- Do you have a history of high bilirubin levels on blood tests?
- Do you have strange, vague, and hard-to-diagnose gut issues with unpredictable triggers?
- Are your bowel movements irregular?
- Do you feel queasy and uncomfortable after fatty foods?
- Do you experience ongoing anxiety and mood imbalances despite working on your health and lifestyle?
- Do you experience symptoms of oestrogen dominance and hormonal imbalances?
You May Have Unmanaged Gilbert’s Syndrome
Many patients present with elevated bilirubin levels on their blood test results that their GP or specialist has never discussed with them as a potential key finding in relation to their symptoms.
They’ve had mysterious gut issues for many years, many investigations with no answers, and a very difficult-to-define symptom picture with no obvious triggers. This is a classic presentation of Gilbert’s Syndrome – and an incredibly frustrating one.
When researching Gilbert’s Syndrome online or discussing it with your doctor, you’ll likely come across the same descriptor: “benign,” “harmless,” or “non-serious.” Doctors are generally dismissive of any connection between Gilbert’s Syndrome and specific symptoms. The research, however, tells a different story.
Gilbert’s Syndrome is most definitely a significant clue on blood testing for anyone experiencing unresolved digestive issues, anxiety and mood swings, fatigue, and hormonal imbalances related to oestrogen metabolism.
What Is Gilbert’s Syndrome?
Also known as familial hyperbilirubinaemia, Gilbert’s Syndrome is a genetic liver condition that affects how the liver processes bilirubin. People with Gilbert’s Syndrome have a reduced expression and activity of enzymes required for an important liver detoxification pathway called glucuronidation.
Bilirubin is a breakdown product of haem, and it is meant to be detoxified via the glucuronidation pathway. People with Gilbert’s Syndrome have a 30% reduction in the activity of a group of enzymes responsible for clearing bilirubin from the body. The main enzyme implicated is the UGT1A1 enzyme.
This means there is more bilirubin circulating in the bloodstream because it has not been detoxified as it should be.
Contrary to conventional medical thinking, there are significant consequences of impaired glucuronidation and high bilirubin levels. This is largely because the pathway also handles dopamine and oestrogen – and elevated bilirubin directly contributes to increased intestinal permeability, commonly known as leaky gut. You can read more about the relationship between leaky gut and chronic health conditions here.
What Is Glucuronidation?
The glucuronidation detoxification pathway is responsible for the handling and clearance of:
- Neurotransmitters – primarily dopamine and glutamate, as well as serotonin
- Hormones – primarily oestrogen
- Drugs – paracetamol, aspirin, NSAIDs, benzodiazepines
- Carcinogens
People with Gilbert’s Syndrome can present with one or a combination of gut issues, psychiatric presentations, and hormonal imbalances related to oestrogen metabolism. Let’s look at each of these in more detail.
Digestive Disorders in Gilbert’s Syndrome
Bilirubin produced in the body is eventually released into bile – a digestive fluid produced by the liver that helps digest and absorb fat. Once bilirubin is mixed in with bile, the liver is meant to “conjugate” it so it can be cleared from the body.
In Gilbert’s Syndrome, bilirubin is only partly conjugated. This causes the body to reabsorb unconjugated bilirubin (UCB) via an enzyme called beta-glucuronidase – meaning it is effectively “retoxified” back into circulation, which explains the persistently elevated bilirubin seen in these patients.
The higher levels of UCB in the gut can produce a range of effects:
- Loose stools or watery diarrhoea
- Delayed gastric emptying – a feeling of food “just sitting there like a brick”; constipation
- Increased paracellular permeability by disrupting tight junctions of the gut wall – directly driving leaky gut
- Upper GIT discomfort – reflux, heartburn, queasiness, or nausea after eating
- Abdominal pain and cramping
- Difficulty digesting fatty foods and high-protein meals
- Increased risk of developing gallstones
Due to the direct effects of elevated bilirubin on gut wall integrity, people with Gilbert’s Syndrome often develop increased intestinal permeability. This compromised barrier function predisposes them to gut microbiome imbalances (dysbiosis) and inflammatory conditions.
Small Intestinal Bacterial Overgrowth (SIBO) is also frequently seen in Gilbert’s Syndrome. This is largely driven by impaired gastrointestinal motility and delayed gastric emptying – both of which are recognised risk factors for SIBO. You can read more about SIBO and IBS here.
For people with Gilbert’s Syndrome, targeted support of glucuronidation pathways and healthy gut transit time are critical. Without this foundation, the risk of recurrent dysbiosis, intestinal permeability, and SIBO remains high – even after initial treatment.
Nervous System and Mental Health
Is unconjugated bilirubin an underestimated neurotoxin? Research is increasingly suggesting that it may be, for a number of reasons:
- Higher levels of UCB are sometimes observed in newborns, and studies show an increased risk of developing mental health disorders in childhood
- There is evidence regarding UCB’s role in schizophrenia – existing studies have observed a 20% prevalence of Gilbert’s Syndrome in schizophrenic patients, although findings have been mixed
- Numerous studies report higher rates of elevated UCB in patients experiencing acute, remitting psychosis – a condition characterised by dopaminergic dysregulation
- UCB damages glial cells – the immune cells of the central nervous system – leading to dysregulation of glutamate metabolism. Glutamate is an excitatory neurotransmitter involved in anxiety, impaired cognition, excitable behaviours, aggression, and the neuropathology of schizophrenia
- Damage to glial cells triggers the release of pro-inflammatory chemicals that impact learning and memory
Impaired dopamine handling, glutamate dysregulation, and inflammatory cytokine production – all influenced by high UCB – can have a dramatic impact on mental health. In many individuals this manifests as anxiety, fatigue, and cognitive impairment.
Hormonal Imbalances – Oestrogen Dominance
Oestrogen-dominant symptoms and conditions are extremely common in Gilbert’s Syndrome, due to inadequate detoxification of oestrogen via the glucuronidation pathway. These can include:
- Heavy and/or painful periods
- PMS and PMDD
- Fibroids
- Endometriosis
- Low libido
- Oedema
- Difficulty losing weight
- Acne
Post-menopausal women may also carry a slightly increased risk of developing breast cancer.
The relationship between oestrogen metabolism, gut health, and hormonal imbalances is something I explore in depth across several related posts. The connections between copper toxicity and oestrogen dominance and histamine intolerance and oestrogen are particularly relevant here – and all three are tied to poor digestive function, gut dysbiosis, and leaky gut.
Men with Gilbert’s Syndrome regularly present with symptoms of low testosterone and impaired oestrogen metabolism, including:
- Low libido
- Erectile dysfunction
- Mood swings
- Hair loss
- Fatigue
- Loss of muscle mass
- Increased body fat
Testing and Diagnosis
A consistent pattern of high total bilirubin (unconjugated bilirubin) across repeated blood tests is the biggest indicator of Gilbert’s Syndrome. Anyone with a persistent pattern of greater than 15 umol/L – not just a one-off elevation – should consider this possibility.
A clearer picture can be obtained by separately testing direct bilirubin (also known as conjugated bilirubin) – the bilirubin that has gone through glucuronidation, which will appear within the normal range in Gilbert’s Syndrome patients.
The Royal College of Pathologists of Australia (RCPA) recommends testing both total and direct bilirubin. Where the diagnosis is uncertain, a fasting blood test alongside a non-fasting test can be useful – the fasting result should exceed the non-fasting level by more than 50%.
In practice, GPs rarely test beyond total bilirubin. Where total bilirubin is persistently above 15 umol/L, this is generally sufficient to indicate a compromised glucuronidation pathway.
Genetic testing for the UGT1A1 enzyme is available to confirm true Gilbert’s Syndrome, but the combination of persistently elevated bilirubin and consistent symptoms is typically enough to proceed with treatment.
If other serious causes of high bilirubin have been excluded – haemolytic anaemia, hepatitis, cirrhosis, blocked bile ducts due to gallstones – then Gilbert’s Syndrome is likely the correct diagnosis.
Treatment Strategies
Treating Gilbert’s Syndrome requires a holistic, multi-layered approach that supports glucuronidation, digestive health, the gut microbiome, intestinal integrity, and relevant dietary and lifestyle factors. Treatment should always be personalised based on pathology results, symptoms, and medical history. Always consult your doctor before stopping any medications.
Factors That Slow UGT Enzyme Function and Increase Bilirubin
- Alcohol
- Oestrogen – for example, the oral contraceptive pill (OCP) and hormone replacement therapy (HRT)
- Retinoids (Vitamin A) – high-dose Vitamin A supplements inhibit the UGT enzyme and are not recommended
- Medications – NSAIDs (e.g. ibuprofen), paracetamol, the oral contraceptive pill, many antidepressants, steroids, opiates, and testosterone replacement therapy
- Fasting – reduces UGT enzyme activity and bilirubin clearance. Breakfast is the most important meal of the day for Gilbert’s Syndrome patients, as gut motility and gastric emptying are fastest in the morning
- Low-fat diets – the absence of dietary fat increases bilirubin levels. Adequate beneficial fats in the diet are important
Stress and Exercise
Stress directly increases bilirubin levels, as does vigorous exercise. Stress management, nervous system regulation, and balancing physical exercise with restorative practices such as breathwork and yoga are all important.
Supplements to Support Glucuronidation
Discuss these with your practitioner:
- Calcium-D-Glucurate
- Broccoli Sprout (Sulforaphane)
- Glucomannan (Konjac)
- Zinc
- SAMe
- Magnesium
- B-Vitamins
- Herbal medicines – bile-stimulating and bitter herbs help increase bile flow, reduce gallbladder stagnation, and increase bilirubin output
Microbiome and Leaky Gut Support
- Fibre and prebiotics – help reduce bacterial species that produce beta-glucuronidase, support transit time, and stimulate the growth of beneficial bacteria that assist bilirubin clearance
- Intestinal permeability support – strain-specific probiotics, quercetin, glutamine, vitamin D, anti-inflammatory herbal medicines, EPA/DHA (omega-3), and zinc carnosine can all be helpful here
The Silver Lining: Gilbert’s Syndrome and Longevity
Discovering you have Gilbert’s Syndrome is not all bad news. Bilirubin is a major antioxidant that appears to protect DNA from damage, lengthen telomeres, and exert a significant anti-ageing effect.
People with Gilbert’s Syndrome have lower rates of cardiovascular disease, better glycaemic control in diabetes, reduced mortality in hereditary haemochromatosis, and lower rates of lung cancer and colon cancer.
The key is to actively support the glucuronidation pathway and gut health so you don’t experience the consequences of elevated UCB – while enjoying the protective benefits that come with it.
