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Gilbert's Syndrome

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

2026-05-09
Falcon MONDO:0007745 Model: Edison Scientific Literature 20 citations

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)

  1. Intermittent jaundice (scleral/skin), often painless and non-pruritic.
  2. Suggested HPO: Jaundice (HP:0000952)

  3. Evidence: described as intermittent mild jaundice with otherwise normal liver tests. (beutler2024gilbertssyndromebrightand pages 1-4)

  4. Laboratory abnormality: unconjugated hyperbilirubinemia

  5. Suggested HPO: Unconjugated hyperbilirubinemia (HP:0003154)
  6. Suggested LOINC (generic): serum/plasma total bilirubin and direct bilirubin measurement (implementation-specific codes)

  7. 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)

  8. Normal liver enzymes (important negative phenotype)

  9. Suggested LOINC (generic): ALT/AST/ALP/GGT panel

  10. 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)

  11. Trigger sensitivity (fasting/caloric restriction/stress-related episodes)

  12. Suggested HPO: could be represented as episodic worsening of jaundice/hyperbilirubinemia; may be modeled as exposure-linked exacerbation in a KB schema
  13. 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

4.2 Pathogenic/associated variants (examples from retrieved sources)

A structured summary is provided in the artifact below.

Table (click to expand)
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 UGT1A1*28; 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), UGT1A1*6 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 UGT1A1*80 (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, UGT1A1*7 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 UGT1A1*36 [A(TA)6TAA], UGT1A1*37 [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)

  1. Heme/hemoglobin catabolism produces bilirubin.
  2. Unconjugated bilirubin must be taken up by hepatocytes and conjugated with glucuronic acid to become bile-soluble.
  3. UGT1A1 is the key enzyme mediating bilirubin glucuronidation; reduced UGT1A1 activity/expression yields impaired conjugation and accumulation of unconjugated bilirubin.
  4. 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

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

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).

Table (click to expand)
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.

Table (click to expand)
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

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  10. (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

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