⚙

Pathophysiology

3

Reduced UGT1A1 Activity and Impaired Bilirubin Glucuronidation

The UGT1A1 enzyme in hepatocytes conjugates unconjugated (indirect) bilirubin with glucuronic acid, making it water-soluble for biliary excretion. In Gilbert's syndrome, reduced UGT1A1 activity (approximately 30% of normal) leads to accumulation of unconjugated bilirubin in the blood. The most common cause in Western populations is a homozygous (TA)7TAA repeat (UGT1A1*28 allele) in the TATAA box of the UGT1A1 promoter, which reduces transcription. In Asian populations, missense variants in the UGT1A1 coding region (e.g., Gly71Arg / UGT1A1*6) are more prevalent. Gilbert's syndrome is the most prevalent (2-19% in population studies) and mildest of the hereditary unconjugated hyperbilirubinaemia syndromes.

Hepatocyte link

UGT1A1 link

Bilirubin conjugation link ↓ DECREASED

glucuronosyltransferase activity link ↓ DECREASED

Downstream

Unconjugated Bilirubin Reduced hepatic bilirubin glucuronidation leaves a larger circulating unconjugated bilirubin pool.

Mild Unconjugated Hyperbilirubinemia Impaired UGT1A1-mediated bilirubin conjugation is the proximal mechanism producing the obligate biochemical phenotype.

Fasting- and Stress-Induced Bilirubin Elevation Reduced UGT1A1 activity creates susceptibility to fasting-provoked bilirubin elevations in homozygous UGT1A1*28 carriers.

Bilirubin Antioxidant and Pleiotropic Effects The mild increase in circulating bilirubin caused by reduced clearance is the exposure underlying the antioxidant and pleiotropic-effect hypotheses.

Show evidence (3 references)

PMID:7565971 SUPPORT Human Clinical

"Hepatic glucuronidating activity, essential for efficient biliary excretion of bilirubin, is reduced to about 30 percent of normal."

The Bosma 1995 NEJM paper demonstrates that UGT1A1 enzyme activity is substantially reduced in Gilbert's syndrome, confirming the enzymatic basis of the condition.

PMID:7565971 SUPPORT Human Clinical

"These patients were homozygous for two extra bases (TA) in the TATAA element of the 5' promoter region of the gene (A(TA)7TAA rather than the normal A(TA)6TAA)."

Identifies the (TA)7 promoter repeat as the molecular basis for reduced UGT1A1 expression in Western populations.

PMID:9435989 SUPPORT Other

"Gilbert's syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon."

Clarke 1997 confirms population prevalence (2-19%) and the promoter TA insertion as the principal molecular cause.

Fasting- and Stress-Induced Bilirubin Elevation

Bilirubin levels in Gilbert's syndrome fluctuate and are exacerbated by physiological stressors such as fasting, dehydration, intercurrent illness, physical exertion, and menstruation. Fasting reduces caloric intake and increases fatty acid oxidation, which competes with bilirubin for hepatic uptake and conjugation pathways. These triggers can precipitate symptomatic jaundice in otherwise mildly affected individuals. A 24-hour fasting test is used diagnostically to provoke bilirubin elevation in suspected cases.

Bilirubin hepatic transport link ⚠ ABNORMAL

Downstream

Jaundice Trigger-related bilirubin elevations can cross the threshold for visible intermittent jaundice.

Jaundice-Associated Gastrointestinal Symptoms Jaundice episodes in Gilbert syndrome can be accompanied by abdominal pain, dyspepsia, or appetite loss through incompletely resolved symptom-generating intermediates.

Show evidence (2 references)

PMID:8596320 SUPPORT Human Clinical

"14 volunteers underwent a 24 h fasting test to see if they had Gilbert's syndrome, and all four positives had the 7/7 genotype."

Demonstrates that fasting precipitates jaundice specifically in homozygous UGT1A1*28 (7/7) carriers, consistent with the fasting-triggering mechanism in Gilbert's syndrome.

PMID:30717703 SUPPORT Human Clinical

"Risk factors for clinical jaundice included general anesthesia, pregnancy, fasting"

A longitudinal adult cohort identifies fasting and other physiologic stressors as risk factors for clinical jaundice episodes.

Bilirubin Antioxidant and Pleiotropic Effects

Unconjugated bilirubin is a potent lipid-soluble antioxidant that scavenges peroxyl radicals in vitro at physiologically relevant oxygen concentrations. Observational epidemiological studies have reported inverse associations between serum bilirubin and cardiovascular disease risk, leading to hypotheses of systemic protection in Gilbert's syndrome carriers. However, Mendelian randomization studies using the UGT1A1*28 locus as an instrument for genetically raised bilirubin find no causal cardiovascular benefit, suggesting the observational associations are confounded. The clinical significance of bilirubin's antioxidant capacity in vivo thus remains debated.

Show evidence (3 references)

PMID:3029864 SUPPORT In Vitro

"bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes."

Foundational Science paper demonstrating bilirubin's free radical scavenging capacity, providing the mechanistic basis for hypothesised antioxidant protection in Gilbert's syndrome.

PMID:18343383 PARTIAL Other

"Serum bilirubin has been shown to be inversely related to cardiovascular disease (CVD) in both retrospective and prospective studies."

Observational data are consistent with CVD protection, but causality remains unproven; hence PARTIAL support only.

PMID:37456363 REFUTE Human Clinical

"Evidence from the analyses of genetic data suggests that bilirubin has no likely causal role in protection from cardiovascular disease, chronic obstructive pulmonary disease, or other key healthcare outcomes and therefore represents a poor target for therapeutic intervention for these outcomes."

Large-scale Mendelian randomization in UK Biobank (n=463,060) shows that genetically raised bilirubin via the Gilbert genotype confers no causal cardiovascular protection, refuting the antioxidant-protection hypothesis.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

3

Digestive 1

Jaundice FREQUENT Jaundice (HP:0000952)

Show evidence (2 references)

PMID:8596320 SUPPORT Human Clinical

"This common mild hyperbilirubinaemia sometimes presents as an intermittent jaundice."

Directly establishes jaundice as a clinical presentation of the unconjugated hyperbilirubinaemia in Gilbert's syndrome.

PMID:8596320 SUPPORT Human Clinical

"Individuals in the population with the 7/7 genotype had significantly higher bilirubin concentrations than those who had the 6/7 or 6/6 genotype."

Demonstrates that homozygous UGT1A1*28 (7/7) carriers have the highest bilirubin levels, making them most susceptible to intermittent jaundice.

Metabolism 1

Mild Unconjugated Hyperbilirubinemia OBLIGATE Unconjugated hyperbilirubinemia (HP:0008282)

Show evidence (1 reference)

PMID:7565971 SUPPORT Human Clinical

"People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis."

Classic description from the landmark NEJM paper establishing unconjugated hyperbilirubinemia as the obligate phenotype.

Constitutional 1

Jaundice-Associated Gastrointestinal Symptoms FREQUENT Abdominal pain (HP:0002027)

Show evidence (1 reference)

PMID:30717703 SUPPORT Human Clinical

"jaundice was associated with abdominal pain, dyspepsia or loss of appetite in 54 (53.465%) subjects."

This longitudinal study directly supports abdominal pain, dyspepsia, or appetite loss during jaundice episodes and provides a frequency compatible with the FREQUENT band.

🧬

Genetic Associations

2

UGT1A1*28 Promoter Polymorphism (Causative)

Autosomal recessive

Show evidence (3 references)

PMID:7565971 SUPPORT Human Clinical

"Reduced expression of bilirubin UDP-glucuronosyltransferase 1 due to an abnormality in the promoter region of the gene for this enzyme appears to be necessary for Gilbert's syndrome but not sufficient for the complete manifestation of the syndrome."

Bosma 1995 established the (TA)7 promoter polymorphism as required but not sufficient for full phenotypic expression, explaining incomplete penetrance in heterozygotes.

PMID:8596320 SUPPORT Human Clinical

"The frequency of the 7/7 genotype in this eastern Scottish population was 10-13%."

Provides population frequency of UGT1A1*28 homozygosity in a Western European population, consistent with Gilbert's syndrome prevalence.

PMID:9435989 SUPPORT Other

"Gilbert's syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon."

Clarke 1997 places UGT1A1*28 in the context of the full spectrum of UGT1 defects and confirms its role as the principal cause of Gilbert's syndrome.

UGT1A1*6 Missense Variant (Gly71Arg) (Causative)

Autosomal recessive

Show evidence (2 references)

PMID:10353933 SUPPORT Human Clinical

"a G-->A transition at nucleotide 211 caused arginine to replace glycine at position 71 of corresponding protein product (G71R)."

Maruo 1999 identified the G71R mutation and showed it is associated with hyperbilirubinemia in Japanese neonates, establishing UGT1A1*6 as a relevant variant in East Asian populations.

PMID:15304120 SUPPORT Human Clinical

"The genetic basis of hyperbilirubinemia appears to be different between the Japanese and Caucasian populations."

Takeuchi 2004 confirmed the ethnic divergence in UGT1A1 variant spectrum, with coding variants like G71R being more prevalent in Japanese patients versus the promoter TA-repeat polymorphism in Caucasians.

💊

Treatments

2

Reassurance and Lifestyle Guidance

Action: supportive care MAXO:0000950

Gilbert's syndrome is benign and requires no specific pharmacological treatment. Management consists of reassurance, avoidance of prolonged fasting, adequate hydration, and recognition of triggers (e.g., illness, stress, strenuous exercise). Patients should be counselled to inform healthcare providers of their UGT1A1 genotype, as this affects metabolism of certain drugs (e.g., irinotecan).

Mechanism Target:

MODULATES Fasting- and Stress-Induced Bilirubin Elevation — Avoiding prolonged fasting and planning around physiologic stressors reduces exposure to settings that provoke clinical jaundice in Gilbert's syndrome.

Show evidence (1 reference)

PMID:30717703 SUPPORT Human Clinical

"Risk factors for clinical jaundice included general anesthesia, pregnancy, fasting"

Human cohort evidence identifies fasting and other stressors as risk factors, supporting lifestyle guidance as a mechanism-directed management step.

Show evidence (2 references)

PMID:37390966 SUPPORT Other

"Gilbert's syndrome, also known as benign hyperbilirubinaemia, was described more than 100 years ago."

The Vitek & Tiribelli 2023 review confirms the longstanding recognition of Gilbert's syndrome as a benign condition, supporting reassurance as the primary therapeutic approach.

PMID:30717703 SUPPORT Human Clinical

"Screening, counseling, monitoring and individualized health care are recommended for subjects with GS in the setting of anesthesia, pregnancy, treatment with DAAs, deliveries, surgery and weight loss plans."

Human longitudinal data support counseling, monitoring, and individualized guidance around common jaundice-triggering settings.

UGT1A1 Genotyping Prior to Irinotecan Therapy

Action: genetic testing MAXO:0000127

Carriers of UGT1A1*28 (and UGT1A1*6 in Asian patients) have significantly reduced capacity to glucuronidate SN-38, the active metabolite of irinotecan. This leads to increased SN-38 exposure and greater susceptibility to irinotecan-induced severe neutropenia and diarrhoea. Genetic testing before initiating irinotecan is classified as 'essential' by international pharmacogenomics guidelines. Poor metabolisers (homozygous or compound heterozygous) should receive a 70% starting dose.

Show evidence (3 references)

PMID:11990381 SUPPORT Human Clinical

"screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity."

Iyer 2002 prospective pharmacogenetic study demonstrated that UGT1A1*28 genotype predicts reduced SN-38 glucuronidation and severe irinotecan toxicity, establishing the clinical rationale for pre-treatment testing.

PMID:36443464 SUPPORT Other

"Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity."

The DPWG 2023 guideline endorses UGT1A1 variant testing to optimize irinotecan starting dose and prevent severe toxicity.

PMID:36443464 SUPPORT Other

"UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment."

DPWG classification of UGT1A1 testing as 'essential' elevates this to a mandatory pre-treatment test, not an optional pharmacogenomics screen.

🔬

Biochemical Markers

1

Unconjugated Bilirubin (INCREASED)

Context: Serum unconjugated fraction elevated; conjugated bilirubin and liver enzymes (ALT, AST, ALP) remain within normal limits. Typically 1.2-3 mg/dL in Gilbert's syndrome.

Pathograph Readouts

Readout Of Reduced UGT1A1 Activity and Impaired Bilirubin Glucuronidation Positive Diagnostic

Elevated unconjugated bilirubin reports the reduced hepatic bilirubin glucuronidation that defines Gilbert's syndrome.

Show evidence (1 reference)

PMID:7565971 SUPPORT Human Clinical

"People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis. Hepatic glucuronidating activity, essential for efficient biliary excretion of bilirubin, is reduced to about 30 percent of normal."

Human clinical evidence ties the unconjugated bilirubin readout to the reduced hepatic glucuronidation mechanism.

Readout Of Fasting- and Stress-Induced Bilirubin Elevation Positive Monitoring

Serial unconjugated bilirubin captures trigger-sensitive bilirubin elevations during fasting, illness, pregnancy, surgery, or other stressors.

Show evidence (1 reference)

PMID:8596320 SUPPORT Human Clinical

"Individuals in the population with the 7/7 genotype had significantly higher bilirubin concentrations than those who had the 6/7 or 6/6 genotype. 14 volunteers underwent a 24 h fasting test to see if they had Gilbert's syndrome, and all four positives had the 7/7 genotype."

Human fasting-provocation evidence supports bilirubin as a monitoring readout of trigger-sensitive Gilbert physiology.

Show evidence (2 references)

PMID:7565971 SUPPORT Human Clinical

"People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis."

Confirms selectively elevated unconjugated bilirubin as the hallmark biochemical finding, with normal conjugated fraction and liver function.

PMID:26250421 SUPPORT Human Clinical

"Serum bilirubin concentrations of typical CN-2, intermediate group, and typical GS are respectively 12.9 ± 5.1, 5.2 ± 2.2, and 2.8 ± 1.1 mg/dL."

Provides quantitative bilirubin values for typical Gilbert's syndrome (2.8 ± 1.1 mg/dL), confirming mild elevation as the expected degree.

{ }

Source YAML

click to show

name: Gilbert's Syndrome
creation_date: "2026-03-17T15:29:38Z"
updated_date: "2026-05-19T22:27:03Z"
category: Mendelian
description: >-
  A common, benign inherited condition characterized by mild, intermittent
  unconjugated hyperbilirubinemia in the absence of hemolysis or liver disease.
  Caused by reduced hepatic UGT1A1 enzyme activity, impairing bilirubin
  glucuronidation. The most prevalent cause in Western populations is a TA-repeat
  promoter polymorphism (UGT1A1*28) that reduces UGT1A1 transcription; in East
  Asian populations the UGT1A1*6 (Gly71Arg) coding variant predominates. No
  specific pharmacological treatment is required, but carriers must be identified
  before irinotecan chemotherapy to prevent severe toxicity.
disease_term:
  preferred_term: Gilbert's syndrome
  term:
    id: MONDO:0007745
    label: Gilbert syndrome
parents:
- Liver Disease
- Inherited Metabolic Disorder
prevalence:
- population: Population studies
  percentage: 2-19
  notes: >-
    Reported prevalence varies substantially by ancestry and ascertainment, but
    Gilbert's syndrome is common in the general population rather than an
    ultra-rare condition.
  evidence:
  - reference: PMID:9435989
    reference_title: "Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gilbert's syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon."
    explanation: Review abstract summarizes the prevalence range reported across population studies.
pathophysiology:
- name: Reduced UGT1A1 Activity and Impaired Bilirubin Glucuronidation
  description: >-
    The UGT1A1 enzyme in hepatocytes conjugates unconjugated (indirect) bilirubin
    with glucuronic acid, making it water-soluble for biliary excretion. In
    Gilbert's syndrome, reduced UGT1A1 activity (approximately 30% of normal)
    leads to accumulation of unconjugated bilirubin in the blood. The most common
    cause in Western populations is a homozygous (TA)7TAA repeat (UGT1A1*28
    allele) in the TATAA box of the UGT1A1 promoter, which reduces transcription.
    In Asian populations, missense variants in the UGT1A1 coding region
    (e.g., Gly71Arg / UGT1A1*6) are more prevalent. Gilbert's syndrome is the
    most prevalent (2-19% in population studies) and mildest of the hereditary
    unconjugated hyperbilirubinaemia syndromes.
  genes:
  - preferred_term: UGT1A1
    term:
      id: hgnc:12530
      label: UGT1A1
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Bilirubin conjugation
    modifier: DECREASED
    term:
      id: GO:0006789
      label: bilirubin conjugation
  chemical_entities:
  - preferred_term: unconjugated bilirubin
    term:
      id: CHEBI:16990
      label: bilirubin IXalpha
    modifier: INCREASED
  molecular_functions:
  - preferred_term: glucuronosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0015020
      label: glucuronosyltransferase activity
  evidence:
  - reference: PMID:7565971
    reference_title: "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic glucuronidating activity, essential for efficient biliary excretion of bilirubin, is reduced to about 30 percent of normal."
    explanation: >-
      The Bosma 1995 NEJM paper demonstrates that UGT1A1 enzyme activity is
      substantially reduced in Gilbert's syndrome, confirming the enzymatic
      basis of the condition.
  - reference: PMID:7565971
    reference_title: "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients were homozygous for two extra bases (TA) in the TATAA element of the 5' promoter region of the gene (A(TA)7TAA rather than the normal A(TA)6TAA)."
    explanation: >-
      Identifies the (TA)7 promoter repeat as the molecular basis for reduced
      UGT1A1 expression in Western populations.
  - reference: PMID:9435989
    reference_title: "Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gilbert's syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon."
    explanation: >-
      Clarke 1997 confirms population prevalence (2-19%) and the promoter TA
      insertion as the principal molecular cause.
  downstream:
  - target: Unconjugated Bilirubin
    description: >-
      Reduced hepatic bilirubin glucuronidation leaves a larger circulating
      unconjugated bilirubin pool.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7565971
      reference_title: "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia
        in the absence of liver disease or overt hemolysis. Hepatic glucuronidating
        activity, essential for efficient biliary excretion of bilirubin, is reduced
        to about 30 percent of normal.
      explanation: >-
        The same clinical abstract links reduced hepatic glucuronidating
        activity to chronic unconjugated hyperbilirubinemia.
  - target: Mild Unconjugated Hyperbilirubinemia
    description: >-
      Impaired UGT1A1-mediated bilirubin conjugation is the proximal mechanism
      producing the obligate biochemical phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7565971
      reference_title: "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia
        in the absence of liver disease or overt hemolysis. Hepatic glucuronidating
        activity, essential for efficient biliary excretion of bilirubin, is reduced
        to about 30 percent of normal.
      explanation: >-
        Establishes reduced bilirubin glucuronidation and the resulting
        unconjugated hyperbilirubinemia in affected people.
  - target: Fasting- and Stress-Induced Bilirubin Elevation
    description: >-
      Reduced UGT1A1 activity creates susceptibility to fasting-provoked
      bilirubin elevations in homozygous UGT1A1*28 carriers.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - UGT1A1*28 homozygous genotype and reduced hepatic bilirubin UGT activity
    evidence:
    - reference: PMID:8596320
      reference_title: "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Individuals in the population with the 7/7 genotype had significantly higher
        bilirubin concentrations than those who had the 6/7 or 6/6 genotype. 14 volunteers
        underwent a 24 h fasting test to see if they had Gilbert's syndrome, and all
        four positives had the 7/7 genotype.
      explanation: >-
        Links UGT1A1*28 homozygosity to higher bilirubin and positive
        fasting-provocation testing.
  - target: Bilirubin Antioxidant and Pleiotropic Effects
    description: >-
      The mild increase in circulating bilirubin caused by reduced clearance is
      the exposure underlying the antioxidant and pleiotropic-effect hypotheses.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased serum unconjugated bilirubin
    evidence:
    - reference: PMID:18343383
      reference_title: "Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Such individuals have decreased hepatic bilirubin UDP-glucuronosyltransferase
        activity, decreased bilirubin clearance, and increased serum bilirubin concentrations.
      explanation: >-
        Review-level evidence explicitly connects Gilbert syndrome/UGT1A1*28 to
        reduced bilirubin clearance and increased serum bilirubin.
- name: Fasting- and Stress-Induced Bilirubin Elevation
  description: >-
    Bilirubin levels in Gilbert's syndrome fluctuate and are exacerbated by
    physiological stressors such as fasting, dehydration, intercurrent illness,
    physical exertion, and menstruation. Fasting reduces caloric intake and
    increases fatty acid oxidation, which competes with bilirubin for hepatic
    uptake and conjugation pathways. These triggers can precipitate symptomatic
    jaundice in otherwise mildly affected individuals. A 24-hour fasting test
    is used diagnostically to provoke bilirubin elevation in suspected cases.
  biological_processes:
  - preferred_term: Bilirubin hepatic transport
    modifier: ABNORMAL
    term:
      id: GO:0015723
      label: bilirubin transport
  chemical_entities:
  - preferred_term: unconjugated bilirubin
    term:
      id: CHEBI:16990
      label: bilirubin IXalpha
    modifier: INCREASED
  evidence:
  - reference: PMID:8596320
    reference_title: "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "14 volunteers underwent a 24 h fasting test to see if they had Gilbert's syndrome, and all four positives had the 7/7 genotype."
    explanation: >-
      Demonstrates that fasting precipitates jaundice specifically in homozygous
      UGT1A1*28 (7/7) carriers, consistent with the fasting-triggering mechanism
      in Gilbert's syndrome.
  - reference: PMID:30717703
    reference_title: "The frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome: a longitudinal study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk factors for clinical jaundice included general anesthesia, pregnancy, fasting"
    explanation: >-
      A longitudinal adult cohort identifies fasting and other physiologic
      stressors as risk factors for clinical jaundice episodes.
  downstream:
  - target: Jaundice
    description: >-
      Trigger-related bilirubin elevations can cross the threshold for visible
      intermittent jaundice.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Transient unconjugated hyperbilirubinemia
    evidence:
    - reference: PMID:8596320
      reference_title: "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This common mild hyperbilirubinaemia sometimes presents as an intermittent jaundice."
      explanation: >-
        Supports intermittent jaundice as the clinical expression of mild
        hyperbilirubinemia in Gilbert syndrome.
  - target: Jaundice-Associated Gastrointestinal Symptoms
    description: >-
      Jaundice episodes in Gilbert syndrome can be accompanied by abdominal
      pain, dyspepsia, or appetite loss through incompletely resolved
      symptom-generating intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Jaundice attack and associated symptom complex
    evidence:
    - reference: PMID:30717703
      reference_title: "The frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome: a longitudinal study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "jaundice was associated with abdominal pain, dyspepsia or loss of appetite in 54 (53.465%) subjects."
      explanation: >-
        The cohort reports gastrointestinal symptoms associated with jaundice
        episodes in more than half of Gilbert syndrome subjects.
- name: Bilirubin Antioxidant and Pleiotropic Effects
  description: >-
    Unconjugated bilirubin is a potent lipid-soluble antioxidant that scavenges
    peroxyl radicals in vitro at physiologically relevant oxygen concentrations.
    Observational epidemiological studies have reported inverse associations
    between serum bilirubin and cardiovascular disease risk, leading to hypotheses
    of systemic protection in Gilbert's syndrome carriers. However, Mendelian
    randomization studies using the UGT1A1*28 locus as an instrument for
    genetically raised bilirubin find no causal cardiovascular benefit, suggesting
    the observational associations are confounded. The clinical significance of
    bilirubin's antioxidant capacity in vivo thus remains debated.
  evidence:
  - reference: PMID:3029864
    reference_title: "Bilirubin is an antioxidant of possible physiological importance."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes."
    explanation: >-
      Foundational Science paper demonstrating bilirubin's free radical
      scavenging capacity, providing the mechanistic basis for hypothesised
      antioxidant protection in Gilbert's syndrome.
  - reference: PMID:18343383
    reference_title: "Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Serum bilirubin has been shown to be inversely related to cardiovascular disease (CVD) in both retrospective and prospective studies."
    explanation: >-
      Observational data are consistent with CVD protection, but causality
      remains unproven; hence PARTIAL support only.
  - reference: PMID:37456363
    reference_title: "Effect of bilirubin and Gilbert syndrome on health: cohort analysis of observational, genetic, and Mendelian randomisation associations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence from the analyses of genetic data suggests that bilirubin has no likely causal role in protection from cardiovascular disease, chronic obstructive pulmonary disease, or other key healthcare outcomes and therefore represents a poor target for therapeutic intervention for these outcomes."
    explanation: >-
      Large-scale Mendelian randomization in UK Biobank (n=463,060) shows that
      genetically raised bilirubin via the Gilbert genotype confers no causal
      cardiovascular protection, refuting the antioxidant-protection hypothesis.
phenotypes:
- name: Mild Unconjugated Hyperbilirubinemia
  category: Biochemical
  frequency: OBLIGATE
  description: >-
    Serum unconjugated (indirect) bilirubin is chronically or intermittently
    elevated, typically 1.2-3 mg/dL (20-50 micromol/L), but may transiently
    reach higher levels with fasting or stress. Conjugated (direct) bilirubin
    and liver enzymes (ALT, AST, ALP) remain normal.
  phenotype_term:
    preferred_term: Unconjugated hyperbilirubinemia
    term:
      id: HP:0008282
      label: Unconjugated hyperbilirubinemia
  evidence:
  - reference: PMID:7565971
    reference_title: "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis."
    explanation: >-
      Classic description from the landmark NEJM paper establishing
      unconjugated hyperbilirubinemia as the obligate phenotype.
- name: Jaundice
  category: Clinical
  frequency: FREQUENT
  description: >-
    Visible yellowing of the sclerae and skin due to bilirubin deposition,
    typically intermittent and mild. Often first noticed during adolescence
    and may be triggered by fasting, illness, or stress.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:8596320
    reference_title: "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This common mild hyperbilirubinaemia sometimes presents as an intermittent jaundice."
    explanation: >-
      Directly establishes jaundice as a clinical presentation of the
      unconjugated hyperbilirubinaemia in Gilbert's syndrome.
  - reference: PMID:8596320
    reference_title: "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals in the population with the 7/7 genotype had significantly higher bilirubin concentrations than those who had the 6/7 or 6/6 genotype."
    explanation: >-
      Demonstrates that homozygous UGT1A1*28 (7/7) carriers have the highest
      bilirubin levels, making them most susceptible to intermittent jaundice.
- name: Jaundice-Associated Gastrointestinal Symptoms
  category: Clinical
  frequency: FREQUENT
  description: >-
    In a longitudinal adult cohort, jaundice episodes were often associated
    with abdominal pain, dyspepsia, or loss of appetite. The causal relationship
    between bilirubin elevation and these symptoms remains incompletely
    resolved, and many affected individuals are otherwise asymptomatic.
  phenotype_term:
    preferred_term: Abdominal pain with dyspepsia or appetite loss
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:30717703
    reference_title: "The frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome: a longitudinal study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "jaundice was associated with abdominal pain, dyspepsia or loss of appetite in 54 (53.465%) subjects."
    explanation: >-
      This longitudinal study directly supports abdominal pain, dyspepsia, or
      appetite loss during jaundice episodes and provides a frequency compatible
      with the FREQUENT band.
biochemical:
- name: Unconjugated Bilirubin
  presence: INCREASED
  context: >-
    Serum unconjugated fraction elevated; conjugated bilirubin and liver
    enzymes (ALT, AST, ALP) remain within normal limits. Typically 1.2-3
    mg/dL in Gilbert's syndrome.
  biomarker_term:
    preferred_term: unconjugated bilirubin
    term:
      id: CHEBI:16990
      label: bilirubin IXalpha
  readouts:
  - target: Reduced UGT1A1 Activity and Impaired Bilirubin Glucuronidation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated unconjugated bilirubin reports the reduced hepatic bilirubin
      glucuronidation that defines Gilbert's syndrome.
    evidence:
    - reference: PMID:7565971
      reference_title: "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        People with Gilbert's syndrome have mild, chronic unconjugated
        hyperbilirubinemia in the absence of liver disease or overt hemolysis.
        Hepatic glucuronidating activity, essential for efficient biliary
        excretion of bilirubin, is reduced to about 30 percent of normal.
      explanation: >-
        Human clinical evidence ties the unconjugated bilirubin readout to the
        reduced hepatic glucuronidation mechanism.
  - target: Fasting- and Stress-Induced Bilirubin Elevation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Serial unconjugated bilirubin captures trigger-sensitive bilirubin
      elevations during fasting, illness, pregnancy, surgery, or other stressors.
    evidence:
    - reference: PMID:8596320
      reference_title: "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Individuals in the population with the 7/7 genotype had significantly
        higher bilirubin concentrations than those who had the 6/7 or 6/6
        genotype. 14 volunteers underwent a 24 h fasting test to see if they
        had Gilbert's syndrome, and all four positives had the 7/7 genotype.
      explanation: >-
        Human fasting-provocation evidence supports bilirubin as a monitoring
        readout of trigger-sensitive Gilbert physiology.
  evidence:
  - reference: PMID:7565971
    reference_title: "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis."
    explanation: >-
      Confirms selectively elevated unconjugated bilirubin as the hallmark
      biochemical finding, with normal conjugated fraction and liver function.
  - reference: PMID:26250421
    reference_title: "Genotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome type II and Gilbert syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum bilirubin concentrations of typical CN-2, intermediate group, and typical GS are respectively 12.9 ± 5.1, 5.2 ± 2.2, and 2.8 ± 1.1 mg/dL."
    explanation: >-
      Provides quantitative bilirubin values for typical Gilbert's syndrome
      (2.8 ± 1.1 mg/dL), confirming mild elevation as the expected degree.
genetic:
- name: UGT1A1*28 Promoter Polymorphism
  gene_term:
    preferred_term: UGT1A1
    term:
      id: hgnc:12530
      label: UGT1A1
  association: Causative
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:8596320
      reference_title: "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Segregation of the 7/7 genotype with the Gilbert phenotype was also demonstrated in the family with four affected members."
      explanation: >-
        Demonstrates autosomal recessive segregation of UGT1A1*28 homozygosity
        with the Gilbert's syndrome phenotype in a Scottish family.
  notes: >-
    The UGT1A1*28 allele contains a (TA)7TAA repeat in the TATAA element of
    the UGT1A1 promoter, compared to the normal (TA)6TAA. Homozygosity for
    UGT1A1*28 is found in approximately 10-13% of Western populations and
    accounts for the majority of Gilbert's syndrome cases in those populations.
    The extra TA repeat reduces promoter transcription, lowering UGT1A1 activity
    to approximately 30% of normal. UGT1A1*28 is also the pharmacogenomic
    variant most relevant to irinotecan toxicity.
  evidence:
  - reference: PMID:7565971
    reference_title: "The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reduced expression of bilirubin UDP-glucuronosyltransferase 1 due to an abnormality in the promoter region of the gene for this enzyme appears to be necessary for Gilbert's syndrome but not sufficient for the complete manifestation of the syndrome."
    explanation: >-
      Bosma 1995 established the (TA)7 promoter polymorphism as required but
      not sufficient for full phenotypic expression, explaining incomplete
      penetrance in heterozygotes.
  - reference: PMID:8596320
    reference_title: "Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of the 7/7 genotype in this eastern Scottish population was 10-13%."
    explanation: >-
      Provides population frequency of UGT1A1*28 homozygosity in a Western
      European population, consistent with Gilbert's syndrome prevalence.
  - reference: PMID:9435989
    reference_title: "Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gilbert's syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon."
    explanation: >-
      Clarke 1997 places UGT1A1*28 in the context of the full spectrum of UGT1
      defects and confirms its role as the principal cause of Gilbert's syndrome.
- name: UGT1A1*6 Missense Variant (Gly71Arg)
  gene_term:
    preferred_term: UGT1A1
    term:
      id: hgnc:12530
      label: UGT1A1
  association: Causative
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:26250421
      reference_title: "Genotype of UGT1A1 and phenotype correlation between Crigler-Najjar syndrome type II and Gilbert syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most patients had biallelic mutations of UGT1A1."
      explanation: >-
        Maruo 2016 demonstrated that Japanese patients with unconjugated
        hyperbilirubinemia typically carry biallelic UGT1A1 mutations,
        consistent with autosomal recessive inheritance.
  notes: >-
    The UGT1A1*6 allele (c.211G>A, p.Gly71Arg) is a coding variant that
    predominates as a cause of Gilbert's syndrome in East Asian (particularly
    Japanese) populations. A G to A transition at nucleotide 211 substitutes
    arginine for glycine at codon 71. In Japanese Gilbert's syndrome patients,
    homozygous G71R (9%), TA7/6 with heterozygous G71R (17%), and compound
    heterozygous UGT1A1*6/*28 genotypes are common, reflecting a different
    ethnic genetic architecture compared to Western populations. UGT1A1*6 is
    also clinically relevant to irinotecan toxicity in Asian patients.
  evidence:
  - reference: PMID:10353933
    reference_title: "Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a G-->A transition at nucleotide 211 caused arginine to replace glycine at position 71 of corresponding protein product (G71R)."
    explanation: >-
      Maruo 1999 identified the G71R mutation and showed it is associated
      with hyperbilirubinemia in Japanese neonates, establishing UGT1A1*6
      as a relevant variant in East Asian populations.
  - reference: PMID:15304120
    reference_title: "Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The genetic basis of hyperbilirubinemia appears to be different between the Japanese and Caucasian populations."
    explanation: >-
      Takeuchi 2004 confirmed the ethnic divergence in UGT1A1 variant spectrum,
      with coding variants like G71R being more prevalent in Japanese patients
      versus the promoter TA-repeat polymorphism in Caucasians.
treatments:
- name: Reassurance and Lifestyle Guidance
  description: >-
    Gilbert's syndrome is benign and requires no specific pharmacological
    treatment. Management consists of reassurance, avoidance of prolonged
    fasting, adequate hydration, and recognition of triggers (e.g., illness,
    stress, strenuous exercise). Patients should be counselled to inform
    healthcare providers of their UGT1A1 genotype, as this affects metabolism
    of certain drugs (e.g., irinotecan).
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:37390966
    reference_title: "Gilbert's syndrome revisited."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gilbert's syndrome, also known as benign hyperbilirubinaemia, was described more than 100 years ago."
    explanation: >-
      The Vitek & Tiribelli 2023 review confirms the longstanding recognition
      of Gilbert's syndrome as a benign condition, supporting reassurance
      as the primary therapeutic approach.
  - reference: PMID:30717703
    reference_title: "The frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome: a longitudinal study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening, counseling, monitoring and individualized health care are recommended for subjects with GS in the setting of anesthesia, pregnancy, treatment with DAAs, deliveries, surgery and weight loss plans."
    explanation: >-
      Human longitudinal data support counseling, monitoring, and individualized
      guidance around common jaundice-triggering settings.
  target_mechanisms:
  - target: Fasting- and Stress-Induced Bilirubin Elevation
    treatment_effect: MODULATES
    description: >-
      Avoiding prolonged fasting and planning around physiologic stressors
      reduces exposure to settings that provoke clinical jaundice in Gilbert's
      syndrome.
    evidence:
    - reference: PMID:30717703
      reference_title: "The frequency, clinical course, and health related quality of life in adults with Gilbert's syndrome: a longitudinal study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Risk factors for clinical jaundice included general anesthesia, pregnancy, fasting"
      explanation: >-
        Human cohort evidence identifies fasting and other stressors as
        risk factors, supporting lifestyle guidance as a mechanism-directed
        management step.
- name: UGT1A1 Genotyping Prior to Irinotecan Therapy
  description: >-
    Carriers of UGT1A1*28 (and UGT1A1*6 in Asian patients) have significantly
    reduced capacity to glucuronidate SN-38, the active metabolite of irinotecan.
    This leads to increased SN-38 exposure and greater susceptibility to
    irinotecan-induced severe neutropenia and diarrhoea. Genetic testing before
    initiating irinotecan is classified as 'essential' by international
    pharmacogenomics guidelines. Poor metabolisers (homozygous or compound
    heterozygous) should receive a 70% starting dose.
  treatment_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:11990381
    reference_title: "UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity."
    explanation: >-
      Iyer 2002 prospective pharmacogenetic study demonstrated that UGT1A1*28
      genotype predicts reduced SN-38 glucuronidation and severe irinotecan
      toxicity, establishing the clinical rationale for pre-treatment testing.
  - reference: PMID:36443464
    reference_title: "Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity."
    explanation: >-
      The DPWG 2023 guideline endorses UGT1A1 variant testing to optimize
      irinotecan starting dose and prevent severe toxicity.
  - reference: PMID:36443464
    reference_title: "Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment.'
    explanation: >-
      DPWG classification of UGT1A1 testing as 'essential' elevates this to
      a mandatory pre-treatment test, not an optional pharmacogenomics screen.
references:
- reference: DOI:10.1097/hc9.0000000000000245
  title: Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia
  found_in:
  - Gilberts_Syndrome-deep-research-falcon.md
  findings:
  - statement: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L).
    supporting_text: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L).
    evidence:
    - reference: DOI:10.1097/hc9.0000000000000245
      reference_title: Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L).
      explanation: Deep research cited this publication as relevant literature for Gilberts Syndrome.
- reference: DOI:10.20944/preprints202405.0500.v1
  title: 'Gilbert’s Syndrome: The Good, the Bad and the Ugly'
  found_in:
  - Gilberts_Syndrome-deep-research-falcon.md
  findings:
  - statement: Gilbert's syndrome (GS) is a common hereditary condition characterized by mild increases in serum bilirubin levels due to inherited defects in bilirubin metabolism.
    supporting_text: Gilbert's syndrome (GS) is a common hereditary condition characterized by mild increases in serum bilirubin levels due to inherited defects in bilirubin metabolism.
    evidence:
    - reference: DOI:10.20944/preprints202405.0500.v1
      reference_title: 'Gilbert’s Syndrome: The Good, the Bad and the Ugly'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Gilbert's syndrome (GS) is a common hereditary condition characterized by mild increases in serum bilirubin levels due to inherited defects in bilirubin metabolism.
      explanation: Deep research cited this publication as relevant literature for Gilberts Syndrome.
- reference: DOI:10.2147/pgpm.s108656
  title: 'UGT1A1 polymorphisms in cancer: impact on irinotecan treatment'
  found_in:
  - Gilberts_Syndrome-deep-research-falcon.md
  findings:
  - statement: 'UGT1A1 polymorphisms in cancer: impact on irinotecan treatment'
    supporting_text: 'UGT1A1 polymorphisms in cancer: impact on irinotecan treatment'
- reference: DOI:10.3389/fgene.2023.1265268
  title: 'Genetic variations underlying Gilbert syndrome and HBV infection outcomes: a cross-sectional study'
  found_in:
  - Gilberts_Syndrome-deep-research-falcon.md
  findings:
  - statement: Constant cellular damage causes a poor prognosis of hepatitis B virus (HBV) infection.
    supporting_text: Constant cellular damage causes a poor prognosis of hepatitis B virus (HBV) infection.
    evidence:
    - reference: DOI:10.3389/fgene.2023.1265268
      reference_title: 'Genetic variations underlying Gilbert syndrome and HBV infection outcomes: a cross-sectional study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Constant cellular damage causes a poor prognosis of hepatitis B virus (HBV) infection.
      explanation: Deep research cited this publication as relevant literature for Gilberts Syndrome.
- reference: DOI:10.3389/fphar.2024.1389968
  title: Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials
  found_in:
  - Gilberts_Syndrome-deep-research-falcon.md
  findings:
  - statement: Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials
    supporting_text: Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant.
    evidence:
    - reference: DOI:10.3389/fphar.2024.1389968
      reference_title: Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant.
      explanation: Deep research cited this publication as relevant literature for Gilberts Syndrome.
- reference: DOI:10.3390/nu16142247
  title: Nutrition in Gilbert’s Syndrome—A Systematic Review of Clinical Trials According to the PRISMA Statement
  found_in:
  - Gilberts_Syndrome-deep-research-falcon.md
  findings:
  - statement: Gilbert syndrome is the most common hyperbilirubinemia, associated with a mutation in the UGT1A1 bilirubin gene, which produces an enzyme that conjugates bilirubin with glucuronic acid.
    supporting_text: Gilbert syndrome is the most common hyperbilirubinemia, associated with a mutation in the UGT1A1 bilirubin gene, which produces an enzyme that conjugates bilirubin with glucuronic acid.
    evidence:
    - reference: DOI:10.3390/nu16142247
      reference_title: Nutrition in Gilbert’s Syndrome—A Systematic Review of Clinical Trials According to the PRISMA Statement
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Gilbert syndrome is the most common hyperbilirubinemia, associated with a mutation in the UGT1A1 bilirubin gene, which produces an enzyme that conjugates bilirubin with glucuronic acid.
      explanation: Deep research cited this publication as relevant literature for Gilberts Syndrome.
- reference: DOI:10.5385/nm.2024.31.1.1
  title: Should We Consider UGT1A1 Mutation Analysis in Evaluating the Prolonged Jaundice of Newborn Infants?
  found_in:
  - Gilberts_Syndrome-deep-research-falcon.md
  findings:
  - statement: Uridine diphosphate glucuronosyltransferase 1A isoform 1 (<i>UGT1A1</i>) is a crucial enzyme in bilirubin metabolism.
    supporting_text: Uridine diphosphate glucuronosyltransferase 1A isoform 1 (<i>UGT1A1</i>) is a crucial enzyme in bilirubin metabolism.
    evidence:
    - reference: DOI:10.5385/nm.2024.31.1.1
      reference_title: Should We Consider UGT1A1 Mutation Analysis in Evaluating the Prolonged Jaundice of Newborn Infants?
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Uridine diphosphate glucuronosyltransferase 1A isoform 1 (<i>UGT1A1</i>) is a crucial enzyme in bilirubin metabolism.
      explanation: Deep research cited this publication as relevant literature for Gilberts Syndrome.

📚

References & Deep Research

References

7

DOI:10.1097/hc9.0000000000000245

Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia

1 finding

Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L).

"Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L)."

Show evidence (1 reference)

DOI:10.1097/hc9.0000000000000245 SUPPORT Human Clinical

"Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 μmol/L)."

Deep research cited this publication as relevant literature for Gilberts Syndrome.

DOI:10.20944/preprints202405.0500.v1

Gilbert’s Syndrome: The Good, the Bad and the Ugly

1 finding

Gilbert's syndrome (GS) is a common hereditary condition characterized by mild increases in serum bilirubin levels due to inherited defects in bilirubin metabolism.

"Gilbert's syndrome (GS) is a common hereditary condition characterized by mild increases in serum bilirubin levels due to inherited defects in bilirubin metabolism."

Show evidence (1 reference)

DOI:10.20944/preprints202405.0500.v1 SUPPORT Human Clinical

"Gilbert's syndrome (GS) is a common hereditary condition characterized by mild increases in serum bilirubin levels due to inherited defects in bilirubin metabolism."

Deep research cited this publication as relevant literature for Gilberts Syndrome.

DOI:10.2147/pgpm.s108656

UGT1A1 polymorphisms in cancer: impact on irinotecan treatment

1 finding

UGT1A1 polymorphisms in cancer: impact on irinotecan treatment

"UGT1A1 polymorphisms in cancer: impact on irinotecan treatment"

DOI:10.3389/fgene.2023.1265268

Genetic variations underlying Gilbert syndrome and HBV infection outcomes: a cross-sectional study

1 finding

Constant cellular damage causes a poor prognosis of hepatitis B virus (HBV) infection.

"Constant cellular damage causes a poor prognosis of hepatitis B virus (HBV) infection."

Show evidence (1 reference)

DOI:10.3389/fgene.2023.1265268 SUPPORT Human Clinical

"Constant cellular damage causes a poor prognosis of hepatitis B virus (HBV) infection."

Deep research cited this publication as relevant literature for Gilberts Syndrome.

DOI:10.3389/fphar.2024.1389968

Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials

1 finding

Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials

"Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant."

Show evidence (1 reference)

DOI:10.3389/fphar.2024.1389968 SUPPORT Human Clinical

"Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant."

Deep research cited this publication as relevant literature for Gilberts Syndrome.

DOI:10.3390/nu16142247

Nutrition in Gilbert’s Syndrome—A Systematic Review of Clinical Trials According to the PRISMA Statement

1 finding

Gilbert syndrome is the most common hyperbilirubinemia, associated with a mutation in the UGT1A1 bilirubin gene, which produces an enzyme that conjugates bilirubin with glucuronic acid.

"Gilbert syndrome is the most common hyperbilirubinemia, associated with a mutation in the UGT1A1 bilirubin gene, which produces an enzyme that conjugates bilirubin with glucuronic acid."

Show evidence (1 reference)

DOI:10.3390/nu16142247 SUPPORT Other

"Gilbert syndrome is the most common hyperbilirubinemia, associated with a mutation in the UGT1A1 bilirubin gene, which produces an enzyme that conjugates bilirubin with glucuronic acid."

Deep research cited this publication as relevant literature for Gilberts Syndrome.

DOI:10.5385/nm.2024.31.1.1

Should We Consider UGT1A1 Mutation Analysis in Evaluating the Prolonged Jaundice of Newborn Infants?

1 finding

Uridine diphosphate glucuronosyltransferase 1A isoform 1 (UGT1A1) is a crucial enzyme in bilirubin metabolism.

"Uridine diphosphate glucuronosyltransferase 1A isoform 1 (UGT1A1) is a crucial enzyme in bilirubin metabolism."

Show evidence (1 reference)

DOI:10.5385/nm.2024.31.1.1 SUPPORT Human Clinical

"Uridine diphosphate glucuronosyltransferase 1A isoform 1 (UGT1A1) is a crucial enzyme in bilirubin metabolism."

Deep research cited this publication as relevant literature for Gilberts Syndrome.

Deep Research

1

Falcon ▸

Gilbert’s Syndrome (GS): Disease Characteristics Research Report

Edison Scientific Literature 20 citations 2026-05-09T09:05:32.387438

Gilbert’s Syndrome (GS): Disease Characteristics Research Report

Target disease

Disease name: Gilbert’s syndrome (GS)
Category: Mendelian (UGT1A1-related bilirubin conjugation deficiency)

1. Disease Information

1.1 Concise overview (current understanding)

Gilbert’s syndrome is a common, generally benign inherited condition characterized by intermittent, non-hemolytic, predominantly unconjugated hyperbilirubinemia in the setting of otherwise normal liver biochemistry and no evidence of hemolysis. Typical total bilirubin values are mild (often in the ~1.2–5.3 mg/dL range) and may fluctuate with physiologic stressors. (gonzaleziglesias2024geneticvariationin pages 1-2, beutler2024gilbertssyndromebrightand pages 1-4)

1.2 Key identifiers and terminology

OMIM disease: Gilbert syndrome (OMIM #143500) is explicitly referenced in multiple papers in the retrieved corpus. (yao2023geneticvariationsunderlying pages 1-2)
Causal gene OMIM: UGT1A1 (OMIM *191740), located on chromosome 2q37, is repeatedly cited as the causal gene for GS-spectrum unconjugated hyperbilirubinemia. (yao2023geneticvariationsunderlying pages 1-2, gonzaleziglesias2024geneticvariationin pages 1-2)
OpenTargets / EFO: OpenTargets returns an association between Gilbert syndrome (EFO_0005556) and UGT1A1 (and also UGT1A10 in a smaller evidence set), with literature-linked evidence. (OpenTargets Search: Gilbert syndrome-UGT1A1)
MONDO: In OpenTargets, a related entity hereditary hyperbilirubinemia maps to MONDO_0002408 and is also associated with UGT1A1. A distinct MONDO identifier for “Gilbert syndrome” itself was not obtained from the retrieved sources in this run. (OpenTargets Search: Gilbert syndrome-UGT1A1)
ICD-10/ICD-11, MeSH, Orphanet: These identifiers were not directly captured from the retrieved full-text chunks; therefore they cannot be reported with primary-source citations here.

1.3 Synonyms / alternative names (from clinical usage)

In the retrieved literature, the disease is referred to as Gilbert syndrome and Gilbert’s syndrome. (beutler2024gilbertssyndromebrightand pages 1-4, yao2023geneticvariationsunderlying pages 1-2)

1.4 Evidence provenance

Evidence summarized below is derived from a mixture of: - Primary human studies (e.g., infant prolonged jaundice cohort; HBV outcome association; healthy volunteer genotype-biochemistry study) (yao2023geneticvariationsunderlying pages 1-2, kim2024shouldweconsider pages 1-2, gonzaleziglesias2024geneticvariationin pages 1-2) - Systematic review of clinical trials related to nutrition/fasting effects in GS (goluch2024nutritioningilbert’s pages 1-2, goluch2024nutritioningilbert’s media eb15b11f) - ClinicalTrials.gov records for UGT1A1 pharmacogenomics studies (NCT05148767 chunk 1, NCT01523431 chunk 1, NCT02680795 chunk 1)

2. Etiology

2.1 Disease causal factors

Primary cause: inherited reduction of UGT1A1 activity/expression, the key UDP-glucuronosyltransferase responsible for bilirubin glucuronidation in humans. (yao2023geneticvariationsunderlying pages 1-2, goluch2024nutritioningilbert’s pages 1-2)

Key causal/associated variants (current consensus in retrieved sources): - UGT1A1*28 promoter TA-repeat expansion (TATA-box; often described as A(TA)7TAA or duplication of TA in promoter) is a principal GS-associated genotype, particularly in European/Caucasian ancestry groups. (goluch2024nutritioningilbert’s pages 2-3, kim2024shouldweconsider pages 1-2) - UGT1A1*6 (c.211G>A; p.Gly71Arg / p.G71R) is emphasized as a common GS-relevant coding variant in East Asian populations and in neonatal/prolonged jaundice workups. (kim2024shouldweconsider pages 1-2)

2.2 Risk factors

Genetic risk factors: reduced-function UGT1A1 alleles/haplotypes, including 28 and 6; additional disease-causing variants are documented in sequencing studies of unconjugated hyperbilirubinemia cohorts (e.g., 27, 63, *7 reported in a 2023 study context). (yao2023geneticvariationsunderlying pages 1-2)

Environmental/physiologic risk factors (gene–environment interaction): caloric restriction/fasting, dehydration, intercurrent illness/infection, stress, surgery/anesthesia, pregnancy, sleep deprivation, and intense physical exertion can precipitate jaundice episodes and transient bilirubin rises in genetically predisposed individuals. (goluch2024nutritioningilbert’s pages 2-3, beutler2024gilbertssyndromebrightand pages 1-4)

2.3 Protective factors

The retrieved evidence supports an active research theme that mildly elevated bilirubin may have cytoprotective/antioxidant and immunomodulatory properties. A 2023 cross-sectional HBV-exposed cohort study reported markedly lower cirrhosis/HCC incidence among individuals carrying disease-causing UGT1A1 variants versus wild type, suggesting a potentially protective association (not necessarily causal for GS itself). (yao2023geneticvariationsunderlying pages 1-2)

2.4 Gene–environment interactions

The 2024 nutrition-focused systematic review explicitly frames GS as a “genetically induced, nutritionally exacerbated” disorder, where caloric restriction can rapidly increase bilirubin levels in affected individuals. (goluch2024nutritioningilbert’s pages 1-2, goluch2024nutritioningilbert’s pages 2-3)

3. Phenotypes

3.1 Core phenotype spectrum (with suggested HPO terms)

Intermittent jaundice (scleral/skin), often painless and non-pruritic.
Suggested HPO: Jaundice (HP:0000952)
Evidence: described as intermittent mild jaundice with otherwise normal liver tests. (beutler2024gilbertssyndromebrightand pages 1-4)
Laboratory abnormality: unconjugated hyperbilirubinemia
Suggested HPO: Unconjugated hyperbilirubinemia (HP:0003154)
Suggested LOINC (generic): serum/plasma total bilirubin and direct bilirubin measurement (implementation-specific codes)
Evidence: mild bilirubin elevation typical of GS; normal bilirubin stated as ~0.1–1.2 mg/dL; GS typically ~1.2–5.3 mg/dL, often not exceeding ~5–6 mg/dL. (gonzaleziglesias2024geneticvariationin pages 1-2, goluch2024nutritioningilbert’s pages 2-3)
Normal liver enzymes (important negative phenotype)
Suggested LOINC (generic): ALT/AST/ALP/GGT panel
Evidence: A 2024 study in 773 healthy volunteers found higher bilirubin in genotype-inferred intermediate/poor UGT1A1 metabolizers without association with liver enzyme abnormalities. (gonzaleziglesias2024geneticvariationin pages 1-2)
Trigger sensitivity (fasting/caloric restriction/stress-related episodes)
Suggested HPO: could be represented as episodic worsening of jaundice/hyperbilirubinemia; may be modeled as exposure-linked exacerbation in a KB schema
Evidence: calorie reduction can cause a 2–3× bilirubin rise within 48 hours; multiple triggers listed above. (goluch2024nutritioningilbert’s pages 2-3)

3.2 Age of onset, severity, and course

Often recognized in adolescence/young adulthood (triggered episodic phenotype); in pediatrics, UGT1A1 variants can be prominent in the setting of prolonged jaundice evaluation. (goluch2024nutritioningilbert’s pages 1-2, kim2024shouldweconsider pages 1-2)
Severity is typically mild and fluctuating; severe neonatal unconjugated hyperbilirubinemia may reflect different variant combinations or overlap with Crigler–Najjar spectrum disorders rather than classic adult GS. (kim2024shouldweconsider pages 1-2)

3.3 Quality of life impact

The 2024 systematic review states that episodes of jaundice in GS negatively affect quality of life and focuses on nutritional strategies to reduce episode frequency. (goluch2024nutritioningilbert’s pages 1-2)

4. Genetic / Molecular Information

4.1 Causal genes

UGT1A1 (UDP glucuronosyltransferase family 1 member A1) is the key gene in the retrieved evidence base for GS. (yao2023geneticvariationsunderlying pages 1-2, OpenTargets Search: Gilbert syndrome-UGT1A1)

4.2 Pathogenic/associated variants (examples from retrieved sources)

A structured summary is provided in the artifact below.

Gene (HGNC symbol)	Locus/OMIM (if available from context)	Common pathogenic/associated variants (HGVS and star allele where available)	Variant type (promoter STR, missense, etc.)	Ethnic distribution notes	Functional effect on UGT1A1 activity	Clinical implications (bilirubin levels, drug toxicity)
UGT1A1	Chromosome 2q37; OMIM *191740; Gilbert syndrome OMIM #143500	A(TA)7TAA promoter repeat, commonly referred to as *UGT1A128**; also described as c.-40_-39dupTA / c.-41_-40dupTA in retrieved texts	Promoter short tandem repeat / insertion in TATA box	Predominant GS-associated allele in Caucasian and many African/European populations; prevalence estimates in Europeans ~5–10%, Sub-Saharan Africans 15–25% for GS-related prevalence context; “almost all” GS individuals in Caucasian/African groups in review context are homozygous for *28 (goluch2024nutritioningilbert’s pages 1-2, gonzaleziglesias2024geneticvariationin pages 1-2, kim2024shouldweconsider pages 1-2)	Reduces UGT1A1 expression/activity; one 2024 review states *28 homozygosity is present in ~90% of GS patients and promoter variant can reduce activity to ~30% of normal; bilirubin glucuronidation reported as ~50% of wild-type in 7/7 vs 6/6 genotype (goluch2024nutritioningilbert’s pages 1-2, beutler2024gilbertssyndromebrightand pages 1-4, gonzaleziglesias2024geneticvariationin pages 2-3, goluch2024nutritioningilbert’s pages 2-3)	Main molecular basis of intermittent unconjugated hyperbilirubinemia in GS; bilirubin often ~1.2–5.3 mg/dL and usually <5–6 mg/dL; relevant pharmacogenomic risk allele for irinotecan toxicity and atazanavir-associated hyperbilirubinemia; useful diagnostically when liver enzymes are otherwise normal (goluch2024nutritioningilbert’s pages 2-3, silva2025gilbert’ssyndromethe pages 5-6, beutler2024gilbertssyndromebrightand pages 1-4, gonzaleziglesias2024geneticvariationin pages 1-2)
UGT1A1	Chromosome 2q37; OMIM *191740	*c.211G>A (p.Gly71Arg, p.G71R), UGT1A16**	Missense variant in exon 1	Common in East Asian populations; highlighted as more prevalent in Asians/Koreans/Chinese than in Caucasians (kim2024shouldweconsider pages 1-2, goluch2024nutritioningilbert’s pages 1-2, silva2025gilbert’ssyndromethe pages 3-5)	Decreases UGT1A1 enzymatic activity; contributes to mild bilirubin conjugation deficiency and GS phenotype; in East Asians accounts for a notable fraction of bilirubin variability (goluch2024nutritioningilbert’s pages 2-3, kim2024shouldweconsider pages 1-2, gonzaleziglesias2024geneticvariationin pages 1-2)	Associated with prolonged neonatal jaundice and adult GS; in a 2024 infant cohort it was the most common variant (46.5% among detected variants); also implicated in irinotecan toxicity literature via reduced SN-38 glucuronidation (kim2024shouldweconsider pages 1-2, gonzaleziglesias2024geneticvariationin pages 1-2)
UGT1A1	Chromosome 2q37; OMIM *191740	c.-3275T>G (PBREM/enhancer-region variant; often discussed with GS haplotypes)	Regulatory/promoter-enhancer variant	Reported in Asian infant cohorts with prolonged jaundice; second most common variant in one Korean infant series (30.2%) (kim2024shouldweconsider pages 1-2)	Presumed reduction in transcription/expression when part of GS-associated haplotypes; contributes to reduced bilirubin conjugation (kim2024shouldweconsider pages 1-2)	Seen in prolonged unconjugated neonatal hyperbilirubinemia and supports molecular diagnosis of GS-spectrum bilirubin disorders when routine workup is unrevealing (kim2024shouldweconsider pages 1-2)
UGT1A1	Chromosome 2q37; OMIM *191740	*UGT1A180 (rs887829)*, used as proxy for 28 in one 2024 pharmacogenetic study	Regulatory SNP in strong linkage disequilibrium with promoter allele	Reported as being in near-complete LD with *28 (r² 0.99) in studied populations; used as a surrogate marker rather than a direct causal assignment in the retrieved study (gonzaleziglesias2024geneticvariationin pages 2-3, gonzaleziglesias2024geneticvariationin pages 1-2)	Serves as indicator of reduced-function *28 haplotype / genotype-informed intermediate or poor metabolizer status (gonzaleziglesias2024geneticvariationin pages 2-3, gonzaleziglesias2024geneticvariationin pages 1-2)	Higher bilirubin in intermediate/poor metabolizers; no associated elevation of liver enzymes in healthy volunteers, supporting benignity of GS-like biochemical phenotype in trial screening contexts (gonzaleziglesias2024geneticvariationin pages 2-3, gonzaleziglesias2024geneticvariationin pages 1-2)
UGT1A1	Chromosome 2q37; OMIM *191740	*UGT1A127, UGT1A163, UGT1A17**	Mixed coding/regulatory disease-causing variants (exact HGVS not provided in retrieved context)	Identified in a 2023 Chinese HBV/GS cross-sectional sequencing study among patients with unconjugated hyperbilirubinemia (yao2023geneticvariationsunderlying pages 1-2)	Disease-causing variants associated with greater UGT1A1 deficiency; study inferred that accumulation/rarity of variants correlated with stronger biologic effect (yao2023geneticvariationsunderlying pages 1-2)	In HBV-exposed individuals, carriers had lower LC/HCC incidence (13.14% vs 78.95%) and some achieved HBsAg clearance only in the variant group; these findings concern comorbidity/outcomes rather than routine GS diagnosis (yao2023geneticvariationsunderlying pages 1-2)
UGT1A1	Chromosome 2q37; OMIM *191740	c.1091C>T (p.Pro364Leu, P364L)	Missense variant	Reported in Chinese neonates with severe prolonged unconjugated hyperbilirubinemia; may blur GS vs Crigler-Najjar type II boundaries (kim2024shouldweconsider pages 1-2)	Residual activity reported in retrieved context as ~35.6% of wild-type enzyme activity (kim2024shouldweconsider pages 1-2)	Can present with bilirubin >15 mg/dL in neonates and respond to phenobarbital, later normalizing; illustrates that some UGT1A1 variants produce phenotypes overlapping GS and CN-II rather than classic mild adult GS alone (kim2024shouldweconsider pages 1-2)
UGT1A1	Chromosome 2q37; OMIM *191740	*UGT1A136 [A(TA)6TAA], UGT1A137* [A(TA)9TAA]	Promoter STR alleles	Mentioned as alternative promoter-repeat alleles in pharmacogenetic context rather than classic GS-causing variants; 36 aligns with normal-function haplotypes, 37 with reduced-function haplotypes (gonzaleziglesias2024geneticvariationin pages 2-3)	36 generally reflects more normal promoter configuration; 37 associates with reduced activity via linkage with low-function haplotypes (gonzaleziglesias2024geneticvariationin pages 2-3)	Important for genotype interpretation in pharmacogenomics and bilirubin phenotyping; less central than 28/6 for classic GS diagnosis in retrieved evidence (gonzaleziglesias2024geneticvariationin pages 2-3)

Table: This table summarizes the main UGT1A1 variants linked to Gilbert syndrome and related unconjugated hyperbilirubinemia phenotypes, including population patterns, functional effects, and pharmacogenomic relevance. It is useful for mapping disease genetics to clinical interpretation and drug-response implications.

4.3 Functional consequences

Reduced-function variants decrease bilirubin glucuronidation capacity; one review/source describes a promoter-repeat variant reducing activity to ~30% of normal, and genotype-activity relationships are reported (e.g., ~50% activity for 7/7 vs 6/6; ~80% for 6/7 vs 6/6). (goluch2024nutritioningilbert’s pages 2-3, gonzaleziglesias2024geneticvariationin pages 2-3)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

No specific modifier genes or epigenetic mechanisms were captured in the retrieved GS-focused evidence snippets in this run.

5. Environmental Information

5.1 Lifestyle and nutritional factors

A 2024 PRISMA-based systematic review of GS-related clinical trials (1963–2023) emphasizes that caloric restriction and dietary composition can meaningfully alter bilirubin levels in GS and suggests practical strategies to reduce episodes (avoid excessive calorie restriction; consider dietary fats and bioactive compounds in certain plant families). (goluch2024nutritioningilbert’s pages 1-2, goluch2024nutritioningilbert’s media eb15b11f)

Visual evidence (systematic review evidence base): PRISMA flow diagram and trial-summary tables are available from the review. - PRISMA diagram and trial tables: (goluch2024nutritioningilbert’s media eb15b11f)

6. Mechanism / Pathophysiology

6.1 Causal chain (from trigger to phenotype)

Heme/hemoglobin catabolism produces bilirubin.
Unconjugated bilirubin must be taken up by hepatocytes and conjugated with glucuronic acid to become bile-soluble.
UGT1A1 is the key enzyme mediating bilirubin glucuronidation; reduced UGT1A1 activity/expression yields impaired conjugation and accumulation of unconjugated bilirubin.
Physiologic stressors (fasting/calorie restriction, illness, dehydration, exertion, etc.) transiently increase bilirubin or reduce clearance, triggering episodic jaundice in genetically predisposed individuals.

This mechanistic framing and the “bottleneck” concept at hepatic conjugation are explicitly described in the 2024 systematic review background. (goluch2024nutritioningilbert’s pages 1-2, goluch2024nutritioningilbert’s pages 2-3)

6.2 Molecular pathways and ontology suggestions

Suggested GO (process/function level): bilirubin metabolic process; glucuronosyltransferase activity; bilirubin glucuronosyltransferase activity (GO term IDs not retrieved in evidence chunks). (goluch2024nutritioningilbert’s pages 1-2)
Primary organ/cell type: liver and hepatocytes.
Suggested UBERON: liver (UBERON:0002107)
Suggested CL: hepatocyte (CL:0000182)
Evidence: UGT1A1 described as key hepatic conjugation enzyme. (yao2023geneticvariationsunderlying pages 1-2, gonzaleziglesias2024geneticvariationin pages 1-2)

6.3 Pharmacogenomics mechanism (drug metabolism)

UGT1A1 also glucuronidates drugs and xenobiotics; thus, reduced UGT1A1 function can increase exposure/toxicity of some UGT1A1 substrates (notably irinotecan’s active metabolite SN-38 in oncology pharmacogenomics literature). (takano2017ugt1a1polymorphismsin pages 1-2)

7. Anatomical Structures Affected

7.1 Organ/tissue/cell

Primary: liver (bilirubin conjugation) and hepatocytes. (gonzaleziglesias2024geneticvariationin pages 1-2)
Secondary/clinical manifestation site: skin/sclera (visible jaundice) as a downstream manifestation of hyperbilirubinemia. (beutler2024gilbertssyndromebrightand pages 1-4)

8. Temporal Development

Onset pattern: typically chronic lifelong predisposition with episodic hyperbilirubinemia; episodes can be triggered by environmental/physiologic stressors. (beutler2024gilbertssyndromebrightand pages 1-4, goluch2024nutritioningilbert’s pages 2-3)
Course: fluctuating; bilirubin may normalize after trigger resolution/diet normalization. (goluch2024nutritioningilbert’s pages 2-3)

9. Inheritance and Population

9.1 Inheritance

The retrieved sources treat GS as a genetically determined disorder due to UGT1A1 variants; a specific Mendelian inheritance label (e.g., autosomal recessive vs complex haplotype) was not consistently provided in the excerpts captured in this run.

9.2 Epidemiology (recently summarized)

Reported prevalence varies substantially by ancestry and region: - One 2024 primary-source background section summarizes ethnic prevalence patterns: Sub-Saharan African ~15–25%, Europeans ~5–10%, East Asian ~0–5%. (gonzaleziglesias2024geneticvariationin pages 1-2) - The 2024 systematic review summarizes wider ranges: ~3–16% overall, ~2% in East Asians, and up to ~20% in India/South Asia/Middle East. (goluch2024nutritioningilbert’s pages 1-2)

Sex differences are repeatedly noted, with male predominance in diagnosis; the nutrition systematic review reports male:female diagnosis ratios and example prevalence estimates by sex in secondary summaries. (goluch2024nutritioningilbert’s pages 1-2)

10. Diagnostics

10.1 Clinical tests and laboratory findings

Typical diagnostic pattern is repeated demonstration of isolated, predominantly unconjugated hyperbilirubinemia with normal liver enzymes and absence of hemolysis or structural liver disease. (goluch2024nutritioningilbert’s pages 2-3, gonzaleziglesias2024geneticvariationin pages 1-2)

Quantitative diagnostic context captured: - Normal bilirubin: ~0.1–1.2 mg/dL; GS often ~1.2–5.3 mg/dL. (gonzaleziglesias2024geneticvariationin pages 1-2) - GS-compatible ranges cited in one review: unconjugated hyperbilirubinemia usually ≤4–5 mg/dL with normal liver tests. (beutler2024gilbertssyndromebrightand pages 1-4)

10.2 Genetic testing (real-world implementation)

UGT1A1 genotyping/sequencing is used in selected clinical scenarios: - In a Korean infant cohort with prolonged jaundice (>21 days), 30/33 tested infants (90.9%) had UGT1A1 variants; the most frequent was c.211G>A (46.5%), followed by c.-3275T>G (30.2%). (kim2024shouldweconsider pages 1-2)

Direct abstract quote (Kim 2024): “Thirty-three infants agreed to UGT1A1 mutation analysis, and 30 (90.9%) were positive for UGT1A1 mutations.” (kim2024shouldweconsider pages 1-2)

10.3 Differential diagnosis

Reviews emphasize diagnosis by exclusion, including excluding hemolysis and other hereditary jaundice disorders such as Crigler–Najjar syndrome, Rotor syndrome, and Dubin–Johnson syndrome. (beutler2024gilbertssyndromebrightand pages 1-4)

11. Outcome / Prognosis

Overall, GS is described as benign with no evidence of liver injury and typically no disease-specific treatment requirement. (beutler2024gilbertssyndromebrightand pages 1-4, gonzaleziglesias2024geneticvariationin pages 1-2)

A key clinically relevant outcome is drug-related toxicity risk for certain UGT1A1 substrates/inhibitors (see Treatment/Applications). (takano2017ugt1a1polymorphismsin pages 1-2)

12. Treatment

12.1 Standard management

No disease-specific pharmacotherapy is typically required; management centers on reassurance, avoidance of triggers (e.g., prolonged fasting/caloric restriction), and appropriate diagnostic workup to exclude other causes. (goluch2024nutritioningilbert’s pages 1-2, beutler2024gilbertssyndromebrightand pages 1-4)

MAXO suggestions (knowledge-base oriented): - Patient education / counseling - Dietary modification / avoidance of prolonged fasting - Genetic testing (selected contexts)

(ontology suggestions summarized in artifact below).

Item (phenotype/diagnostic test/mechanism)	Suggested ontology term(s)	Brief description	Evidence notes
Intermittent jaundice	HPO: Jaundice (HP:0000952); HPO: Intermittent jaundice (suggested specific child term if used locally)	Episodic mild scleral/skin icterus, usually benign and fluctuating	Typical GS presentation is intermittent jaundice with otherwise normal liver tests; bilirubin usually ~1.2–5.3 mg/dL and often ≤4–5 mg/dL in adults (gonzaleziglesias2024geneticvariationin pages 1-2, beutler2024gilbertssyndromebrightand pages 1-4)
Unconjugated hyperbilirubinemia	HPO: Hyperbilirubinemia (HP:0002904); HPO: Unconjugated hyperbilirubinemia (HP:0003154); LOINC: Total bilirubin in Serum/Plasma; Direct bilirubin in Serum/Plasma	Core laboratory abnormality with predominantly indirect bilirubin elevation	GS is defined by mild unconjugated hyperbilirubinemia; diagnostic ranges cited include bilirubin <5–6 mg/dL with direct bilirubin <0.7 mg/dL and no hemolysis/liver disease (goluch2024nutritioningilbert’s pages 2-3)
Normal liver enzymes	HPO: Abnormality of liver physiology (negated/normal finding in local schema); LOINC: ALT, AST, ALP, GGT panels	Absence of hepatocellular injury markers helps distinguish GS from liver disease	2024 healthy-volunteer study found higher bilirubin in UGT1A1 IM/PM phenotypes but no association with liver enzyme abnormalities (gonzaleziglesias2024geneticvariationin pages 1-2)
Triggered bilirubin rises with fasting/stress	HPO: Abnormality of metabolism/homeostasis (context-dependent); MAXO: Dietary modification / avoidance of fasting (suggested); LOINC: serial bilirubin measurement	Hyperbilirubinemia worsens during fasting, illness, dehydration, exertion, surgery, stress	Caloric restriction can increase bilirubin 2–3-fold within 48 h; triggers include fasting >12 h, dehydration, infection, intense exercise, surgery, pregnancy, stress, alcohol, sleep deprivation (goluch2024nutritioningilbert’s pages 2-3, beutler2024gilbertssyndromebrightand pages 1-4)
Gallstones / cholelithiasis risk	HPO: Cholelithiasis (HP:0001081)	Recognized complication/comorbidity, especially with coexisting hemolysis	UK Biobank analysis found cholelithiasis significantly higher in men with GS, OR 1.50 (95% CI 1.3–1.7); review sources also note gallstone risk (goluch2024nutritioningilbert’s pages 2-3, beutler2024gilbertssyndromebrightand pages 1-4)
UGT1A1 deficiency / reduced bilirubin glucuronidation	GO: bilirubin glucuronosyltransferase activity; GO: glucuronosyltransferase activity; GO: bilirubin metabolic process	Molecular defect is reduced UGT1A1-mediated conjugation of bilirubin	Common variants include promoter TA repeat 28 and coding variant 6; promoter variant may reduce activity to ~30% of normal, with 7/7 genotype ~50% bilirubin glucuronidation relative to 6/6 (gonzaleziglesias2024geneticvariationin pages 2-3, goluch2024nutritioningilbert’s pages 2-3, yao2023geneticvariationsunderlying pages 1-2)
Hepatocyte involvement	UBERON: liver (UBERON:0002107); CL: hepatocyte (CL:0000182); GO Cellular Component: endoplasmic reticulum membrane	Primary affected cell type and organ for bilirubin conjugation	UGT1A1 is the key bilirubin-conjugating enzyme in liver; GS reflects reduced hepatic glucuronidation rather than structural liver disease (yao2023geneticvariationsunderlying pages 1-2, gonzaleziglesias2024geneticvariationin pages 1-2)
Genetic confirmation / UGT1A1 testing	LOINC: Molecular genetics tests for UGT1A1 (local implementation-specific); MAXO: Genetic testing; HPO: Abnormality of bilirubin metabolism	Sequencing/genotyping can support diagnosis, especially atypical or prolonged cases	Common tested variants include UGT1A128, 6, c.-3275T>G, c.211G>A; in prolonged infant jaundice, 30/33 tested infants had UGT1A1 variants (kim2024shouldweconsider pages 1-2)
Differential diagnosis exclusion	MAXO: Diagnostic laboratory testing; HPO terms for hemolysis/liver disease used as exclusions	Diagnosis is typically by exclusion of hemolysis and other hereditary/acquired jaundice disorders	Reviews emphasize ruling out hemolysis, Crigler–Najjar syndrome, Rotor syndrome, Dubin–Johnson syndrome, and other liver disease before labeling GS (beutler2024gilbertssyndromebrightand pages 1-4, silva2025gilbert’ssyndromethe pages 3-5)
Supportive management / reassurance	MAXO: Patient education; MAXO: Counseling; MAXO: Dietary modification	Usually no disease-specific pharmacotherapy required; management focuses on education and trigger avoidance	GS is generally benign, no hepatic toxicity demonstrated in 2024 volunteer data; avoiding excessive calorie restriction may reduce jaundice episodes (goluch2024nutritioningilbert’s pages 1-2, gonzaleziglesias2024geneticvariationin pages 1-2)

Table: This table maps the core clinical features, diagnostics, and mechanisms of Gilbert syndrome to practical ontology suggestions (HPO, LOINC, GO, UBERON, CL, MAXO). It is useful for structuring disease knowledge-base entries and annotating phenotypes, pathways, and clinical workflows with recent evidence.

12.2 Pharmacogenomics / precision medicine applications (real-world)

UGT1A1 genotyping is widely implemented in oncology and other drug-safety contexts; many trials and clinical programs use UGT1A1 (28/6) status to mitigate toxicity.

ClinicalTrials.gov examples (UGT1A1-guided dosing/PK; not GS-specific interventions): - NCT05148767 (posted 2022; recruiting; Phase 4): UGT1A1-guided irinotecan dosing in neoadjuvant chemoradiotherapy for locally advanced rectal cancer; requires UGT1A1 6 and 28 testing and assigns irinotecan dose by genotype. (NCT05148767 chunk 1) - NCT01523431 (posted 2012; completed; Phase 2/3): genotype-guided irinotecan dosing in metastatic colorectal cancer; homozygotes randomized to standard vs 50% reduced irinotecan dose. (NCT01523431 chunk 1) - NCT02680795 (posted 2016; completed; Phase 1): belinostat PK/safety stratified by UGT1A1*28 genotype. (NCT02680795 chunk 1)

12.3 Experimental / advanced therapeutics

For severe UGT1A1 deficiency disorders (Crigler–Najjar type I), gene replacement is under study (not GS): - NCT06641154 (posted 2024; recruiting; Phase 1/2): AAV8 vector carrying normal human UGT1A1 for Crigler–Najjar type I. (NCT06641154 chunk 1)

13. Prevention

Primary prevention of GS is not applicable (genetic predisposition). Practical prevention of symptomatic episodes is framed as trigger avoidance, particularly avoiding excessive caloric restriction/fasting and dehydration. (goluch2024nutritioningilbert’s pages 2-3)

14. Other Species / Natural Disease

No naturally occurring GS-equivalent disease in non-human species was captured in the retrieved GS-specific snippets; however, Ugt1a1 deficiency models exist (see Model Organisms).

15. Model Organisms

Model systems in the retrieved literature largely address UGT1A1 deficiency and neonatal hyperbilirubinemia (often more severe than classic GS), and also include humanized UGT1A1*28 mouse models used for drug-metabolism work.

Examples retrieved (not fully extracted as evidence snippets in this run but available as papers in the corpus): - Humanized UGT1 mouse models expressing human UGT1 locus and/or UGT1A1*28 allele for studying bilirubin metabolism and drug clearance. (silva2025gilbert’ssyndromethe pages 8-9) - Ugt1 locus knockout mice modeling severe unconjugated hyperbilirubinemia (Crigler–Najjar type I-like). (silva2025gilbert’ssyndromethe pages 8-9)

Recent developments and latest research (2023–2024 prioritized)

The table below summarizes key recent (2023–2024) evidence sources captured in this run.

Year	First author	Type (primary study/review/systematic review)	Population/setting	Key findings (quantitative where possible)	PMID/DOI/URL	Notes
2024	Goluch	Systematic review of clinical trials	Clinical studies in people with Gilbert syndrome, literature 1963–2023; 19 studies included	GS described as the most common benign hyperbilirubinemia due to reduced UGT1A1 activity; prevalence reported as 3–16% overall, ~2% in East Asians, up to ~20% in India/South Asia/Middle East; ~90% of GS patients carry homozygous A(TA)7TAA (*28); fasting/caloric restriction can raise bilirubin 2–3× within 48 h; avoiding excessive calorie restriction and consuming certain fats/bioactive plant compounds may reduce jaundice episodes; episodes negatively affect quality of life (goluch2024nutritioningilbert’s pages 2-3, goluch2024nutritioningilbert’s pages 1-2, goluch2024nutritioningilbert’s media eb15b11f)	DOI: 10.3390/nu16142247; https://doi.org/10.3390/nu16142247	Diet/nutrition; triggers; QoL; ethnicity-specific genetics
2024	González-Iglesias	Primary study	773 healthy volunteers in 29 bioequivalence trials, Spain	Bilirubin higher in UGT1A1 intermediate and poor metabolizers vs normal metabolizers; decreased uric acid in poor metabolizers; no association between UGT1A1 phenotype and liver enzyme levels; supports inclusion of likely GS participants in bioequivalence studies; paper cites prevalence by ancestry: Sub-Saharan African 15–25%, Europeans 5–10%, East Asian 0–5% (gonzaleziglesias2024geneticvariationin pages 2-3, gonzaleziglesias2024geneticvariationin pages 1-2)	DOI: 10.3389/fphar.2024.1389968; https://doi.org/10.3389/fphar.2024.1389968	Pharmacogenomics; real-world trial eligibility; benign liver biochemistry
2024	Kim	Primary study	74 Korean infants with prolonged jaundice >21 days; 33 underwent UGT1A1 testing	30/33 tested infants (90.9%) had UGT1A1 mutations; common variants were c.211G>A (46.5%) and c.-3275T>G (30.2%); breastfeeding was the only significant factor associated with mutation-positive cases (P=0.027); supports utility of UGT1A1 testing in prolonged unexplained neonatal jaundice (kim2024shouldweconsider pages 1-2)	DOI: 10.5385/nm.2024.31.1.1; https://doi.org/10.5385/nm.2024.31.1.1	Neonatal/prolonged jaundice; East Asian variant spectrum
2024	Beutler	Review	Literature review	GS summarized as the most common inherited jaundice affecting ~5–10% of people, more common in men; common promoter variant reduces UGT activity to ~30% of normal; typical unconjugated bilirubin usually up to ~4–5 mg/dL with normal liver tests; triggers include stress, alcohol, dehydration, heavy exercise, surgery, sleep deprivation, starvation; notes gallstones/cholelithiasis and hemolytic anemia associations (beutler2024gilbertssyndromebrightand pages 1-4)	2024 review; journal/PMID not available in context	Clinical overview; triggers; comorbidity; protective vs adverse aspects
2023	Poynard	Primary study	UK Biobank, apparently healthy middle-aged Europeans with liver data (n=138,125)	GS phenotypically defined using stratified total bilirubin centiles; in women, stratified approach identified 10% GS (7,741/76,809) vs 3.7% using the historical ≥1 mg/dL cutoff; after adjustment/Mendelian randomization, only cholelithiasis remained significantly higher in men with GS (OR 1.50, 95% CI 1.3–1.7; P=0.001); no adjusted survival difference over 15 years (poynard2023clinicalandgenetic pages 1-1)	DOI: 10.1097/HC9.0000000000000245; https://doi.org/10.1097/HC9.0000000000000245	Population definition; sex-specific diagnostic thresholds; gallstones risk
2023	Yao	Primary study	Single-ethnic Chinese cross-sectional study; 2,792 screened for unconjugated hyperbilirubinemia, 175 with confirmed HBV exposure analyzed	Five disease-causing UGT1A1 variants detected (28, 6, 27, 63, *7); cirrhosis/HCC incidence lower in UGT1A1-variant hosts than wild type (13.14% vs 78.95%, P<0.0001); HBsAg clearance in non-cirrhotic patients seen only in variant group (12.32% vs 0%); suggests mildly elevated bilirubin may be protective in HBV outcomes (yao2023geneticvariationsunderlying pages 1-2)	DOI: 10.3389/fgene.2023.1265268; https://doi.org/10.3389/fgene.2023.1265268	Comorbidity/prognosis; potential protective biology of mild hyperbilirubinemia

Table: This table summarizes key 2023–2024 evidence sources for Gilbert syndrome, prioritizing recent primary studies and systematic reviews. It highlights epidemiology, genetics, triggers, diagnostics, pharmacogenomics, and comorbidity findings useful for a disease knowledge base.

Important note: Some identifier-level items (e.g., ICD/MeSH/Orphanet codes) and some mechanistic details (e.g., detailed transcriptional regulation of the TA-repeat promoter) were not directly available in the retrieved full-text snippets; this report avoids asserting those details without primary-source capture.

References

(gonzaleziglesias2024geneticvariationin pages 1-2): Eva González-Iglesias, Dolores Ochoa, Manuel Román, Paula Soria-Chacartegui, Samuel Martín-Vilchez, Marcos Navares-Gómez, Alejandro De Miguel, Pablo Zubiaur, Andrea Rodríguez-Lopez, Francisco Abad-Santos, and Jesús Novalbos. Genetic variation in ugt1a1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials. Frontiers in Pharmacology, May 2024. URL: https://doi.org/10.3389/fphar.2024.1389968, doi:10.3389/fphar.2024.1389968. This article has 3 citations.
(beutler2024gilbertssyndromebrightand pages 1-4): K Beutler and J Lewandowski. Gilbert's syndrome-bright and dark sides of the disease-literature review. Unknown journal, 2024.
(yao2023geneticvariationsunderlying pages 1-2): Bilian Yao, Qi Xu, Xinxin Zhang, and Yue Han. Genetic variations underlying gilbert syndrome and hbv infection outcomes: a cross-sectional study. Frontiers in Genetics, Nov 2023. URL: https://doi.org/10.3389/fgene.2023.1265268, doi:10.3389/fgene.2023.1265268. This article has 3 citations and is from a peer-reviewed journal.
(OpenTargets Search: Gilbert syndrome-UGT1A1): Open Targets Query (Gilbert syndrome-UGT1A1, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(kim2024shouldweconsider pages 1-2): Young Don Kim. Should we consider ugt1a1 mutation analysis in evaluating the prolonged jaundice of newborn infants? Neonatal Medicine, 31:1-8, Feb 2024. URL: https://doi.org/10.5385/nm.2024.31.1.1, doi:10.5385/nm.2024.31.1.1. This article has 0 citations.
(goluch2024nutritioningilbert’s pages 1-2): Zuzanna Goluch, Aldona Wierzbicka-Rucińska, and Ewelina Książek. Nutrition in gilbert’s syndrome—a systematic review of clinical trials according to the prisma statement. Nutrients, 16:2247, Jul 2024. URL: https://doi.org/10.3390/nu16142247, doi:10.3390/nu16142247. This article has 2 citations.
(goluch2024nutritioningilbert’s media eb15b11f): Zuzanna Goluch, Aldona Wierzbicka-Rucińska, and Ewelina Książek. Nutrition in gilbert’s syndrome—a systematic review of clinical trials according to the prisma statement. Nutrients, 16:2247, Jul 2024. URL: https://doi.org/10.3390/nu16142247, doi:10.3390/nu16142247. This article has 2 citations.
(NCT05148767 chunk 1): Ji Zhu, MD. UGT1A1-Based Irinotecan Therapy for Locally Advanced Rectal Cancer. Zhejiang Cancer Hospital. 2022. ClinicalTrials.gov Identifier: NCT05148767
(NCT01523431 chunk 1): Xu jianming. Individual Dosage Selection of Irinotecan (CPT-11) Based on UGT1A1 Genotype in Metastatic Colorectal Cancer Patients. The Affiliated Hospital of the Chinese Academy of Military Medical Sciences. 2012. ClinicalTrials.gov Identifier: NCT01523431
(NCT02680795 chunk 1): Establish the PK of Belinostat in Patients With Wild-type, Heterozygous, and Homozygous UGT1A1*28 Genotypes. Acrotech Biopharma Inc.. 2016. ClinicalTrials.gov Identifier: NCT02680795
(goluch2024nutritioningilbert’s pages 2-3): Zuzanna Goluch, Aldona Wierzbicka-Rucińska, and Ewelina Książek. Nutrition in gilbert’s syndrome—a systematic review of clinical trials according to the prisma statement. Nutrients, 16:2247, Jul 2024. URL: https://doi.org/10.3390/nu16142247, doi:10.3390/nu16142247. This article has 2 citations.
(gonzaleziglesias2024geneticvariationin pages 2-3): Eva González-Iglesias, Dolores Ochoa, Manuel Román, Paula Soria-Chacartegui, Samuel Martín-Vilchez, Marcos Navares-Gómez, Alejandro De Miguel, Pablo Zubiaur, Andrea Rodríguez-Lopez, Francisco Abad-Santos, and Jesús Novalbos. Genetic variation in ugt1a1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials. Frontiers in Pharmacology, May 2024. URL: https://doi.org/10.3389/fphar.2024.1389968, doi:10.3389/fphar.2024.1389968. This article has 3 citations.
(silva2025gilbert’ssyndromethe pages 5-6): Arjuna P De Silva, Nilushi Nuwanshika, Madunil A Niriella, and Janaka H De Silva. Gilbert’s syndrome: the good, the bad and the ugly. Unknown journal, May 2025. URL: https://doi.org/10.20944/preprints202405.0500.v1, doi:10.20944/preprints202405.0500.v1.
(silva2025gilbert’ssyndromethe pages 3-5): Arjuna P De Silva, Nilushi Nuwanshika, Madunil A Niriella, and Janaka H De Silva. Gilbert’s syndrome: the good, the bad and the ugly. Unknown journal, May 2025. URL: https://doi.org/10.20944/preprints202405.0500.v1, doi:10.20944/preprints202405.0500.v1.
(takano2017ugt1a1polymorphismsin pages 1-2): Masashi Takano and Toru Sugiyama. Ugt1a1 polymorphisms in cancer: impact on irinotecan treatment. Pharmacogenomics and Personalized Medicine, 10:61-68, Feb 2017. URL: https://doi.org/10.2147/pgpm.s108656, doi:10.2147/pgpm.s108656. This article has 141 citations and is from a peer-reviewed journal.
(NCT06641154 chunk 1): Gene Therapy for Crigler Najjar Syndrome Type I (AlphaCN). Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare. 2024. ClinicalTrials.gov Identifier: NCT06641154
(silva2025gilbert’ssyndromethe pages 8-9): Arjuna P De Silva, Nilushi Nuwanshika, Madunil A Niriella, and Janaka H De Silva. Gilbert’s syndrome: the good, the bad and the ugly. Unknown journal, May 2025. URL: https://doi.org/10.20944/preprints202405.0500.v1, doi:10.20944/preprints202405.0500.v1.
(poynard2023clinicalandgenetic pages 1-1): Thierry Poynard, Olivier Deckmyn, Valentina Peta, Mehdi Sakka, Pascal Lebray, Joseph Moussalli, Raluca Pais, Chantal Housset, Vlad Ratziu, Eric Pasmant, and Dominique Thabut. Clinical and genetic definition of serum bilirubin levels for the diagnosis of gilbert syndrome and hypobilirubinemia. Hepatology Communications, Sep 2023. URL: https://doi.org/10.1097/hc9.0000000000000245, doi:10.1097/hc9.0000000000000245. This article has 8 citations and is from a peer-reviewed journal.

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Gilbert’s Syndrome (GS): Disease Characteristics Research Report

Target disease

1. Disease Information

1.1 Concise overview (current understanding)

1.2 Key identifiers and terminology

1.3 Synonyms / alternative names (from clinical usage)

1.4 Evidence provenance

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotype spectrum (with suggested HPO terms)

3.2 Age of onset, severity, and course

3.3 Quality of life impact

4. Genetic / Molecular Information

4.1 Causal genes

4.2 Pathogenic/associated variants (examples from retrieved sources)

4.3 Functional consequences

4.4 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental Information

5.1 Lifestyle and nutritional factors

6. Mechanism / Pathophysiology

6.1 Causal chain (from trigger to phenotype)

6.2 Molecular pathways and ontology suggestions

6.3 Pharmacogenomics mechanism (drug metabolism)

7. Anatomical Structures Affected

7.1 Organ/tissue/cell

8. Temporal Development

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology (recently summarized)

10. Diagnostics

10.1 Clinical tests and laboratory findings

10.2 Genetic testing (real-world implementation)

10.3 Differential diagnosis

11. Outcome / Prognosis

12. Treatment

12.1 Standard management

12.2 Pharmacogenomics / precision medicine applications (real-world)

12.3 Experimental / advanced therapeutics

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Recent developments and latest research (2023–2024 prioritized)