Gilbert's Syndrome

Author: stefano serra
Date: 03/10/2008



Gilbert's syndrome is a mild liver disorder in which the liver does not properly process bilirubin. Many people never have symptoms. Occasionally a slight yellowish color of the skin or whites of the eyes may occur. Other possible symptoms include feeling tired, weakness, and abdominal pain

UGT1A1 is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites

Kegg's Pathway Bilirubin

Kegg's Pathway UGT1A1

Also the link to the corresponding Mesh term has to be created

The Diseases DatabaseURL
OMIM single geneUGT1A1
Kegg PathwayAGAL

Se ci sono più voci su OMIM usare questo formato di ricerca:

Gilbert Syndrome



age, sex, seasonality, etc



laboratory tests










anatomical (due its structure)

vascular (due to the local circulation)

physiopathological (due to tissue function and activity)

No correlation between Bilirubin and TSH or T4 level

Relationship_between_unconjugated_hyperbilirubinemia_and_lipoprotein_spectrum 2011

The Relationship of the Anti-Oxidant Bilirubin with Free Thyroxine Is Modified by Insulin Resistance in Euthyroid Subjects, 2014

  • The strong anti-oxidative properties of bilirubin largely explain its cardioprotective effects. Insulin resistance is featured by low circulating bilirubin. Thyroid hormone affects both bilirubin generation and its biliary transport, but it is unknown whether circulating bilirubin is associated with thyroid function in euthyroid subjects. Aim is to determine relationships of bilirubin with TSH, free T4 and free T3 in euthyroid subjects without type 2 diabetes mellitus (T2DM), and to assess whether such a relationship would be modified by the degree of insulin resistance.
  • Low bilirubin relates to low free T4 in euthyroid non-diabetic subjects. Low normal free T4 may particularly confer low bilirubin in more insulin resistant individuals.

Bilirubin may affect TH transport

la bilirubina inibisce l'uptake del t4 negli astrociti
ecco l'effetto sull'ipotalamo

Francon J

Cytotoxicity of bilirubin for human fibroblasts and rat astrocytes in culture. Effect of the ratio of bilirubin to serum albumin. 1996

Competitive inhibition of thyroid hormone uptake into cultured rat brain astrocytes by bilirubin and bilirubin conjugates. 1993

  • Thyroid hormone (TH) metabolism is altered in cases of unconjugated hyperbilirubinemia. These effects might involve inhibition of TH uptake by their target cells. Astrocytes, which are in close contact with the membranes of brain capillaries, might be the first brain cells to come into contact with bilirubin. Cultured rat brain astrocytes were used as a model to study the effects of bilirubin and bilirubin analogues on TH uptake. The initial uptake of [125I]T3 and [125I]T4 was inhibited by unconjugated bilirubin, biliverdin, ditaurobilirubin and bilirubin glucuronides. The inhibition of T3 uptake by the bilirubin analogues was competitive. The Ki values were: unconjugated bilirubin (31 microM), biliverdin (48 microM), ditaurobilirubin (2.5 microM) and bilirubin glucuronides (1.2 microM). This last value is similar to the Km of T3 transport (0.4 microM), indicating that bilirubin glucuronides have a high affinity for the TH transport system. By contrast, the uptakes of [3H]tryptophan and ]3H]glutamine were not inhibited. These results suggest that the astrocyte plasma membrane bears specific bilirubin-interaction sites that are closely related to the TH transport system. However, uptake of [14C]bilirubin by cultured astrocytes was a non-saturable process. Binding of bilirubin to the astrocyte plasma membrane may inhibit the TH uptake and impair their metabolism and their action on the intracellular targets.



Int J Vitam Nutr Res. 1999 Jan;69(1):16-22.
Retinoic acid in association with tin-metalloporphyrins influences heme metabolism in vivo in rats.
Chandra R, Aneja R, Sharma A, Tiwari M.
Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, India.
In the current study we report the perturbation of key enzymes of the heme metabolic pathway, i.e. delta-amino levulinic acid synthase, heme oxygenase and biliverdin reductase, in vivo by administration of retinoic acid (RA) and retinoic acid in association with tin-metalloporphyrins, viz., tin-protoporphyrin (SnPP) and tin-mesoporphyrin (SnMP) in the liver, spleen, heart and lung of rats. RA at a dosing regimen of 50,000 I.U. stimulated splenic ALA-S activity, whereas co-administration of tin-metalloporphyrins with RA antagonised the RA mediated induction of ALA-S. In the other tissues viz., liver, heart and lung our results showed a diminution of ALA-S activity on RA administration, the level of repression was further attenuated when tin-metalloporphyrins were co-administered with RA. This marked suppression of ALA-S brought forth by concurrent administration of RA and tin-metalloporphyrins is suggestive of the beneficial effect of this formulation in acute attacks of porphyria, similar to heme. Furthermore, our results emphasize that the combined dosing of RA with tin-metalloporphyrins leads to a substantial decline in bilirubin levels due to a profound inhibition of HMOX in the probed tissues. The features of the combined action of RA and tin-metalloporphyrins in vivo lead to a substantial suppression of formation of the potentially toxic metabolite bilirubin, and the enhancement of disposal of the untransformed substrate (heme) of the enzyme that is inhibited. These results define some of the characteristics of a therapeutically useful formulation and represent a new therapeutic approach for the amelioration and management of hyperbilirubinemia.

bilirubin respiratory chain

Perturbation of membrane dynamics in nerve cells as an early event during bilirubin-induced apoptosis. 2002

Increased levels of unconjugated bilirubin, the end product of heme catabolism, impair crucial aspects of nerve cell function. In previous studies, we demonstrated that bilirubin toxicity may be due to cell death by apoptosis. To characterize the sequence of events leading to neurotoxicity, we exposed developing rat brain astrocytes and neurons to unconjugated bilirubin and investigated whether changes in membrane dynamic properties can mediate apoptosis. Bilirubin induced a rapid, dose-dependent increase in apoptosis, which was nevertheless preceded by impaired mitochondrial metabolism. Using spin labels and electron paramagnetic resonance spectroscopy analysis of whole cell and isolated mitochondrial membranes exposed to bilirubin, we detected major membrane perturbation. By physically interacting with cell membranes, bilirubin induced an almost immediate increase in lipid polarity sensed at a superficial level. The enhanced membrane permeability coincided with an increase in lipid fluidity and protein mobility and was associated with significant oxidative injury to membrane lipids. In conclusion, apoptosis of nerve cells induced by bilirubin is mediated by its primary effect at physically perturbing the cell membrane. Bilirubin directly interacts with membranes influencing lipid polarity and fluidity, protein order, and redox status. These data suggest that nerve cell membranes are primary targets of bilirubin toxicity.

Francon J and bilirubin

Francon J

Competitive inhibition of thyroid hormone uptake into cultured rat brain astrocytes by bilirubin and bilirubin conjugates

The Relationship of the Anti-Oxidant Bilirubin with Free Thyroxine Is Modified by Insulin Resistance in Euthyroid Subjects

Gilbert's syndrome sex prevalence

Coronary Artery Disease in Patients With Disorders of Bilirubin Excretion. 2015

  • We aimed to determine the predictors of coronary artery disease (CAD) in patients with abnormal bilirubin excretion, that is, Gilbert syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, and Rotor syndrome. We analyzed data from the Healthcare Cost and Utilization Project (HCUP) of the Agency for Healthcare Research and Quality, Rockville, MD for the period 2009 to 2010. All patients ≥18 years of age with a primary diagnosis of "disorders of bilirubin excretion" [International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9CM) code 277.4] were included in the study. Primary outcome was to determine predictors of CAD in adult patients diagnosed with abnormal bilirubin excretion. We identified a total of 12,423 adult patients with bilirubin excretion disorder hospitalized during 2009-2010 (0.03% of all inpatient admissions). CAD was seen in 18% of patients, with a higher prevalence in men (21% in men vs. 13% in women, P < 0.0001). In multivariate logistic regression adjusted for demographic and traditional risk factors, hypertension [odds ratio (OR): 1.74; 95% confidence interval (CI), 1.33-2.27, P < 0.001], hyperlipidemia (OR: 2.49; 95% CI, 1.95-3.18, P < 0.001), diabetes (OR: 1.46; 95% CI, 1.12-1.91, P = 0.01), and age (OR: 1.05; 95% CI, 1.04-1.06, P < 0.001) were found to be independent predictors of CAD in adult patients with abnormal bilirubin excretion. Female sex (OR: 0.49; 95% CI, 0.36-0.65, P < 0.001) demonstrated an inverse association in predicting CAD. There was increased prevalence of CAD in our patient population with increased prevalence of cardiovascular risk factors. Age, diabetes mellitus, hypertension, and hyperlipidemia were found to be independent predictors of CAD.

Haem catabolism: a novel modulator of inflammation in Gilbert's syndrome. 2013

  • Abstract
    Moderately elevated unconjugated bilirubin concentrations protect against inflammatory diseases and are present in individuals with Gilbert's syndrome. This study examined the relationship between circulating haem oxygenase catabolites, unconjugated bilirubin, carboxy haemoglobin, iron and inflammatory parameters.
    Seventy-six matched individuals were allocated to Gilbert's syndrome (GS) or control group (unconjugated bilirubin ≥ or < 17.1 μM). Iron, carboxy haemoglobin and high-sensitivity C-reactive protein were analysed using routine diagnostic tests. Unconjugated bilirubin and haem were analysed using high-performance liquid chromatography. The cytokines IL-1β, TNF-α and IL-6 were assessed using high-sensitivity enzyme-linked immunosorbent assays.
    Gilbert's syndrome subjects had significantly greater levels of unconjugated bilirubin (P < 0.05), carboxy haemoglobin (P < 0.05), iron (P < 0.05), IL-1β (P < 0.05), a significantly lower body mass index (P < 0.05) and IL-6 concentrations (P < 0.05) vs. controls. Regression analysis revealed that unconjugated bilirubin mainly explained IL-1β results (16%), and body mass index+IL-6 predicted 26% of the variance in C-reactive protein concentrations.
    A positive relationship between unconjugated bilirubin and free plasma haem, iron and carboxy haemoglobin indicated a positive feedback loop of haem oxygenase induction possibly mediated by unconjugated bilirubin. Furthermore, reduced body mass index in Gilbert's syndrome individuals was linked to reduced inflammation status, which could be influenced by circulating haem oxygenase catabolites and contribute to reduced risk of noncommunicable diseases in this population.
2021-11-23T16:05:44 - Gianpiero Pescarmona

Bilirubina scende nel Gilbert con Laroxyl e Tegretol

Bilirubin >Ahr/Nrf2/CAR/PXR> UT1A1 e CYP24 (inattivazione Vit D, molto alta nei tumori)


Results: Lignans including SinA, SinB, SinC, SolA, SolB, StnA, StnB were found to significantly protect against LCA-induced intrahepatic cholestasis, as evidenced by significant decrease in liver necrosis, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activity. More importantly, serum total bile acids (TBA) and total bilirubin (Tbili) were also significantly reduced. Metabolomic analysis revealed these lignans accelerated the metabolism of bile acids and increased the bile acid efflux from liver into the intestine or feces. Gene analysis revealed these lignans induced the hepatic expressions of PXR- target genes such as Cyp3a11 and Ugt1a1. Luciferase reporter gene assays illustrated that these bioactive lignans can activate hPXR. Additionally, they can all upregulate hPXR-regulate genes such as CYP3A4, UGT1A1 and OATP2.
Conclusion: These results clearly demonstrated the lignans from Schisandra sphenanthera exert hepatoprotective effects against LCA-induced cholestasis by activation of PXR. These lignans may provide an effective approach for the prevention and treatment of cholestatic liver injury.

. 2011 Dec;219(2):728-33. doi: 10.1016/j.atherosclerosis.2011.07.094. Epub 2011 Jul 23.

Statine bloccano sintesi eme e bilirubin scende. Bel risultato!

Association of lower total bilirubin level with statin usage: the United States National Health and Nutrition Examination Survey 1999-2008, 2011
Kwok Leung Ong 1, Ben J Wu, Bernard M Y Cheung, Philip J Barter, Kerry-Anne Rye
Affiliations expand
PMID: 21840000 DOI: 10.1016/j.atherosclerosis.2011.07.094
Objective: A low circulating level of bilirubin is associated with increased cardiovascular risk. As statins can stimulate heme oxygenase-1 (HO-1), which increases bilirubin production, we investigated whether statins in routine use increase total bilirubin levels in subjects at high cardiovascular risk.

Methods: Data from 3290 subjects with self-reported history of hypercholesterolemia, diabetes, or cardiovascular diseases in the United States National Health and Nutrition Examination Survey (NHANES) 1999-2008 were analyzed.

Results: Subjects taking statins (n = 1156) had lower total bilirubin levels than those not taking any lipid-lowering medication (n = 2134) after adjusting for age, sex, race/ethnicity, and survey period (adjusted mean = 0.699 vs 0.729 mg/dl respectively, P=0.001). The association remained significant after adjusting for more covariates (P = 0.002), but was attenuated after further adjusting for glycosylated hemoglobin, insulin resistance index, and low-density lipoprotein (LDL) cholesterol (P = 0.043). The use of lovastatin, rosuvastatin, and cerivastatin was associated with lower total bilirubin levels in the full adjustment model (P < 0.05).

Conclusion: The use of statins was associated unexpectedly with lower total bilirubin levels. This could be explained at least partly by the effect of statins on glycemia and LDL cholesterol. Our results do not suggest that the anti-oxidant and anti-inflammatory effects of statins are due to HO-1 induction and increased serum bilirubin levels.

2021-01-13T23:21:14 - Gianpiero Pescarmona

Gilbert syndrome and cancer

Is Gilbert syndrome a new risk factor for breast cancer? 2011

Patients with Gilbert syndrome have an impaired function of the enzyme UGT1A1, responsible for the degradation of 4-OH-estrogens. These elements are produced by the degradation of estrogens and are well-known carcinogens. In theory, patients with Gilbert syndrome accumulate 4-OH-estrogens and, therefore, might have a higher risk for breast cancer, especially when exposed to higher levels of estrogens. If this theory is true, a new risk group for breast cancer would be described, producing new insights in breast carcinogenesis.

Dual polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: a novel mechanism for hyperserotoninaemia in Gilbert's syndrome mimicking carcinoid syndrome? 2007

On the basis of a case of hyperserotoninaemia in the absence of a detectable carcinoid tumour in a patient with Gilbert's syndrome, who presented with a history of night sweats, flushing, abdominal discomfort and intermittent diarrhoea, we propose that in a subgroup of Gilbert's syndrome patients, homozygocity for dual uridine diphosphate-glucuronosyltransferase 1A1 and uridine diphosphate-glucuronosyltransferase 1A6 polymorphisms may lead to combined hyperbilirubinaemia and hyperserotoninaemia.


2013-08-28T07:59:28 - Gianpiero Pescarmona


Patologia benigna del fegato che evidenzia una maggiore presenza di bilirubina nel sangue (iperbilirubinemia).
Scoperta par la prima volta nel 1901 dal gastroenterologo Augustin Gilbert, la patologia è dovuta ad un deficit di una specifica proteina epatica, la ligandina. Essa è la principale proteina deputata al trasporto della bilirubina dal torrente sanguigno al fegato. La bilirubina (che deriva dal catabolismo dell' EME), è presente nel sangue in forma non coniugata (bilirubina indiretta) la quale è liposolubile; grazie alla proteina trasportatrice, per l’appunto la ligandina, entra nel fegato, dove viene coniugata con acido glucuronico ad opera di particolari enzimi epatici e diventa bilirubina coniugata (quindi diretta ed idrosolubile). A questo punto è pronta ad entrare nella bile e quindi ad essere riversata nell'intestino a livello del duodeno. Di conseguenza un' inefficienza da parte del sistema di trasporto intra-extra epatico causa aumento di bilirubina indiretta nel sangue.
I valori di bilirubina indiretta nel sangue di una persona sana sono compresa tra 0,3 mg/100ml e 1 mg/100ml,quelli di bilirubina diretta sono inferiori ai 0,5mg/100ml. Nel sangue di un individuo con tale patologia si ha,sia un aumento poco significativo della bilirubina diretta, sia un modesto aumento dell’ indiretta: se la quantità di quest’ultima è maggiore di 2.5mg/100ml si manifesta l’ittero ,ovvero la colorazione "giallastra" delle sclere e della cute.
Tale aumento è ulteriormente accentuato in alcuni casi: digiuno, alcool, stress, febbre, attività fisica intensa.


A livello epidemiologico colpisce sia maschi che femmine, anche se le statistiche dei casi evidenziati hanno dimostrato che il rapporto di uomini aventi la sindrome di Gilbert è di 2:1 rispetto alle donne. Inoltre tale patologia, anche se presente sin dalla nascita, si manifesta solitamente nella seconda decade di vita (tra 10 e 20 anni).
Quanti hanno il Gilbert? Tanti; si è calcolato che su 100 persone circa 7 presentino tale patologia (7%) e solo nei casi più marcati ed evidenti il soggetto si rendo conto di esserne affetto.


I sintomi sono evidenti solamente a livello della cute e della sclere quando i livelli di bilirubinemia sono abbastanza elevati. In ogni caso sia che i valori siano maggiori o minori di 2.5mg/100ml la malattia non porta a nessuna conseguenza significativa nè a livello epatico, nè a livello sistemico, nè a livello cerebrale: la bilirubina indiretta è liposolubile, quindi affine alle membrane delle cellule del tessuto nervoso,molto ricche di strutture lipidiche. Essendo tossica può determinare una parziale degenerazione delle cellule nervose con conseguente diminuzione delle prestazioni intellettuali; i livelli di bilirubina indiretta nel Gilbert non sono però così elevati da portare a conseguenze patologiche.
Oltre ad aumento della bilirubinemia diretta ed indiretta, nel paziente affetto da Gilbert si nota anche un leggero aumento della produzione di insulina, non costante durante la giornata,e, anche se di lieve entità, ciò comporta una leggera carenza di nutrimento delle cellule nervose con conseguente depressione del tono neuro-umorale.


A livello istopatologico il tessuto epatico non presenta nessun tipo di disfunzione istologica o funzionale; nemmeno a livello radiologico è evidenziabile qualcosa poichè la suddetta sindrome non causa distruzione epatica. Il solo sistema di diagnosi che può essere effettuato è l’esame obiettivo, col quale si va ad analizzare la condizione generale del paziente e l'eventuale presenza di ittero. In seguito deve essere analizzata la bilirubinemia per valutarne l’eventuale valore superiore alla norma (tali esami vanno effettuati a digiuno). Nel caso le due caratteristiche del morbo venissero evidenziate è opportuna una diagnosi differenziale con lo scopo di escludere le altre patologie epatiche che si manifestano con iperbilirubinemia, solitamente più feroci e dannose. Tale diagnosi differenziale viene effettuata analizzando particolari enzimi-strutture indicanti la degenerazione epatica (valutazione ALT, AST, GTT), la sintesi proteica epatica ( valutabile con PT, PTT, albuminemia, protidemia) e inoltre studiando l'emocromo così come l'eritrocitopenia (da possibile emolisi)
La più semplice ed efficace prova per diagnosticare il morbo è la prova del digiuno prolungato per 36 ore; i valori in tale situazione aumentano del doppio.


La suddetta sindrome non è contraibile durante la vita: il suo sviluppo è esclusivamente di tipo genetico-ereditario. Nello specifico è una malattia autosomica dominante a penetranza incompleta, poligenica ,ovvero malattie dovute a mutazioni di geni dominanti che esprimono il loro fenotipo sia in eterozigosi che in omozigosi e che sono localizzati sugli autosomi, con una variabile espressività;la penetranza è la frequenza (probabilità) che un genotipo esprima il fenotipo; inoltre è multifattoriale (non è pertanto possibile prevedere l'ereditarietà). Da ciò si evince che ogni soggetto può essere sano, malato, o portatore.Il rischio di trasmissione, nonostante sia a dominanza incompleta, è ad ogni modo presente,indipendentemente dal numero di soggetti affetti o non che sono già nati.


La patologia è trasmissibile solo geneticamente,non esistono fattori di rischio esterni .Essendo una patologia poligenica e multifattoriale è difficilissimo se non quasi impossibile calcolare matematicamente la probabilità per un genitore affetto da tale sindrome di avere un figlio anch’egli affetto da Gilbert.


Non ci sono fattori di rischio specifici dei tessuti.


Tutte le “complicanze” non hanno nessuna influenza sulla corretta funzionalità del fegato e del resto dell'organismo; l'unica visibile è appunto un leggero ittero accentuato da:
DIETA: Cibi contenti molti grassi oppure fritti andrebbero tendenzialmente evitati in ogni caso, in particolar modo nel Gilbert; anche se non ha nessuna relazione con un danno epatico, l'ittero potrebbe accentuarsi
Stress,attività fisica : Aumentano i livelli di bilirubina indiretta nel sangue e di conseguenza è maggiore l'ittero
Digiuno: Il digiuno è la situazione che più in assoluto accentua la bilirubinemia (metodo usato appunto per la diagnosi)
FARMACI: Anche i farmaci non danno luogo a conseguenze significative a carico di un fegato con Gilbert. Tuttavia tale patologia riduce la capacità del fegato di detossificare particolari sostanze farmaceutiche; per esempio pazienti con Gilbert che assumono Irinotecano (metabolizzato da UGT1A1) si manifesta una forte diarrea associata a neutropenia.
In generale tutte queste sono solo complicazioni dal punto di vista prettamente estetico.
Il morbo di Gilbert non da complicanze neanche nel sociale in quanto un individuo con la sindrome di Gilbert non si può considerare un malato! Permette la donazione di organi e del sangue; non influisce sui concorsi per diventare membri di carabinieri, polizia, finanza...;si può accedere ,senza essere in difetto, ai concorsi militari; il morbo di Gilbert non può, inoltre, essere causa di esclusione da concorsi pubblici.

Data la estrema benignità della condizione di portatore della Sindrome di Gilbert, non esistono medicine o comportamenti alimentari/stile di vita tali da determinare la riduzione dei valori della bilirubinemia. Tuttavia è noto che, in tale condizione, si determina un ulteriore incremento della bilirubina in occasione di digiuni o semidigiuni e/o di sforzi fisici. Una particolare attenzione a questi fattori può dunque essere utile per impedire un eccessivo aumento della bilirubinemia.
Esiste comunque la possibilità di ottenere una regressione dell’aumento della bilirubinemia indiretta mediante l’uso di vari farmaci, cosiddetti “induttori enzimatici”, quali la glutetimide, la clorciclizina, i barbiturici non ipnotici. Più comunemente, il fenobarbital (anti-epilettico), somministrato alla dose di 100 mg al dì, cioè una compressa la sera, per 15 giorni consecutivi, può rendere più bassi i valori alterati della bilirubinemia. Tuttavia, l’uso di questi farmaci, oltre a non portare nessun beneficio, provoca effetti collaterali soggettivi spiacevoli e anche dannosi e possono interferire sul metabolismo di altri farmaci: non ne è consigliato l’uso in questo ambito.


In conclusione questa sindrome non penalizza in alcun modo i soggetti che ne sono affetti, ma anzi, un lieve aumento dei livelli di bilirubina porta a vantaggio selettivo (i portatori sani sono protetti da ictus e infarti).

Thyroid hormones and the hepatic handling of bilirubin. II. Effects of hypothyroidism and hyperthyroidism on the apparent maximal biliary secretion of bilirubin in the Wistar rat. 1988

  • Abstract
    This study was undertaken in the Wistar R/A Pfd rat to investigate the effects of hypothyroidism and of hyperthyroidism on the maximal biliary excretion ™ of bilirubin and on the concentration and composition of bilirubin in liver and plasma at the end of a bilirubin load. Hypothyroidism caused a cholestatic condition with a 50% decrease in bile flow and in bilirubin Tm, and with an increased proportion of conjugated bilirubin in liver and plasma. This was associated with an increased ratio of bilirubin diconjugates to monoconjugates in bile, liver, and plasma, which can be ascribed to the increased hepatic conjugation activity towards bilirubin and/or to the prolonged retention of bile pigments in the hepatocytes with increased conversion of monoconjugates to diconjugates. Cholestasis induced by hypothyroidism was further characterized by a decreased biliary output of unconjugated bilirubin. The latter phenomenon might represent an indirect effect related to a decreased output of bilirubin monoconjugates with impaired hydrolysis to unconjugated bilirubin; it might also reflect the cholestatic condition with decreased excretion of the unesterified bile pigment as such. Hyperthyroidism resulted in a 1.3-1.4-fold increase in bile flow. The maximal bilirubin concentration in bile decreased 1.3-1.4-fold, so that the apparent maximal bilirubin excretion rate remained unchanged at 115 nmol.min-1.100 g-1, as observed in untreated rats. Hyperthyroidism lowered the bilirubin UDP-glucuronosyltransferase activity, produced a decreased ratio of bilirubin di- to monoconjugates in bile and plasma, and a decreased ratio of conjugated to total bile pigment concentration in liver and in plasma. Similar findings are present in the heterozygous Gunn rat strain and in patients with hepatic bilirubin UDP-glucuronosyltransferase deficiency. We therefore propose the hyperthyroid rat as an experimental animal model of Gilbert's syndrome.
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