Gilberts and the glucuronidation gap

Gilbert’s and the Glucuronidation Gap

Your Liver's Detox System: Understanding Phase 1 and Phase 2

Your liver is one of the hardest-working organs in your body, constantly filtering, processing, and detoxifying what you eat, breathe, and absorb. Its detox system works in two main phases.

Phase 1: The Processing Stage

Think of Phase 1 as the "prep department." It takes everyday substances—hormones, medications, environmental toxins—and breaks them down into smaller parts. Here's the catch: this stage can actually make those substances more reactive (and sometimes temporarily more toxic) before they're fully processed.

Phase 2 is where the magic happens. Like a "packaging and shipping" department, your liver takes those reactive byproducts from Phase 1 and attaches other molecules to them through processes like glucuronidation, sulfation, and methylation. This makes them water-soluble so your body can safely eliminate them through bile or urine.

Phase 2 has six main detox pathways:

1. Acetylation

2. Sulfation

3. Glucuronidation

4. Methylation

5. Amino acid conjugation

6. Glutathione conjugation

Each pathway handles different types of substances—some specialize in hormones, others in medications or toxins—and they often work together to keep everything balanced.

Phase 2: The Packaging & Removal Stage

The Glucuronidation Pathway and Gilbert's Syndrome

The glucuronidation pathway is especially important when it comes to Gilbert's syndrome. This pathway helps your body attach a molecule called glucuronic acid to substances like bilirubin, hormones, thyroid hormones, bile acids, and many medications so they can be excreted.

In people with Gilbert's syndrome, the UGT1A1 enzyme that drives this process works slower than normal (depending on your genetic variant), which means detoxification can sometimes be less efficient.

UGT Enzymes: The Family Behind Glucuronidation

UGT1A1 isn't working alone—it's part of a larger family known as UGTs (Uridine 5'-diphospho-glucuronosyltransferases). This family includes several enzymes like UGT1A3, UGT1A6, UGT1A7, and UGT2B17, each responsible for detoxifying different substances.

For example:

• Estrogen is processed by UGT1A1, UGT1A3, UGT1A9, and UGT2B7

• Bilirubin, however, is only cleared by UGT1A1

That's why people with Gilbert's syndrome tend to accumulate bilirubin—there's no "backup enzyme" to help out. Other UGT enzymes can cover for estrogen detox, but not for bilirubin.

Genetic Overlaps: More Than Just UGT1A1

Interestingly, research shows that Gilbert's syndrome doesn't just affect the UGT1A1 enzyme. According to a landmark study, people with Gilbert's syndrome are much more likely to have variations (polymorphisms) in other UGT enzymes as well:

• UGT1A3 – found in 91% of people with Gilbert's syndrome

• UGT1A6 – found in 77%

• UGT1A7 – also found in 77%

This means that while UGT1A1 is the main enzyme responsible for bilirubin clearance, many individuals with Gilbert's syndrome may also have a broader pattern of reduced glucuronidation capacity. In other words, their ability to detoxify certain hormones, drugs, and environmental compounds might be subtly different too—which could help explain why people with Gilbert's syndrome sometimes report heightened sensitivity to stress, medications, or hormonal changes. This is just one of several studies indicating that glucuronidation is less efficient in people with Gilbert's syndrome.

When Detox Pathways Compete

Here's where it gets interesting: Because UGT1A1 handles both bilirubin and estrogen, when the system is overloaded—for example, during hormonal changes, illness, fasting, or toxin exposure—these substances can compete for clearance

In simple terms, your liver may have to prioritize which substance to process first. Since bilirubin depends entirely on UGT1A1 (with no backups), it tends to build up more easily, leading to that familiar mild yellow tinge some people with Gilbert's syndrome notice during stress or fasting.