperbilirubinemia. The study found a decrease in the enzyme protoporphyrinogen oxidase (PROTO oxidase) and an increase in the enzyme delta-aminolaevulinic acid, among peripheral blood cells of subjects (R). The authors administered the antibiotic rifampicin. This caused a subsequent decrease in bilirubin values. Based upon their findings, the author’s speculated that elevated unconjugated bilirubin seen in Gilbert’s inhibits the PROTO enzyme, and the heme biosynthesis pathways. What’s curious is that unlike patients with variegate porphyria, Gilbert’s patients did not excrete porphyrins into their urine. However, Gilbert’s patients frequently report symptoms that are very similar to variegate porphyria. These include:
- Abdominal pain
- Loss of focus and concentration
This relationship deserves much deeper attention, and may prove to be a central player in the overlooked symptoms among individuals with UGT1a1 genetics.
Tracking Gene Expression & Potential Therapeutic Workarounds
I don’t like to state that the status of a gene or SNP (singular nucleotide polymorphism) is equivalent to gene expression. It’s becoming increasingly more clear that gene expression is controlled by many different factors. From a clinical standpoint, we look to use certain lab testing biomarkers to monitor gene expression. In short, I believe that by monitoring levels of total bilirubin (you can also measure indirect bilirubin, which corresponds with unconjugated bilirubin) over time (among carriers of UGT1a1 polymorphisms), we can gauge the relative expression of UGT1a1 activity. Right now, it’s the best we have. Maybe in the future there will be better lab tests available to look at this, but for now, I’m monitoring bilirubin values. Here’s what I’ve observed:
- Calcium D-glucarate is a supplement that is readily available. I’ve noted for adults 1,000mg of Calcium D-Glucarate typically lowers total bilirubin values about 30%, among those with UGT1a1 polymorphisms. This is good. Someone should perform a study on this, because it’s an inexpensive supplement, and one that can provide a partial workaround for UGT1a1.
- Are carbohydrates important if you’re UGT1a1? This is an odd question, but I’ve thought about it because I know that individuals with porphyrias are often recommended diets higher in glucose and carbohydrates, as they can prevent porphyrin production in the liver. Granted, UGT1a1 is not a porphyria condition by definition. However, as stated in my article above, individuals with Gilbert’s have shown to feature characteristics in their blood cells similar to variegate porphyria. I have observed at least in a few Gilbert’s clients that carbohydrates in the diet are important. More data is needed. If you have UGT1a1 or Gilbert’s, please let me know if carbohydrates seem to be important for you.
- Certain herbal preparations should be considered as potential workarounds for UGT1a1 polymorphisms. A Chinese herb known as Evodia has been shown to increase UGT1a1 expression (R). Deeper research finds that the UGT1a1 gene is controlled by a nuclear transcription factor known as CAR (constitutive androstane receptor), as well as PXR (pregnane X receptor) and the glucocorticoid receptor (GC) (R). Modulating GC, CAR and PXR may be a viable workaround for UGT1a1 polymorphisms.
- A Chinese herbal formula, historically used for neonatal jaundice has been shown to induce expression of both UGT1a1 as well as CAR (R). The formula consists of hepatic-specific herbs: artemesia capillaris, gardenia, rhubarb and scutilleria baicalensis.
I hope this short article provides some helpful bits of information regarding UGT1a1 and Gilbert’s syndrome. It’s an overlooked problem, and one that doesn’t get enough attention.