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What: Too much Bilirubin!
Gilbert's syndrome is brought on by the lack of enzymatic activity of one step in the heme destruction pathway. Normally, heme is released from old red blood cells or those broken open by vigorous exercise. The heme in the hemoglobin is the carried in the bloodstream to the liver, where a few enzymes (proteins) break it down into something to be excreted in the urine. This is necessary because bilirubin (BR) is mildly neurotoxic and generally unwanted as a metabolite. It is, in chemical terms, "hydrophobic", which means it cannot dissolve well in water. The way the body takes care of hydrophobic compunds like this is to chemically add a sugar molecule to the structure of it. This makes it dissolve well in water, and allows it to be metabolized further into urobilinogen and other products that can be eliminated by urination. Normally, the unsugared "unconjugated" bilirubin attaches to a blood protein called albumin, which also carries all kinds of fatty substances. When the unconjugated BR reaches the liver, and enzyme in a particular place in the cell (called the endoplasmic reticulum) puts the sugar molecule on, the bilirubin becomes "conjugated" and water soluble.
Why: Not enough breakdown of it by an enzyme!
The problem in Gilbert's syndrome is that there isn't enough of the enzyme activity that puts the sugar onto the BR, so it languishes in the blood, causing problems. If you take a Glibert's patient liver, slice it in a thin biopsy section, and stain for the presence of the enzyme that does this, you will see about 30% of the normal amount of the enzyme. The problem seems to be how much enzyme is made, not how long the enzyme lives in the cell or how it itself is degraded. This enzyme is called UGT. The problem in Gilbert's livers is that, while the enzyme itself is completely unmutated and otherwise normal, the cellular machinery that turns it on is dysfunctional. The DNA that "promotes" the production of this enzyme is slightly different than normal, in that it has a few too many molecules in its code. Regular UGT promoters possess 6 copies of the genetic code that recruits the cellular machinery to make enzyme. Gliberts DNA has a different number, either 3,4,5, or 7, or even 8. Anything besides six seems to be suboptimal, and in general makes less enzyme. More is not necessarily better! Molecular geneticists have pinpointed this to a repeat in the "tata" promoter box, where Gilberts are usually (TA)7 instead of (TA)6.
One thing that makes UGT an interesting enzyme is the wealth of compunds that it can take. UGT puts a sugar molecule onto many drugs and chemical compunds that need to be eliminated. For this reason, it is necessary to keep a close eye on the things that are metabolized by this enzyme! You certainly dont want to take up all of your precious enzyme cycles getting rid of something to crowds its way into the protein, and takes up its time. Think of how you would operate in a conversation if ten other people were attempting to talk to you. Hard indeed!
Why are plasma Bilrubin levels variable?
a) Water, Sugar, and Bilirubin, the three substrates. b) Changeable amounts of enzyme produced.
The other thing that makes this biology interesting
is that you can temporarily raise the amount of UGT in your
liver, by consuming compounds that stimulate UGT production. In
effect, you can trick the liver into making the enzyme, but really
not have anything for it to work on. Generally, the production of
the enzyme is stimulated by things that UGT1 should metabolize. One
report shows that green tea flavonoids can stimulate production of
the enzyme. Also, many food substances modulate the levels of the UGT
enzyme, as we saw above. The liver senses everything in the bloodstream
and reacts accordingly. It may start up more production of the UGT1
enzyme, which would lead to less bilirubin. Or, it may slow down.
One thing for sure is that Gilbert's seems to get worse after fasting. It would be interesting to log the diet vs the BR levels, and see if the Gilbert's community could come up with a list of helpful and harmful compounds. The diet is so very important in management of this disorder; perhaps it can even be controlled that way. It could easily be recommended that patients keep a mental note of what they ate before a bad day. All this can contribute to a normal lifestyle and successful management of the disorder.
Bioinformatics Links to sources of knowledge about GS.
Currently this page is number two on MSN for the search "Gilbert's
syndrome". You can find another resource, and other links to GS, by
going to the number one hit, Gilbert's Web.
This is the locuslink source. There are multiple UGT genes, as reviewed here. The actual culprit in Gilbert's, though, is UGT1A1.
Find the most historical information about the enzyme at OMIM, the online mendelian inheritance in man
This is the knowledge management platform for drug discovery I pioneered. Other related Disorders
A more serious form of UGT deficiency occurs in Crigler-Najjar syndrome.
This occurs when both genetic copies of the gene are disrupted, or one
gene has multiple mutations and cannot function well at all (50% enzyme
activity rather than 70% common in GS). Recently, a
genetic linkage analysis discovered three simliar mutations in CN
type I and GS. In these Chinese patients, not only were there mutations
in the promotor region (tat box) but also two coding region changes at
R341X and P229Q. Hopefully, screening for these mutations will be available
at infancy by "PCR" so that diagnosis can be carried out early.