Gilbert’s Syndrome, UGT1A1: More Than Meets The Eye

Gilbert’s syndrome is a condition involving a genetic polymorphism 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, that only features elevations of bilirubin. I strongly disagree with that contention. A review of the scientific literature finds that UGT1a1 is centrally involved in the glucuronidation of a wide variety of compounds, including hormones, drugs, and metabolites. I believe that homozygote carriers of 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
• Risk of increased hepatotoxicity caused by a wide number of pharmaceutical drugs
• 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 biliary insufficiency: SIBO, nausea, bloating and constipation
• Mood-related symptoms, such as anxiety

Overview of Bilirubin Metabolism, Hepatic Function & Biliary 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 has been described as one of the most important DME’s (drug metabolizing enzymes).

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 Reverse T3 (RT3). I’ve observed a trend towards a positive association between them. In other words, when bilirubin levels are higher, thyroxine and RT3 levels also move higher. What’s the possible reason for this? UGT1a1 is one of several glucuronidation enzymes that control levels of thyroxine (Kato, Ikushiro, et al; 2008), and Reverse T3 level is also controlled by UGT glucuronidation (R). 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:

• PMS
• 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. For example, research by Suganti found that cortisol receptor activation is able to induce the expression of UGT1a1 (Suganti, et al; 2005). To date, no research has been conducted to determine how cortisol affects Gilbert’s patients.

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:

• Nausea
• Constipation
• Diarrhea
• Abdominal pain
• Fatigue
• Loss of focus and concentration

This relationship between porphyrins and Gilbert’s deserves much deeper attention, and may prove to be a central player in the overlooked symptoms among individuals with UGT1a1 genetics.

Drugs That May Be Hepatotoxic for UGT1a1 Gilbert’s

UGT1a1 is centrally involved in drug metabolism. As such, a wide variety of drugs must be metabolized through glucuronidation pathways. Various drugs may have hepatoxic effects among carriers of Gilbert’s UGT1a1 polymorphisms. Some of these include:

• Acetaminophen
• Carvedilol (congestive heart failure)
• Etoposide (chemotherapy)
• Lamotrigine (anti-convulsant)
• Simvastatin (cholesterol-lowering)
• Atazanavir (anti-retroviral)
• Raltegravir (anti-retroviral)
• Protease inhibitors:
• PAH’s (polycyclic aromatic hydrocarbons)
• Ethinylestradiol (often in birth control)
• 7-ethyl-10-hydroxycamptothecin (Irinotecan, chemotherapy drug used in colon cancer)
• Buprenorphine (opioid)

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. For example, UGT1a1 activity is greatly influenced by 3 nuclear receptor genes:

• NRF2 (nuclear factor erythroid 2-related factor 2) (Yueh, et al 2002)
• CAR (constitutive androstane receptor) (Suganti, et al; 2005)
• PXR (pregnane x receptor) (Suganti, et al; 2005)

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.
• Taurine is an amino acid that has reportedly improved or helped to improve bile acid deficiency symptoms of Gilbert’s patients (anecdotal evidence). Taurine is necessary in the formation and conjugation of bile acids.
• 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, Yin Zhi Wang, historically used for neonatal jaundice has been shown to induce expression of both UGT1a1 as well as the nuclear receptor CAR (R). The formula consists of hepatic-specific herbs: artemesia capillaris, gardenia, rhubarb and scutilleria baicalensis.

Natural Product Modulators of CAR (constitutive androstane receptor)

The CAR nuclear receptor has been found to control the expression of UGT1a1. As such, this method of nuclear receptor activation may prove useful as an upstream nutrigenomics bypass of UGT1a1 polymorphisms. No doubt, more research is needed.

• Artemisinin is a plant compound derived from artemesia annua. Artemisinin is a powerful plant medicine that is subject to a wide variety of research regarding malaria, babesia, cancer and infections. Artemisinin is an agonist of the CAR (Chang, Waxman, 2008)
• 6,7-dimethylesculetin is a plant extract derived from another artemesia, this one artemesia capillaris. 6,7-dimethylesculetin is a agonist of the CAR. This compound is found in the Yin Zhi wang formula (Chang, Waxman, 2008)
• Guggulsterone – is a ketosteroid derived from the resin of guggul. Guggul has been used in Ayurvedic medicine for thousands of years. Guggul has traditionally been used to modulate hepatic function, biliary stasis, and it has been shown to induce CAR expression (Chang, Waxman, 2008)

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.