Gilbert's Syndrome: Why Benign Does Not Mean Without Consequence
- 6 days ago
- 13 min read
You had a blood test. Your bilirubin came back mildly elevated. The result was flagged, and you were told it was Gilbert's syndrome. Nothing to worry about. No treatment required. A benign condition.
And then you went home and kept putting up with the nausea that comes and goes without explanation. The fatigue that descends sometimes for days. The periods that are heavier than they should be. The mood that shifts in the second half of your cycle and turns into intense anxiety. The digestive symptoms that have never been properly explained.
The connection between all of those things and Gilbert's syndrome is real. While the conventional framing of Gilbert's as benign is true - in that it doesn't cause liver damage, we also need to take seriously the lived experience of women seriously.
Benign means it does not damage the liver. It does not mean it has no consequences. For many women, the consequences are significant and the connection is never made.
What Gilbert's Syndrome Actually Is
Gilbert's syndrome is a common genetic variant affecting the UGT1A1 gene, which encodes an enzyme called UDP-glucuronosyltransferase 1A1. This enzyme governs a liver detoxification process called glucuronidation, one of the body's primary pathways for packaging substances for elimination. In Gilbert's syndrome, UGT1A1 activity is reduced, and bilirubin, which depends on this pathway for clearance, accumulates mildly in the bloodstream.
It affects an estimated five to ten percent of people of European descent, with higher prevalence in some other populations. The diagnosis is almost universally framed as benign and reassuring. Bilirubin is elevated but liver enzymes are normal. There is no liver damage and no increased risk of liver disease. Life expectancy is unaffected. No treatment is required.
All of that is accurate, as far as it goes. But what it does not address is what else the UGT1A1 enzyme is responsible for, and what accumulates when its activity is impaired.
The Problem With Stopping at Bilirubin
Glucuronidation is not a single-purpose pathway. The UGT1A1 enzyme that clears bilirubin also plays a significant role in clearing oestrogen, certain neurotransmitters and their metabolites, a range of medications and pharmaceutical compounds, and environmental toxins that enter the body from food, water, and personal care products.
When UGT1A1 activity is reduced, bilirubin rises because bilirubin is what gets measured. But the same reduction in enzyme activity affects everything else that competes for the same pathway. Oestrogen clearance is impaired. The metabolism of certain medications is slowed. The body's capacity to handle environmental toxin load through this pathway is reduced.
This is the piece of the Gilbert's syndrome picture that almost never makes it into the clinical conversation. Not because it is unknown, but because the focus on bilirubin as the only relevant downstream effect has dominated the framing of the condition for over a century.
A 2026 review published in ScienceDirect, examining novel insights into UGT1A1 dysfunction and Gilbert's syndrome on oestrogen metabolism, confirmed that the UGT1A1 enzyme is responsible for both bilirubin and oestrogen conjugation and elimination. The review noted that reduced UGT1A1 activity in Gilbert's syndrome could increase oestrogen levels and cited clinical studies reporting an increased risk of breast cancer associated with the UGT1A1 polymorphism (ScienceDirect, 2026).
Put simply: bilirubin and oestrogen compete for the same clearance enzyme. When that enzyme is impaired and bilirubin is elevated, oestrogen clearance is also impaired. The two processes are not independent.
Why Symptoms Feel Random and Why That Gets You Dismissed
One of the most frustrating aspects of Gilbert's syndrome is that symptoms fluctuate. They are not constant and predictable. They come and go in a way that makes them difficult to describe, difficult to track, and very easy for a doctor to minimise or attribute to stress, anxiety, or lifestyle.
This variability is not random. It is directly tied to what is driving bilirubin levels at any given time. Bilirubin rises with fasting or skipped meals, stress and cortisol elevation, illness or infection, poor sleep, vigorous exercise, dehydration, alcohol consumption, certain medications, and hormonal fluctuations across the menstrual cycle. In a low-stress week with regular meals and good sleep, symptoms may be mild or absent. In a week with disrupted sleep, skipped meals and a hectic schedule, symptoms can be significant.
The underlying enzyme impairment is constant. What varies is the demand being placed on it at any given time. When the system is not being heavily taxed, it copes. When it is, symptoms emerge. This explains why the same woman can feel fine one month and significantly unwell the next, why symptoms do not follow a pattern that is easy to explain, and why the connection between a mild blood test result and a cluster of seemingly unrelated symptoms is almost never made.
A 2025 study published in PubMed, using electronic health records from over 1.8 million UK patients, found that abdominal pain and fatigue were significantly more common in people with Gilbert's syndrome compared to matched controls. The researchers concluded that large-scale health data supports the existence of a pre-diagnostic symptom picture in Gilbert's syndrome that goes beyond jaundice, and that using such data could help better understand the symptoms of conditions with delayed diagnosis. The study confirmed that symptoms including nausea, fatigue, and abdominal pain were present at higher rates in Gilbert's syndrome patients than in the general population (PubMed / UCL, 2025).
This is significant. It means that the clinical picture of Gilbert's syndrome, in a large real-world population, includes fatigue, abdominal pain, and nausea at rates that are statistically elevated compared to controls. The conventional framing that these symptoms are coincidental or unrelated to the Gilbert's is directly contradicted by this data.
The symptoms feel random because the triggers are variable. The underlying impairment is constant. That distinction is what makes Gilbert's syndrome so easy to dismiss and so important to understand.
The Digestive System
Bilirubin is not only a waste product. It is directly involved in gut function. Unconjugated bilirubin affects bile acid metabolism, gut motility, and the composition of the gut microbiome. Elevated bilirubin in the gut environment alters the microbial balance and can impair the normal digestive processes that depend on adequate bile flow and healthy gut motility.
In women with Gilbert's syndrome this often presents as nausea, particularly in the morning or when fasted, a sensation of food sitting heavily for hours after eating, sluggish or unpredictable digestion, alternating bowel habits, and food intolerances that seem to shift over time. The gallbladder is also relevant: Gilbert's syndrome is associated with an increased risk of pigment gallstone disease, because elevated unconjugated bilirubin predisposes to gallstone formation. Gallbladder dysfunction adds its own digestive symptom layer, including right upper quadrant discomfort, nausea after fatty meals, and bloating.
These symptoms are frequently investigated as IBS, functional dyspepsia, or food intolerance in isolation. The Gilbert's note on the blood test, if it is noticed at all, is not considered part of the digestive picture. The connection is rarely made. But it should be.
The Oestrogen and Period Picture
For women, the impaired oestrogen clearance that follows from reduced UGT1A1 activity has direct consequences for hormonal health. Oestrogen that should be eliminated gets reactivated and recirculated rather than excreted. The result is a state of functional oestrogen dominance, meaning oestrogen is not necessarily being over-produced, but it is not being adequately cleared.
The symptoms of oestrogen dominance are well recognised. Heavy or painful periods, breast tenderness and cyclical breast pain, bloating and fluid retention in the premenstrual phase, mood changes and irritability in the luteal phase, conditions including endometriosis, uterine fibroids, and fibrocystic breast changes have all been associated with relative oestrogen excess. In women with Gilbert's syndrome, these symptoms may be driven not by hormonal imbalance in the conventional sense but by impaired clearance of hormones that are being produced in normal amounts.
This matters for treatment. Addressing oestrogen dominance symptoms in a woman with Gilbert's syndrome without understanding the underlying clearance impairment is likely to produce incomplete results. The oestrogen keeps accumulating because the pathway responsible for clearing it is not functioning at full capacity.
“What I find in clinical practice is that women with Gilbert’s syndrome often have a long history of oestrogen dominance symptoms that have been treated symptomatically without anyone asking why oestrogen clearance is impaired. Once we understand that the UGT1A1 impairment is the connecting thread, treatment becomes much more targeted. We work on reducing the overall glucuronidation burden, supporting gut health and the estrobolome, addressing nutritional gaps relevant to phase two detoxification, and making the lifestyle and dietary adjustments that reduce the demand on an already impaired pathway. The symptom picture often improves significantly when this is approached comprehensively.”
- Gemma Knaap, Naturopath (BHSc Naturopathy, Certified Natural Fertility Educator, Gut Microbiome Analyst) | Southernwood Apothecary & Clinic
Gilbert's Syndrome, Perimenopause, and HRT
The perimenopausal years introduce a particular challenge for women with Gilbert's syndrome that is almost never discussed in the clinical management of either condition.
In perimenopause, oestrogen becomes erratic, swinging between relative excess and relative deficiency before ultimately declining. Progesterone declines first and more consistently. The result is a period of hormonal instability that is often characterised by relative oestrogen dominance, precisely the hormonal state that Gilbert's syndrome predisposes women to through impaired clearance.
For women in perimenopause with Gilbert's syndrome, this creates a compounding picture. The hormonal fluctuations of the transition are amplified by the impaired ability to clear oestrogen through glucuronidation. Heavy perimenopausal bleeding, worsening premenstrual mood disruption, breast tenderness, and cyclical symptom exacerbation may all be more pronounced than they would be in a woman without the UGT1A1 impairment.
The HRT picture adds another layer of complexity. Many of the oestrogen compounds used in hormone replacement therapy, including both oral and some transdermal oestrogens, are metabolised through glucuronidation. In a woman with reduced UGT1A1 activity, HRT oestrogen may be cleared more slowly than expected, resulting in higher circulating levels from a standard dose. This can produce oestrogen excess symptoms, headaches, breast tenderness, bloating, and mood changes, at doses that are well tolerated by most women.
It can also mean that the estrobolome-driven reactivation of oestrogen, where gut bacteria deconjugate and recirculate oestrogen that has already been packaged for elimination, operates at a higher baseline in women with Gilbert's syndrome, compounding the effect of exogenous oestrogen from HRT.
This does not mean women with Gilbert's syndrome cannot or should not use HRT. It means that supporting gut health, the estrobolome, and oestrogen clearance pathways alongside HRT is clinically relevant rather than optional.
Medication Sensitivity
The UGT1A1 pathway is responsible for metabolising a significant number of pharmaceutical medications, including the oral contraceptive pill, certain antibiotics, paracetamol, ibuprofen and other NSAIDs, and a range of other medications. In women with Gilbert's syndrome, these compounds are cleared more slowly than in the general population, which can produce stronger or more prolonged effects from standard doses and can worsen symptoms by adding to the overall glucuronidation burden.
This has practical implications. Women with Gilbert's syndrome who feel unusually sensitive to medications, who experience side effects at doses that others tolerate well, or who find that hormonal contraceptives produce more pronounced effects than expected, are likely experiencing the consequences of impaired drug metabolism through the UGT1A1 pathway. This is a known feature of Gilbert's syndrome, acknowledged in the research literature, and yet it is rarely communicated to patients at the time of diagnosis.
What Supporting Gilbert's Syndrome Actually Looks Like
There is no pharmaceutical treatment for Gilbert's syndrome and none is needed for the bilirubin elevation itself. What is needed is an understanding of the glucuronidation burden and a strategy for reducing it, alongside support for the downstream consequences of impaired clearance. From a naturopathic perspective this involves several areas:
• Gut health and the estrobolome: the gut microbiome directly influences oestrogen recirculation via beta-glucuronidase activity. Addressing dysbiosis reduces the amount of already-cleared oestrogen that gets reactivated and returned to circulation.
• Nutritional support for phase two detoxification: glucuronidation depends on adequate levels of glucuronic acid, magnesium, B vitamins, and antioxidant nutrients. Nutritional deficiencies that compromise the pathway further can be identified and addressed.
• Dietary factors that reduce glucuronidation burden: cruciferous vegetables support the liver detox pathways that feed into glucuronidation. Reducing dietary and environmental oestrogen load reduces the demand on an already impaired pathway.
• Avoiding unnecessary medications where possible: minimising the use of compounds that compete for the UGT1A1 pathway reduces the burden on a system that is already working at reduced capacity.
• Meal timing and fasting: fasting raises bilirubin in Gilbert's syndrome. Eating regular meals, avoiding long gaps between eating, and not skipping breakfast significantly reduces the bilirubin load and associated symptoms.
• Stress management: cortisol elevation is a direct trigger for bilirubin rises and symptom exacerbation in Gilbert's syndrome. Supporting the stress response is not peripheral to managing this condition.
• HRT and hormonal support: for women in perimenopause using HRT, understanding the glucuronidation picture allows for more targeted dose selection, monitoring, and adjunctive support to optimise the outcome.
You Deserve Better
If you have Gilbert's syndrome and a symptom cluster that has never been properly explained or connected, the problem is not that the symptoms are imagined or coincidental. The problem is that the conventional framing of Gilbert's syndrome as a benign, asymptomatic condition has meant that the downstream consequences of UGT1A1 impairment have not been part of the conversation.
The research supports a more nuanced picture. Fatigue, abdominal pain, and nausea are significantly more prevalent in people with Gilbert's syndrome than in the general population. Oestrogen clearance is impaired through the same enzyme that fails to clear bilirubin. Medication metabolism is affected. And for women in perimenopause, the combination of erratic oestrogen, declining progesterone, and impaired clearance capacity creates a hormonal picture that is more complex and more symptomatic than either condition would produce alone.
You deserve a practitioner who will look at all of this together. Who will take the Gilbert's note on your blood test seriously as a piece of a larger picture rather than a reassuring footnote. Who will connect the digestive symptoms, the period problems, the mood shifts, and the fatigue rather than investigating and managing each of them in isolation.
That is what I do. In person consultations are available at my Albany clinic and can be booked online. Telehealth consultations are available from anywhere in Australia.
Frequently Asked Questions
What is Gilbert's syndrome?
Gilbert's syndrome is a common genetic variant affecting the UGT1A1 gene, which governs a liver detoxification process called glucuronidation. It results in mildly elevated bilirubin in the blood because bilirubin is not being efficiently cleared by the impaired enzyme. It affects approximately five to ten percent of people of European descent. It does not cause liver damage and is almost universally described as benign and asymptomatic in conventional medical settings. However, the UGT1A1 enzyme also clears oestrogen, certain medications, and other compounds, meaning the consequences of its impairment extend beyond bilirubin.
Why do Gilbert's syndrome symptoms fluctuate so much?
The underlying UGT1A1 enzyme impairment in Gilbert's syndrome is constant, but the demand placed on it varies. Bilirubin rises with fasting, stress, poor sleep, illness, vigorous exercise, alcohol, and hormonal fluctuations. In periods of lower demand, symptoms may be mild or absent. In periods of higher demand, symptoms can be significant. This variability is one of the primary reasons Gilbert's syndrome symptoms are attributed to stress or anxiety rather than connected to the underlying condition. A 2025 UCL study using data from over 1.8 million UK patients confirmed that fatigue and abdominal pain were significantly more prevalent in people with Gilbert's syndrome than in matched controls, contradicting the conventional framing that these symptoms are coincidental.
Does Gilbert's syndrome affect oestrogen levels?
Research published in 2026 confirmed that the UGT1A1 enzyme is responsible for clearing both bilirubin and oestrogen, and that the two compete for the same enzyme. In vitro studies demonstrate reciprocal competitive inhibition between bilirubin and oestrogens, meaning elevated bilirubin reduces oestrogen clearance capacity. For women with Gilbert's syndrome, this can produce a state of functional oestrogen dominance, where oestrogen is not necessarily over-produced but is not being adequately cleared, driving symptoms including heavy periods, breast tenderness, and cyclical mood changes.
Can Gilbert's syndrome affect how HRT works?
Yes. Many oestrogen compounds used in hormone replacement therapy are metabolised through the glucuronidation pathway governed by UGT1A1. In women with reduced UGT1A1 activity, HRT oestrogen may be cleared more slowly than expected, resulting in higher circulating levels from a standard dose and producing oestrogen excess symptoms at doses that are well tolerated by most women. Additionally, the gut microbiome's role in oestrogen recirculation via the estrobolome may operate at a higher baseline in women with Gilbert's syndrome, compounding the effect of exogenous oestrogen. This means that supporting gut health and oestrogen clearance pathways alongside HRT is important for women with Gilbert's syndrome.
Why does Gilbert's syndrome cause digestive symptoms?
Bilirubin is directly involved in gut function, affecting bile acid metabolism, gut motility, and the composition of the gut microbiome. Elevated unconjugated bilirubin in Gilbert's syndrome can impair normal digestive processes, contributing to nausea, sluggish digestion, bloating, and altered bowel habits. Gilbert's syndrome is also associated with an increased risk of pigment gallstone disease, which adds its own digestive symptom layer. The 2025 UCL study confirmed that abdominal pain and nausea were significantly more common in people with Gilbert's syndrome than in the general population in the years before diagnosis.
Does Gilbert's syndrome affect medication metabolism?
Yes. The UGT1A1 pathway metabolises a range of pharmaceutical compounds including the oral contraceptive pill, paracetamol, ibuprofen, certain antibiotics, and others. Women with Gilbert's syndrome clear these medications more slowly than the general population, which can produce stronger or more prolonged effects from standard doses and can worsen symptoms by increasing the overall burden on an already impaired pathway. This is a recognised feature of Gilbert's syndrome in the research literature and is why women with the condition often report unusual sensitivity to medications and hormonal contraceptives.
Can a naturopath help with Gilbert's syndrome?
Yes. A naturopathic approach to Gilbert's syndrome focuses on reducing the overall glucuronidation burden, supporting gut health and the estrobolome, addressing nutritional gaps relevant to phase two liver detoxification, and managing the downstream consequences of impaired oestrogen and toxin clearance. This includes dietary strategies that support liver detoxification, meal timing recommendations to reduce bilirubin fluctuations, gut microbiome support to reduce oestrogen recirculation, and hormonal support where oestrogen dominance is part of the clinical picture. For women in perimenopause using HRT, naturopathic support can help optimise the response to treatment by addressing the clearance impairment that affects how HRT oestrogen is metabolised. In person consultations are available in Albany WA and Telehealth consultations are available across Australia.
About the Author
Gemma Knaap is a naturopath specialising in women's hormonal health, gut health, fertility, and reproductive wellbeing. She holds a Bachelor of Health Science in Naturopathy and is a Certified Natural Fertility Educator and Gut Microbiome Analyst. In person consultations are available at her Albany, WA clinic. Telehealth consultations are available across Australia.
References
ScienceDirect. (2026). Novel insights into UDP-glucuronosyltransferase 1A1 dysfunction and Gilbert's syndrome on estrogen metabolism and breast cancer. https://www.sciencedirect.com/science/article/pii/S1040842826001526
PubMed / UCL. (2025). Prevalence and Data-Driven Exploration of Pre-Diagnostic Symptoms and Features of Gilbert's Syndrome in the UK Primary Care Population. https://pubmed.ncbi.nlm.nih.gov/40904555/
Journal of Hepatology. (2023). Gilbert's syndrome revisited. https://www.journal-of-hepatology.eu/article/S0168-8278(23)00421-X/fulltext
PMC. (2025). Gilbert's syndrome: The good, the bad and the ugly. https://pmc.ncbi.nlm.nih.gov/articles/PMC11866151/
Frontiers in Pharmacology. (2024). Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials. https://doi.org/10.3389/fphar.2024.1389968
ResearchGate. (2012). Gilbert syndrome: The UGT1A1*28 Promoter Polymorphism as a Biomarker of Multifactorial Diseases and Drug Metabolism. https://www.researchgate.net/publication/221981236
Cleveland Clinic. (2023). Gilbert's Syndrome: Symptoms, Causes, Tests and Treatment. https://my.clevelandclinic.org/health/diseases/17661-gilberts-syndrome
Berkeley Herbal Center. Gilbert's Syndrome: A Look at a Common Liver Enzyme Disorder. https://www.berkeleyherbalcenter.org/wp-content/uploads/2020/05/Furrow_C_Gilberts_Syndrome.pdf
Comments