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Hepatology (Baltimore, Md.) Jun 2020We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate...
BACKGROUND AND AIMS
We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years.
APPROACH AND RESULTS
Unbound ("free") bilirubin (B ) was measured in patient sera to characterize the binding of unconjugated bilirubin (B ) to albumin (A) and validate their molar concentration ratio (B /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep B /A at least 30% below intravascular B binding capacity (i.e., B /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (L ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to B (R = 0.71) and B /A (R = 0.76), and B as a percentage of B correlated inversely to the bilirubin-albumin equilibrium association binding constant (R = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak B ≥ 30 mg/dL and B /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm •nm for 9.2 ± 1.1 hours/day kept B and B /A within safe limits throughout childhood, but B increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized B and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe.
CONCLUSION
Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.
Topics: Adolescent; Bilirubin; Brain Diseases; Crigler-Najjar Syndrome; Female; Glucuronosyltransferase; Homozygote; Humans; Infant, Newborn; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Transplantation; Male; Phototherapy; Risk Assessment; Serum Albumin; United States
PubMed: 31553814
DOI: 10.1002/hep.30959 -
Annales de Biologie Clinique 2001Gilbert syndrome (GS), characterized by mild, chronic and isolated unconjugated hyperbilirubinemia is due to a partial deficiency of... (Review)
Review
Gilbert syndrome (GS), characterized by mild, chronic and isolated unconjugated hyperbilirubinemia is due to a partial deficiency of bilirubin-UDP-glucuronosyltransferase (UGT1A1). Recently, the genetic basis of GS has been identified in caucasian populations : it is related to the insertion of a dinucleotide (TA) in the promoter region of the UGT1A1 gene. In Asian populations, GS is due to missense mutations (either homozygous or heterozygous) in the coding sequence. The aim of this study was to develop a simple and rapid method to detect both genetic polymorphisms and mutations. This technique was performed (1) to explore unrelated unconjugated hyperbilirubinemia; (2) to evaluate the frequency of GS in a population of 97 healthy caucasian volunteers: 17% of them were homozygous for the TA7/TA7 polymorphism; (3) to determine the incidence of this syndrome in a population of 105 neonates with unconjugated hyperbilirubinemia. The incidence of GS (15%) was not significantly higher than it was in the control group. A correlation between GS genotype and neonatal jaundice was not established; (4) to seek a relationship between GS and preeclampsia with or without Hellp syndrome. The incidence in the Hellp syndrome group (n = 19) was 26%, two fold higher than in preeclampsia group (n = 22) and control group (n = 50) with only 14% and 13% respectively, (5) to start a study regarding the toxicity of irinotecan treatment in a population of homozygous children for the UGT1A1 polymorphism.
Topics: Gilbert Disease; Humans; Molecular Biology
PubMed: 11174102
DOI: No ID Found -
World Journal of Clinical Cases May 2020Both Gilbert's syndrome (GS) and hereditary spherocytosis (HS) are common genetic disorders. However, comorbidity of GS with HS has always been considered a rare...
BACKGROUND
Both Gilbert's syndrome (GS) and hereditary spherocytosis (HS) are common genetic disorders. However, comorbidity of GS with HS has always been considered a rare phenomenon, and it can impede accurate diagnoses in the presence of isolated unconjugated hyperbilirubinemia.
CASE SUMMARY
In a study on Levitt's carbon monoxide (CO) breath test for the differential diagnosis of isolated hyperbilirubinemia, we found six GS patients with HS in 6 mo. The patients, including five males and one female, aged 25-58 years, were from four families and generally in good health. Their chronic fluctuating jaundice and/or hyperbilirubinemia had been diagnosed as simple constitutional jaundice for 6-30 years. Liver function tests showed isolated unconjugated hyperbilirubinemia with serum total bilirubin ranging from 20.7-75.4 μmol/L. Blood hemoglobin was normal in five cases, and slightly decreased in one (11.5 g/dL). Overt hemolytic signs were absent, while erythrocyte lifespan determined by the newly developed Levitt's CO breath test was significantly short (15-50 d), definitely demonstrating the presence of hemolysis. Given that their unconjugated hyperbilirubinemia compared inappropriately with hemolytic severity, as indicated by the hemoglobin level, further combined genetic tests for both and hereditary erythrocyte deficiencies were conducted. These tests confirmed, at last, the coexistence of GS with HS.
CONCLUSION
Comorbidity of GS and HS might not be uncommon in isolated unconjugated hyperbilirubinemia. While CO breath test would sensitively detect the hemolysis, the discordance between the hyperbilirubinemia and hemoglobin level could strongly indicate the coexistence of GS and HS.
PubMed: 32518793
DOI: 10.12998/wjcc.v8.i10.2001 -
American Journal of Veterinary Research May 2018OBJECTIVE To identify the genetic cause for congenital photosensitivity and hyperbilirubinemia (CPH) in Southdown sheep. ANIMALS 73 Southdown sheep from a CPH research...
OBJECTIVE To identify the genetic cause for congenital photosensitivity and hyperbilirubinemia (CPH) in Southdown sheep. ANIMALS 73 Southdown sheep from a CPH research flock and 48 sheep of various breeds from commercial flocks without CPH. PROCEDURES Whole-genome sequencing was performed for a phenotypically normal Southdown sheep heterozygous for CPH. Heterozygous variants within Slco1b3 coding exons were identified, and exons that contained candidate mutations were amplified by PCR assay methods for Sanger sequencing. Blood samples from the other 72 Southdown sheep of the CPH research flock were used to determine plasma direct and indirect bilirubin concentrations. Southdown sheep with a plasma total bilirubin concentration < 0.3 mg/dL were classified as controls, and those with a total bilirubin concentration ≥ 0.3 mg/dL and signs of photosensitivity were classified as mutants. Sanger sequencing was used to determine the Slco1b3 genotype for all sheep. Genotypes were compared between mutants and controls of the CPH research flock and among all sheep. Protein homology was measured across 8 species to detect evolutionary conservation of Slco1b. RESULTS A nonsynonymous mutation at ovine Chr3:193,691,195, which generated a glycine-to-arginine amino acid change within the predicted Slco1b3 protein, was significantly associated with hyperbilirubinemia and predicted to be deleterious. That amino acid was conserved across 7 other mammalian species. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested a nonsynonymous mutation in Slco1b3 causes CPH in Southdown sheep. This disease appears to be similar to Rotor syndrome in humans. Sheep with CPH might be useful animals for Rotor syndrome research.
Topics: Animals; Bilirubin; Breeding; Disease Models, Animal; Female; Genetic Variation; Genotype; Heterozygote; Hyperbilirubinemia, Hereditary; Male; Mutation; Phenotype; Photosensitivity Disorders; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Sheep; Sheep Diseases; Solute Carrier Organic Anion Transporter Family Member 1B3
PubMed: 29688779
DOI: 10.2460/ajvr.79.5.538 -
Liver Transplantation : Official... Jan 2009More than 30 years after the first hepatocyte transplant to treat the Gunn rat, the animal model for Crigler-Najjar syndrome, there are still a number of impediments to... (Review)
Review
More than 30 years after the first hepatocyte transplant to treat the Gunn rat, the animal model for Crigler-Najjar syndrome, there are still a number of impediments to hepatocyte transplantation. Numerous animal models are still used in work aimed at improving hepatocyte engraftment and/or long-term function. Although other cell sources, particularly hepatic and extrahepatic stem cells, are being explored, adult hepatocytes remain the cells of choice for the treatment of liver diseases by cell therapy. In recent years, diverse approaches have been developed in various animal models to enhance hepatocyte transduction and amplification in vitro and cell engraftment and functionality in vivo. They have led to significant progress in hepatocyte transplantation for the treatment of patients with metabolic diseases and for bridging patients with acute injury until their own livers regenerate. This review presents and considers the results of this work with a special emphasis on procedures that might be clinically applicable.
Topics: Animals; Cell Transplantation; Cell- and Tissue-Based Therapy; Crigler-Najjar Syndrome; Disease Models, Animal; Hepatocytes; Humans; Liver; Liver Regeneration; Mice; Rats; Stem Cells; Syndrome; Tissue Engineering
PubMed: 19109838
DOI: 10.1002/lt.21670 -
Gut Jun 1978This review deals with the development of our understanding of the chemistry of bilirubin and its glucuronide derivatives during the years 1952-1977. It examines the... (Review)
Review
This review deals with the development of our understanding of the chemistry of bilirubin and its glucuronide derivatives during the years 1952-1977. It examines the relation between haem metabolism and bilirubin formation and our present knowledge of hepatic transport of bilirubin. The heterogeneity of familial hyperbilirubinaemia is discussed.
Topics: Animals; Bilirubin; Biological Transport; Carrier Proteins; Chemical Phenomena; Chemistry; Glucuronates; Glucuronosyltransferase; Heme; Humans; Hyperbilirubinemia, Hereditary; Liver
PubMed: 98394
DOI: 10.1136/gut.19.6.481 -
Cells Sep 2023Bilirubin-induced neurological damage (BIND), which might progress to kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus...
Bilirubin-induced neurological damage (BIND), which might progress to kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus enabling albumin-unbound free bilirubin (BF) to cross the blood-brain barrier and accumulate within. A defect in the UGT1A1 enzyme-encoding gene, which is directly responsible for bilirubin conjugation, can cause Crigler-Najjar syndrome (CNS) and Gilbert's syndrome. We used human-induced pluripotent stem cell (hiPSC)-derived 3D brain organoids to model BIND in vitro and unveil the molecular basis of the detrimental effects of BF in the developing human brain. Healthy and patient-derived iPSCs were differentiated into day-20 brain organoids, and then stimulated with 200 nM BF. Analyses at 24 and 72 h post-treatment point to BF-induced neuro-inflammation in both cell lines. Transcriptome, associated KEGG, and Gene Ontology analyses unveiled the activation of distinct inflammatory pathways, such as cytokine-cytokine receptor interaction, MAPK signaling, and NFκB activation. Furthermore, the mRNA expression and secretome analysis confirmed an upregulation of pro-inflammatory cytokines such as IL-6 and IL-8 upon BF stimulation. This novel study has provided insights into how a human iPSC-derived 3D brain organoid model can serve as a prospective platform for studying the etiology of BIND kernicterus.
Topics: Humans; Crigler-Najjar Syndrome; Induced Pluripotent Stem Cells; Kernicterus; Brain; Cytokines; Bilirubin
PubMed: 37759499
DOI: 10.3390/cells12182277 -
Gastroenterologie Clinique Et Biologique May 2004
Review
Topics: Bile Ducts; Carrier Proteins; Cholestasis, Intrahepatic; Cholesterol; Cystic Fibrosis; Female; Humans; Jaundice, Chronic Idiopathic; Lithiasis; Liver; Multidrug Resistance-Associated Proteins; Pregnancy; Pregnancy Complications; Receptors, Cytoplasmic and Nuclear; Sitosterols
PubMed: 15213671
DOI: 10.1016/s0399-8320(04)94995-0 -
Saudi Journal of Gastroenterology :... 2023Dubin-Johnson syndrome (DJS) presents during the neonatal period with a phenotype that overlaps with a broad list of causes of neonatal cholestasis (NC), which makes the... (Review)
Review
BACKGROUND
Dubin-Johnson syndrome (DJS) presents during the neonatal period with a phenotype that overlaps with a broad list of causes of neonatal cholestasis (NC), which makes the identification of DJS challenging for clinicians. We conducted a case-controlled study to investigate the utility of urinary coproporphyrins (UCP) I% as a potential diagnostic biomarker.
METHODS
We reviewed our database of 533 cases of NC and identified 28 neonates with disease-causing variants in ATP-binding cassette-subfamily C member 2 (ABCC2) gene "Cases" (Study period 2008-2019). Another 20 neonates with cholestasis due to non-DJS diagnoses were included as "controls." Both groups underwent UCP analysis to measure CP isomer I percentage (%).
RESULTS
Serum alanine aminotransferase (ALT) levels were within the normal range in 26 patients (92%) and mildly elevated in 2 patients. ALT levels were significantly lower in neonates with DJS than in NC from other causes (P < 0.001). The use of normal serum ALT levels to predict DJS among neonates with cholestasis had a sensitivity of 93%, specificity 90%, positive predictive value (PPV) 34%, and negative predictive value (NPV) 99.5%. The median UCPI% was significantly higher in DJS patients [88%, interquartile range (IQR) 1-IQR3, 84.2%-92.7%] than in NC from other causes [67%, (IQR1-IQR3, 61%-71.5%; Confidence interval 0.18-0.28; P< 0.001)]. The use of UCPI% >80% to predict DJS had a sensitivity, specificity, PPV, and NPV of 100%.
CONCLUSION
Based on the results from our study, we propose sequencing of the ABCC2 gene in neonates with normal ALT, presence of cholestasis and UCP1% >80%.
Topics: Humans; Alanine Transaminase; Biomarkers; Cholestasis; Coproporphyrins; Jaundice, Chronic Idiopathic; Infant, Newborn
PubMed: 37313948
DOI: 10.4103/sjg.sjg_480_22 -
CMAJ : Canadian Medical Association... Sep 2006Severe hyperbilirubinemia is the most common cause of neonatal readmission to hospital in Canada even though, in the majority of cases, risk factors can be identified...
BACKGROUND
Severe hyperbilirubinemia is the most common cause of neonatal readmission to hospital in Canada even though, in the majority of cases, risk factors can be identified before discharge. Severe neonatal hyperbilirubinemia and kernicterus continue to be reported worldwide in otherwise healthy term infants. We conducted this study to estimate the incidence of severe neonatal hyperbilirubinemia in Canada and to determine underlying causes, improved knowledge of which would be valuable to help identify strategies for risk reduction.
METHODS
Data on term infants 60 days of age and younger with unconjugated hyperbilirubinemia were collected prospectively through the Canadian Paediatric Surveillance Program from 2002 to 2004. Infants were included if they had a peak serum total bilirubin level of more than 425 micromol/L or underwent an exchange transfusion. Infants with rhesus iso-immunization or who were born at less than 36 weeks' gestation were excluded.
RESULTS
Of 367 cases reported, 258 were confirmed to be severe neonatal hyperbilirubinemia, for an estimated incidence of 1 in 2480 live births. Causes were identified in 93 cases and included ABO incompatibility (n = 48), glucose-6-phosphate dehydrogenase deficiency (n = 20), other antibody incompatibility (n = 12) and hereditary spherocytosis (n = 7). The mean peak bilirubin level reported was 471 micromol/L (standard deviation [SD] 76 micromol/L, range 156-841 micromol/L). Fifty-seven infants (22.1%) underwent an exchange transfusion. A total of 185 infants (71.7%) were readmitted to hospital, 121 (65.4%) of them within 5 days of age.
INTERPRETATION
Severe neonatal hyperbilirubinemia continues to occur frequently in Canada. In the majority of cases, the underlying cause was not identified. The high readmission rate within days after initial discharge indicates a need for a more thorough assessment of newborn infants and consideration of strategies to identify at-risk newborns, such as predischarge measurement of serum bilirubin levels.
Topics: Adult; Bilirubin; Canada; Exchange Transfusion, Whole Blood; Female; Humans; Hyperbilirubinemia, Neonatal; Incidence; Infant; Infant, Newborn; Male; Patient Readmission; Population Surveillance; Risk Factors
PubMed: 16966660
DOI: 10.1503/cmaj.060328