Understanding Gilbert’s syndrome

Gilbert’s syndrome is a genetic condition characterised by excess bilirubin resulting from inefficient detoxification pathways, a process known as glucuronidation.

Gilbert’s syndrome often goes undiagnosed, as conventional medicine considers it to be benign. However, the excess bilirubin has many flow-on effects in the body and can result in sometimes serious dysfunction.

Detoxification issues in Gilbert’s syndrome

When someone is homozygous (+/+) or positive for the UGT1A1 gene mutation, some glucuronidation enzymes have reduced expression and activity, resulting in less effective detoxification of neurotransmitters, hormones, drugs and chemical compounds.

What is glucuronidation?

Phase 2 liver detoxification relies heavily on these enzymes to process metabolic wastes. In phase 2 detoxification, metabolites created in phase 1 liver detoxification are bound (conjugated) to another component, making them heavier and more soluble in water. The extra water solubility results in the metabolites being easier to excrete.

Not all glucuronidation enzymes are impaired, generally just a small group of enzymes under the UGT1A1 umbrella.

Understanding glucuronidation and bilirubin

Bilirubin is the breakdown product of heme in red blood cells, and it must be detoxified when a red blood cell dies. The UGT1A1 enzyme is what is used for this detoxification step to make bilirubin able to be modified and, therefore, ultimately able to be fully detoxified.

Genetic mutations in the UGT1A1 enzyme slow this detoxification process, resulting in an increase in bilirubin, typically about 30 per cent less. Without this extra bilirubin detoxification, undetoxified (unconjugated) bilirubin is left roaming in the body.

Drug detoxification

Glucuronidation is the process used for detoxifying bilirubin, but many other substances, such as painkillers, also use this pathway to exit the body – paracetamol/acetaminophen (Panadol, Tylenol), ibuprofen (Nurofen, Advil), aspirin and non-steroidal anti-inflammatory drugs, and others. The processing power of these drugs is significantly reduced.

The impacts of Gilbert’s syndrome on the body

These sluggish detoxification pathways impact overall wellbeing because so many metabolic waste products require this exit route, such as dopamine and oestrogen, with impaired serotonin turnover. There can be significant consequences to the build-up of these products.

Diagnosis of Gilbert’s syndrome

Gilbert’s syndrome is usually picked up if a child has jaundice or elevated bilirubin is consistently found on a blood test. Typically, Gilbert’s syndrome is not found or diagnosed, leaving children to become adults with sometimes severely compromised detoxification processes and the fallout of the buildup of toxic metabolites.

In routine tests as adults, elevated bilirubin is rarely discussed.

Total bilirubin that is consistently higher than >10-15 μmol/L (>0.58-0.87 mg/dL) may indicate Gilbert’s syndrome. It’s important to note that one blood test with elevated bilirubin doesn’t equate to Gilbert’s syndrome – there are a lot of causes of temporarily elevated bilirubin, including fasting before a blood test.

A genetic test can also be performed to confirm the DNA components.

Total bilirubin and direct bilirubin blood tests

Total bilirubin is unconjugated (unbound) bilirubin. The most common test is total bilirubin, which measures bilirubin that has not gone through glucuronidation.

To clarify, a second test – direct bilirubin – may be requested. Direct bilirubin measures bilirubin that has been through the glucuronidation process.

If there is elevated total bilirubin (unconjugated) but in-range direct bilirubin, there is an abundance of unconjugated bilirubin. The question is, why?

Causes of high unconjugated bilirubin

Gilbert’s syndrome is not the only cause of elevated unconjugated bilirubin. More serious causes include haemolysis (red cell death) caused by haemolytic anaemia, sickle cell anaemia and resolution of a large haematoma (collection of blood under the skin caused by trauma).

Elevated bilirubin can also be caused by hepatitis and liver cirrhosis.

DNA in Gilbert’s syndrome

The gene – UGT1A1 – is passed down in families, with some children homozygous (+/+) and some heterozygous (-/+). Homozygous means both biological parents passed on the mutation, while heterozygous means just one parent did. If both parents are +/+ (homozygous), all children will be +/+.

Not everyone in the family will be affected, but there will likely be a pattern among family members. Estimations are about 10-15 per cent of the population has these genetic variations. There may be a family history of older relatives with stressed livers, for example, alcoholism or farming with a heavy load of pesticides.

But my doctor and the internet say it’s benign…

As you can see, Gilbert’s syndrome is not benign for most people. Approximately eight per cent of people with Gilbert’s syndrome are genuinely asymptomatic.

Symptoms of Gilbert’s syndrome

• Often unusual sets of symptoms
• Can be vague, difficult to diagnose digestive problems
• Brain, mood, mental health and psychiatric presentations
• Acute transient psychotic disorder
• Hot flashes (vasomotor symptoms)
• Nausea
• Panic attacks
• Sleep problems, insomnia, even strong sedatives don’t work
• Irritable bowel syndrome (IBS)
• Oestrogen dominance, difficulty clearing oestrogen
• Menstrual issues – heavy periods, short menstrual cycles, heavy clotting
• Greater incidence in Indians, South East Asians, and Middle Eastern cultures – up to 1 in 4 

How unconjugated bilirubin impacts the digestive system

Unconjugated bilirubin is excreted into bile, and its effect is immediate. The bile itself is modified, and gallbladder function and ducting are impacted. Gilbert’s syndrome can be a cause of gallbladder stones and sludge and increase the risk of gallstones in children.

When bilirubin enters the small intestine, normally bacteria create reactions that produce a substance known as urobilinogen – a form of bilirubin that has undergone further detoxification. The bacteria that act upon bilirubin here are of the Clostridium species, which are normally considered unfriendly; however, they are beneficial because they help detoxify bilirubin. There are others, including Bacteroides fragilis, with likely many unidentified bilirubin helpers.

We can see here how bilirubin-loving species will proliferate if there is an abundance of bilirubin. If there is a lack of bacteria in the colon overall (in heavy antibiotic use, newborns), higher bilirubin may be the natural outcome, as there are no bacteria to detoxify bilirubin at all.

Research has shown that elevated bilirubin increases intestinal permeability, disrupting the tight gap junctions of the intestine. When gap junctions are loosened, larger molecules can travel from the digestive system into the bloodstream, causing a greater susceptibility to allergies.

How elevated bilirubin contributes to mental health issues

Impaired glucuronidation caused by Gilbert’s syndrome results in impaired dopamine metabolism and changes blood-brain barrier function.

Unconjugated bilirubin collects in neurons and microglia and causes overwhelm and inflammation to the nervous system. This unconjugated bilirubin inside the central nervous system increases glutamate release, increases oxidative pressure on the system, and causes damage to cell membranes.

Some research examines elevations in bilirubin and certain psychotic disorders. An otherwise mentally well person experiencing a psychotic episode may present with elevated bilirubin that has no explanation. There isn’t a cohesive trend of elevated bilirubin in schizophrenia.

Damaged cell membranes, oxidative stress in the nervous system and increased glutamate could provide a reasonable explanation for these episodes.

How UGT1A1 detoxifies bilirubin

The UGT1A1 process makes bilirubin water soluble so it can be excreted. Most Gilbert’s patients have more than one inefficient enzyme – we can have up to four enzymes working at sub-par function. This variety of effects means each person is different in terms of bilirubin levels and symptoms.

The underlying problem is poor glucuronidation and the subsequent buildup of unconjugated bilirubin. The bilirubin needs to be in the water-soluble form to be excreted, but this conversion is not happening as quickly as it should.

The liver conjugates bilirubin by binding it to glucuronide. This process is only partially completed in Gilbert’s patients when the bilirubin is loaded back into the bile. The enzyme beta-glucuronidase can easily undo this partial job in the gallbladder or large intestine upon contact with unconjugated bilirubin.

This completely undoes the work of conjugating bilirubin, and the bilirubin goes back to the beginning – unconjugated.

Glucuronidase is a by-product of some bacteria, and it is normally found in the small intestine.

How unconjugated bilirubin impacts the intestine

Higher levels of unconjugated bilirubin modify the behaviour of the intestine. While nutrient absorption and brush border enzyme activities are not affected, it can cause watery diarrhoea and loosen tight gap junctions, resulting in what’s known as leaky gut.

Gut impacts of higher levels of unconjugated bilirubin

• Delayed gastric emptying – food stays in the stomach for double the normal time (about three hours vs. 1.5 hours)
• Upper digestive system discomfort
• Burping/belching
• Not getting hungry for longer than others
• Avoidance of certain foods that sit for longer, like meat and dense proteins (feels like it sits like a lump of concrete in the stomach for hours)
• Faster transit times in the intestine (tendency to diarrhoea)
• Loosens tight gap junctions – leaky gut, allergies, immune activation
• Gallstones
• Gallbladder sludge
• Poor fat tolerance
• Pain around the diaphragm area
• Fat malabsorption
• Watery diarrhoea
• Queasy/nausea
• Bowel movements change every day
• Lighter-coloured stools (bilirubin darkens stools)
• Mysterious ‘trigger’ foods, can’t work out the problem

The gallbladder in Gilbert’s syndrome

The gallbladder produces bile, which is the main route of excretion for bilirubin. Normally, the majority of bilirubin in the bile in the gallbladder has been completely detoxified. In Gilbert’s, it’s partially detoxified and then goes right back to the beginning due to the enzyme beta-glucuronidase.

The impact of this is that gallstones can develop. Conventional theories say this is caused by supersaturation with cholesterol, where bile has too much cholesterol in it (from high cholesterol), but this theory is being challenged.

It may, in fact, be the partially detoxified bilirubin core collecting cholesterol around it, alongside gallbladder sludge. The core of these stones are known as black stones – made of dark bilirubin, affecting children the most since children have much less cholesterol buildup.

The gut microbiome in Gilbert’s syndrome

Unusual microbiomes may appear in Gilbert’s patients, and no consistent pattern has so far been found. Regular commensals may be absent, and unusual species may thrive.

How to increase bilirubin (undesirable)

• Stress
• Fasting
• Synthetic oestrogens (oral contraceptive pill, hormone therapy)
• Some painkillers
• Recreational drugs (cause high dopamine, problems eliminating)
• Intense cardiac exercise