SLCO1B1 and SLCO1B3 genetic mutations in Taiwanese patients with Rotor syndrome.

Rotor syndrome is a rare, benign, inherited disorder that is commonly associated with mild hyperbilirubinemia. It is caused by bi-allelic pathological variants in both SLCO1B1 and SLCO1B3 genes, causing defective OATP1B1 and OATP1B3 in the sinusoidal membrane and interrupted bilirubin uptake of the hepatocytes. We report five Taiwanese pediatric and adult patients aged 5-32 years presenting with conjugated hyperbilirubinemia, and were found to have genetic variants of SLCO1B1 and SLCO1B3. Two also had history of prolonged neonatal jaundice. Genetic analysis using panel-based next generation sequencing revealed three patients with homozygous mutations c.1738C>T (p.R580∗) in SLCO1B1 and a transposon LINE-1 insertion in SLCO1B3, one patient with homozygous mutations for another haplotype, c.757C>T (p.R253∗) in SLCO1B1 and c.1747+1G>A in SLCO1B3. Another patient had heterozygous c.1738C>T (p.R580∗) in SLCO1B1 linked with a LINE-1 insertion in SLCO1B3, and heterozygous c.757C>T (p.R253∗) in SLCO1B1 linked with c.1747+1G>A in SLCO1B3. In conclusion, we present the first time of genetic diagnosis of Rotor syndrome in Taiwan. Advanced genetic testing has enhanced the diagnosis of rare diseases with mild symptoms.

Benign inheritable disorders of bilirubin metabolism manifested by conjugated hyperbilirubinemia-A narrative review.

Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. Hyperbilirubinemia is an important clinical sign that needs to be investigated under a stepwise evaluation. Inherited non-hemolytic conjugated hyperbilirubinemic conditions include Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes). Although classically viewed as benign conditions requiring no treatment, they lately gained an increased interest since recent studies suggested that mutations in the responsible genes leading to hyperbilirubinemia, as well as minor genetic variants, may result in an increased susceptibility to drug toxicity. This article provides a comprehensive review on the pathophysiology of Dubin-Johnson and Rotor syndromes, presenting the current knowledge concerning the molecular details and basis of these conditions.

Intronic LINE-1 insertion in SLCO1B3 as a highly prevalent cause of rotor syndrome in East Asian population.

Rotor syndrome is caused by digenic loss-of-function variants in SLCO1B1 and SLCO1B3 but only a few studies have reported co-occurring inactivating variants from both genes. A rotor syndrome-causing long interspersed element-1 (LINE-1) insertion in SLCO1B3 had been reported to be highly prevalent in the Japanese population but there has been no additional report. In spite of its known association with various human diseases, LINE-1 is hard to detect with current sequencing technologies. In this study, we aimed to devise a method to screen the LINE-1 insertion variant and investigate the frequency of this variant in various populations. A chimeric sequence, that was generated by concatenating the reference sequence at the junction and a part of inserted LINE-1 sequence, was searched from 725 raw sequencing data files. In cases containing the chimeric sequence, confirmatory long-range PCR and gap-PCR were performed. In total, 95 (13.1%) of 725 patients were positive for the chimeric sequence, and all were confirmed to have the SLCO1B3 LINE-1 insertion by PCR-based tests. The same chimeric sequence was searched from the 1000 Genomes Project data repository and the carrier frequency was remarkably high in the East Asian populations (10.1%), especially in Southern Han Chinese (18.5%), but almost absent in other populations. This SLCO1B3 LINE-1 insertion should be screened in a population-specific manner under suspicion of Rotor syndrome and the methods proposed in this study would enable this in a simple way.

Complete Absence of the Extrahepatic Biliary Tree in a Newborn With Pigmented Stools.

"Yellow stools in neonatal cholestasis exclude biliary atresia." This conventional wisdom led to the development of the infant stool color card, which alerts parents to seek medical referral when pale stools are observed, a strategy that has been shown to improve survival in infants with biliary atresia (BA). Here, we present a case of a newborn with significant direct hyperbilirubinemia (direct bilirubin level of up to 9.2 mg/dL on day of life 10) who continued to produce colored stools. Whole-genome sequencing results were negative for genetic causes of cholestasis. Hepatobiliary scintigraphy findings were nonexcretory. A liver biopsy specimen revealed cholestasis, ductular hyperplasia, giant cell formation, minimal inflammation, minimal portal or periportal fibrosis, and no evidence of viral changes. On day of life 38, during the exploratory laparotomy, the patient was found to have complete absence of the extrahepatic biliary tree, or biliary aplasia, possibly a rare, severe form of BA. This report aims to increase our vigilance and help prevent diagnostic error in patients with signs and symptoms of BA who may produce pigmented stools. Primary care physicians should hence refer an infant (early and urgently) to a pediatric gastroenterologist for further workup for a direct bilirubin level >1.0 mg/dL with any total bilirubin level, irrespective of the color of the infant's stools.

Rotor Syndrome: Glucuronidated Bile Acidemia From Defective Reuptake by Hepatocytes.

Organic anion transporting polypeptide (OATP) 1B1 (gene, solute carrier organic anion transporter family member 1B1 [SLCO1B1]) and OATP1B3 (SLCO1B3) serve as transporters for hepatic uptake of important endogenous substances and several commonly prescribed drugs. Inactivation of both proteins together causes Rotor syndrome. How this OATP1B1/1B3 defect disturbs bile acid (BA) metabolism is largely unknown. In this study, we performed detailed BA analysis in 3 patients with genetically diagnosed Rotor syndrome. We found that BAs glucuronidated at the C-3 position (BA-3G) accounted for 50% or more of total BAs in these patients. In contrast but similarly to healthy controls, only trace amounts of BA-3G were detected in patients with constitutional indocyanine green excretory defect (OATP1B3 deficiency) or sodium-taurocholate cotransporting polypeptide (NTCP; gene, solute carrier family 10 member 1 [SLC10A1]) deficiency. Therefore, substantial amounts of BA-3G are synthesized in hepatocytes. The cycling pathway of BA-3G, consisting of excretion from upstream hepatocytes and uptake by downstream hepatocytes by OATP1B1/1B3 may exist to reduce the burden on upstream hepatocytes. Conclusion: Detailed BA analysis revealed glucuronidated bile acidemia in patients with Rotor syndrome. Further exploration of the physiologic role of glucuronidated BAs is necessary.

[Analysis of genetic variants in a case with Rotor syndrome].

OBJECTIVE: To explore the genetic basis for a patient featuring Rotor syndrome. METHODS: Clinical data of the patient was collected. Whole exome sequencing (WES) based on high-throughput sequencing technology was carried out. Long-interspersed element-1 (LINE-1) insertion in intron 5 of the SLCO1B3 gene was detected by using tri-primer single tube PCR. RESULTS: WES revealed that the patient has carried homozygous c.1738C>T nonsense variants of the SLCO1B1 gene. He was also found to harbor a homozygous insertion of LINE-1 in intron 5 of the SLCO1B3 gene, which has caused skipping of exon 5 or exons 5 to 7 and introduced a stop codon in the SLCO1B3 transcript. CONCLUSION: The homozygous c.1738C>T variant of the SLCO1B1 gene and homozygous insertion of LINE-1 in intron 5 of the SLCO1B3 gene probably underlay the Rotor syndrome in this patient.

Low efficacy of recombinant SV40 in Ugt1a1-/- mice with severe inherited hyperbilirubinemia.

In contrast to AAV, Simian Virus 40 (rSV40) not inducing neutralizing antibodies (NAbs) allowing re-treatment seems a promising vector for neonatal treatment of inherited liver disorders. Several studies have reported efficacy of rSV40 in animal models for inherited liver diseases. In all studies the ubiquitous endogenous early promoter controlled transgene expression establishing expression in all transduced tissues. Restricting this expression to the target tissues reduces the risk of immune response to the therapeutic gene. In this study a liver specific rSV40 vector was generated by inserting a hepatocyte specific promoter. This increased the specificity of the expression of hUGT1A1 in vitro. However, in vivo the efficacy of rSV40 appeared too low to demonstrate tissue specificity while increasing the vector dose was not possible because of toxicity. In contrast to earlier studies, neutralizing antibodies were induced. Overall, the lack of a platform to produce high titered and pure rSV40 particles and the induction of NAbs, renders it a poor candidate for in vivo gene therapy.

Is Hepatobiliary Scintigraphy Sufficient to Diagnose Rotor Syndrome in a 3-Year-Old Boy?

Rotor syndrome (RS) is a benign, inherited, commonly misdiagnosed cause of conjugated hyperbilirubinemia whose identification prevents unnecessary invasive investigations. We present the case of a 3-y-old boy with phenotypic and laboratory findings of RS but negative genetic test results, whose diagnosis was confirmed by hepatobiliary scintigraphy.

UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children: A retrospective analysis and quantitative correlation.

To retrospectively analyze and quantitatively correlate UGT1A1 (bilirubin UDP- glucuronosyltransferase gene) genotypes and unconjugated hyperbilirubinemia (UCH) phenotypes among Chinese children.We retrospectively reviewed UCH patients, quantitatively analyzed genotype-phenotype correlation by comparing with healthy controls. Pfam database, SWISS-model, and Pymol were used for UGT1A1 protein domain analysis and protein modeling for assessing the effect of novel missense variants on protein structure.Seventy four cases, including 21 prolonged unconjugated hyperbilirubinemia (PUCH), 30 Gilbert syndrome (GS), 22 Crigler-Najjar syndrome type II (CNS-II), and 1 Crigler-Najjar syndrome type I (CNS-I) phenotypes were analyzed. Total of 21 variants, including 7 novel variants (c.764T>A/p.L255Q, c.1112C>T/p.T371I, c.1028C>A/p.S343X, c.1047delG/p.I350YfsX16, c.996 + 5G>C/g.6923G>C, c.287G>A/p.G96E, and c.1142G>A/p.S381N) were found. In the multiple regression model, heterozygous A(TA)7TAA, G71R/P364L, and Y486D/other mutations were significantly associated with increased risk of GS, PUCH, and CNS-II, respectively. Total allele number is significantly associated with GS and CNS-II, with each increase in total allele number, the odds ratio (OR) of having GS and CNS-II increased by 1.46 and 4.47 fold, respectively. Having only functional polymorphisms in UGT1A1 gene is associated with increased risk of PUCH, and GS with OR values of 5.67 (95% CI: 1.52-21.13), and 3.88 (95% CI: 1.02-14.78), respectively. Having only mutation is associated with significantly increased risk of having GS phenotype (OR: 34.00, 95% CI: 4.65-248.37), but not CNS-II. Polymorphism plus mutation had the strongest association with CNS-II with OR value of 64.80 (95% CI: 7.68-546.41), followed by GS (OR: 4.53, 95% CI: 1.08-19.08).We detected 7 novel variants, and quantitatively calculated risks of having specific phenotypes using genetic data. Among Chinese children, G71R and P364L is independently associated with PUCH, A(TA)7TAA is associated with GS, and Y486D or other disease-causing mutations were associated with CNS-II. Multiple alleles were associated with more severe phenotypes. Combined variant of G71R+Y486D is a common occurrence among Chinese children with UCH.

Mutation responsible for congenital photosensitivity and hyperbilirubinemia in Southdown sheep.

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.

Coronary Artery Disease in Patients With Disorders of Bilirubin Excretion.

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.

Large copy-number variations in patients with statin-associated myopathy affecting statin myopathy-related loci.

Some patients are susceptible to statin-associated myopathy (SAM) either because of genetic variations affecting statin uptake and metabolism, or because they predispose their carriers to muscular diseases. Among the frequent variants examined using the genome-wide association study approach, SLCO1B1 c.521T>C represents the only validated predictor of SAM in patients treated with high-dose simvastatin. Our aim was to ascertain the overall contribution of large copy-number variations (CNVs) to SAM diagnosed in 86 patients. CNVs were detected by whole genome genotyping using Illumina HumanOmni2.5 Exome BeadChips. Exome sequence data were used for validation of CNVs in SAM-related loci. In addition, we performed a specific search for CNVs in the SLCO1B region detected recently in Rotor syndrome subjects. Rare deletions possibly contributing to genetic predisposition to SAM were found in two patients: one removed EYS associated previously with SAM, the other was present in LARGE associated with congenital muscular dystrophy. Another two patients carried deletions in CYP2C19, which may predispose to clopidogrel-statin interactions. We found no common large CNVs potentially associated with SAM and no CNVs in the SLCO1B locus. Our findings suggest that large CNVs do not play a substantial role in the etiology of SAM.

Clinical utility of next-generation sequencing in the diagnosis of hereditary haemolytic anaemias.

Hereditary haemolytic anaemias are genetically and phenotypically heterogeneous disorders characterized by increased red cell destruction, with consequences ranging from innocuous to severe life-threatening anaemia. Diagnostic laboratories endeavour to assist clinicians reach the exact patient diagnosis by using tests principally based on morphological and biochemical techniques. However, these routine studies may be inconclusive, particularly in newborn infants and when transfusions have recently been administered. Large numbers and size of the potentially involved genes also impose a practical challenge for molecular diagnosis using routine sequencing approaches. To overcome these diagnostic shortcomings, we have utilized next-generation sequencing to provide a high-throughput, highly sensitive assay. We developed a panel interrogating 28 genes encoding cytoskeletal proteins and enzymes with sequencing coverage of the coding regions, splice site junctions, deep intronic and regulatory regions. We then evaluated 19 samples, including infants with unexplained extreme hyperbilirubinaemia and patients with transfusion-dependent haemolytic anaemia. Where possible, inheritance patterns of pathogenic mutations were determined by sequencing of immediate relatives. We conclude that this next-generation sequencing panel could be a cost-effective approach to molecular diagnosis of hereditary haemolytic anaemia, especially when the family history is uninformative or when routine laboratory testing fails to identify the causative haemolytic process.

Analysis of uridine diphosphate glucuronosyl transferase 1A1 gene mutations in neonates with unconjugated hyperbilirubinemia.

This study was carried out to analyze uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) gene mutations in neonates with unconjugated hyperbilirubinemia, from two different ethnic groups. Polymerase chain reaction and gene sequencing were used to analyze the differences in genotypes and allele frequencies of different gene mutations among the ethnic groups; this was followed by checking their correlation with the serum bilirubin level and the occurrence of unconjugated hyperbilirubinemia in neonates. Our results reveal that the UGT1A1 mutant genotype, 211G>A, is distributed differently in the case vs control groups, as well as in the Zhuang vs Han ethnic groups. Moreover, this difference is statistically significant (P < 0.05); the total serum bilirubin (TSB) and unconjugated bilirubin (UCB) levels in patients carrying the single homozygous mutation, 211G>A, were markedly higher than that in patients without the mutation (P < 0.05). Furthermore, the TSB and UCB levels were significantly different between patients carrying single or compound 211G>A heterozygous mutation, (TA)6/7, and 1941C>G/2042C>G heterozygous mutation, and patients without mutation (P > 0.05). Our findings suggest that the 211G>A mutation in the first exon may be a risk factor for unconjugated hyperbilirubinemia in Zhuang and Han neonates. The serum bilirubin levels seem to be affected by the homozygosity or heterozygosity of the UGT1A1 gene mutation; 211G>A homozygous mutation is an important factor that causes a rise in bilirubin in neonates with unconjugated hyperbilirubinemia.

Causes of prolonged jaundice in infancy: 3-year experience in a tertiary paediatric centre.

UNLABELLED: Although prolonged jaundice (PJ) commonly occurs in infancy, there is not yet agreement as to the appropriate extent of investigations, particularly in otherwise well children. Significant pathologies may present with PJ in this age group and need to be considered. AIM: The aim of this retrospective study was to ascertain the causes of PJ in infants referred to a single tertiary paediatric centre. METHODS: Infants referred with PJ over a 3-year period were identified. Clinical documentation, electronic notes and results of investigations performed prior to and after referral were reviewed. RESULTS: One hundred and sixty-seven infants with PJ were seen. Fifty-eight percent were over 28 days of age. Four patients had conjugated hyperbilirubinaemia. Eighteen percent of patients were found to have a specific medical diagnosis causing or contributing to PJ, almost half of whom had normal clinical examination. The single most common pathological cause for PJ was hypothyroidism found in six patients. CONCLUSIONS: This study demonstrates that normal clinical examination and exclusion of conjugated hyperbilirubinaemia are insufficient to exclude pathological causes of PJ. Overall, these children were referred late. Guidelines, in conjunction with education initiatives, are required to optimise the management of prolonged jaundice in infancy.

Inherited disorders of bilirubin clearance.

Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective (i) unconjugated bilirubin uptake and intrahepatic storage, (ii) conjugation of glucuronic acid to bilirubin (e.g., Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), (iii) bilirubin excretion into bile (Dubin-Johnson syndrome), or (iv) conjugated bilirubin re-uptake (Rotor syndrome). In this review, the molecular mechanisms and clinical manifestations of these conditions are described, as well as current approaches to diagnosis and therapy.

Radionuclide cholescintigraphy in genetically confirmed Rotor syndrome.

A 7-year-old girl had been followed up for persistent conjugated hyperbilirubinemia since birth. Alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transpeptidase activity was within the normal range, and liver protein synthesis had always been normal. Infectious etiology of jaundice, autoimmune diseases, drug-induced liver injury, hemolytic anemia, α-1 anti-trypsin deficiency, Wilson disease and Gilbert syndrome were ruled out. At the age of 8 years the patient underwent radionuclide dynamic cholescintigraphy, indicating poor accumulation of the radiotracer in the liver on one hand, and severe retention of the radiopharmaceutical in the blood pool (including the heart) on the other hand. Rotor syndrome was suspected and finally confirmed on molecular analysis. This case represents the first cholescintigraphy report in a pediatric patient with genetically proven Rotor syndrome.

Recessive inheritance of population-specific intronic LINE-1 insertion causes a rotor syndrome phenotype.

Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases.

Gene replacement therapy for genetic hepatocellular jaundice.

Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy.

Hereditary hyperbilirubinemias.

Inherited disorders of bilirubin metabolism involve four autosomal recessive syndromes: Gilbert, CriglerNajjar, Dubin-Johnson and Rotor, among which the first two are characterized by unconjugated and the second two by conjugated hyperbilirubinemia. Gilbert syndrome occurs in 2%-10% of general population, while others are rare. Except for Crigler-Najjar syndrome, hereditary hyperbilirubinemias belong to benign disorders and thus no treatment is required.