Hiperbilirrubinemias hereditarias: un diagnóstico diferencial a considerar en ictericia / Hereditary hiperbilirrubinemias: a differential diagnosis to considerer in icterus

Las hiperbilirrubinemias hereditarias (HBH) son patologías originadas por defectos en las enzimas y proteínas que participan del metabolismo de la bilirrubina. El clearence de bilirrubina incluye captación y almacenamiento en hepatocitos, conjugación, excreción hacia la bilis y recaptura de su forma conjugada por hepatocitos. Las HBH varían de acuerdo a su patogenia, presentación clínica, niveles de bilirrubinemia y tratamientos disponibles. En general son poco frecuentes, a excepción del Síndrome de Gilbert. Están las que son de predominio indirecto, como el Síndrome de Gilbert y el de Crigler-Najjar, y las de predominio directo, como el Síndrome de Dubin-Johnson y el de Rotor. En general no requieren tratamiento específico y tienen curso benigno, a excepción del Síndrome de Crigler-Najjar para el cual existen medidas terapéuticas específicas a considerar, teniendo un pronóstico reservado para algunas de sus formas de presentación. Es importante el conocimiento de estos síndromes dado el alto índice de sospecha requerido para su diagnóstico y para su diferenciación de otras patologías hepatobiliares de mayor riesgo y severidad.

Hereditary hiperbilirrubinemias (HBH) are pathologies originated from the defect of the enzymes and proteins involved in the metabolism of bilirubin. The bilirubin clearance includes uptake and storage in hepatocytes, conjugation, excretion into bile and recapture of its conjugated form by hepatocytes. HBH vary according to their pathogenesis, clinical presentation, levels of bilirubin and available treatments. Generally they are infrequent, except for Gilbert Syndrome. There are those with indirect bilirubin predominance, such as Gilbert and Crigler-Najjar syndromes, and those with direct bilirubin predominance, including Dubin-Johnson and Rotor syndromes. In general, they do not require specific treatment and have a benign course, with the exception of the Crigler-Najjar Syndrome, for which there are specific therapeutic measures to consider, as well as a reserved prognosis for some of their forms of presentation. The knowledge of these syndromes is important 2 given the high index of suspicion required for its diagnosis and for its differentiation from other hepatobiliary pathologies of greater risk and severity.

Identification of a novel mutation in UDP-glucuronosyltransferase (UGT1A1) gene in a child with neonatal unconjugated hyperbilirubinemia.

Genetic alterations of the UGT1A1 gene result in Crigler-Najjar (CNS) and Gilbert's (GS)-Syndromes, two autosomal recessive conditions characterized by non-hemolytic unconjugated hyperbilirubinemia. While GS is characterized by mild hyperbilirubinemia, CNS is classified as follows: type I (CNS-I), often associated with irreversible neurological damage due to total deficiency of the UGT1A1 enzyme activity, and type II (CNS-II) where a minimal level of UGT1A1 enzyme activity is maintained. In this context, differential diagnosis of CNS forms needs to be supported by clinical molecular laboratory, in order to correlate biochemical findings to specific genetic mutations. Our paper describes in detail the peculiar clinical feature found in a child with severe neonatal unconjugated hyperbilirubinemia, where DNA analysis showed a new compound heterozygosis determined by two mutations, a known (c.508_510delTTC) and a novel mutation (c.1099C>T) giving a genotype compatible with clinical picture of CNS-II. This novel genotype extends the spectrum of known UGT1A1 mutations, which, in our opinion, could be higher than that currently reported in the literature. Finally, genetic analysis may also be helpful for patients' management.

Hiperbilirrubinemia indirecta de origen genético: informe de un caso de síndrome de Crigler-Najjar de tipo II / Indirect hyperbilirubinemia of genetic origin: case report of Crigler-Najjar syndrome type II

El síndrome de Crigler Najjar II aparece por un déficit en la conjugación de la bilirrubina debido a la deficiencia parcial de la enzima uridindifosfato-glucuronil transferasa. Por lo general, tiene un curso benigno, a diferencia del Crigler Najjar de tipo I, donde el déficit enzimático es total y los afectados mueren a edades tempranas. Se presenta el caso de una adolescente de16 años con hiperbilirrubinemia indirecta, síndrome convulsivante y parálisis cerebral. Una correcta historia clínica con estudio genealógico y pruebas funcionales apropiadas, permitieron determinar el diagnóstico definitivo. Esta enfermedad genética se transmite de forma autosómica recesiva, tiene una prevalencia muy baja a nivel mundial y constituye, en general, un reto diagnóstico para los médico.

Crigler Najjar syndrome type II is related to a defect of bilirubin conjugation due to partial deficiency of the enzyme uridine diphosphate-glucuronyl transferase. Usually has a benign course, unlike Crigler Najjar type I, where the enzyme deficiencyis total and the affected patients usually die at early ages. We present the case of a teenager with indirect hyperbilirubinemia, seizures and cerebral palsy. A good clinical historywith pedigree and appropriate functional tests allowed us to determine the definitive diagnosis. This is an autosomal recessive disorder, has a very low prevalence worldwide, and is adiagnostic challenge for physicians in general.

Hiperbilirrubinemia indirecta de origen genético: informe de un caso de síndrome de Crigler-Najjar de tipo II / Indirect hyperbilirubinemia of genetic origin: case report of Crigler-Najjar syndrome type II

El síndrome de Crigler Najjar II aparece por un déficit en la conjugación de la bilirrubina debido a la deficiencia parcial de la enzima uridindifosfato-glucuronil transferasa. Por lo general, tiene un curso benigno, a diferencia del Crigler Najjar de tipo I, donde el déficit enzimático es total y los afectados mueren a edades tempranas. Se presenta el caso de una adolescente de16 años con hiperbilirrubinemia indirecta, síndrome convulsivante y parálisis cerebral. Una correcta historia clínica con estudio genealógico y pruebas funcionales apropiadas, permitieron determinar el diagnóstico definitivo. Esta enfermedad genética se transmite de forma autosómica recesiva, tiene una prevalencia muy baja a nivel mundial y constituye, en general, un reto diagnóstico para los médico.(AU)

Crigler Najjar syndrome type II is related to a defect of bilirubin conjugation due to partial deficiency of the enzyme uridine diphosphate-glucuronyl transferase. Usually has a benign course, unlike Crigler Najjar type I, where the enzyme deficiencyis total and the affected patients usually die at early ages. We present the case of a teenager with indirect hyperbilirubinemia, seizures and cerebral palsy. A good clinical historywith pedigree and appropriate functional tests allowed us to determine the definitive diagnosis. This is an autosomal recessive disorder, has a very low prevalence worldwide, and is adiagnostic challenge for physicians in general.(AU)

Coding defect and a TATA box mutation at the bilirubin UDP-glucuronosyltransferase gene cause Crigler-Najjar type I disease.

Mutations at the bilirubin UDP-glucuronosyltransferase (transferase) gene in a severely hyperbilirubinemic Crigler-Najjar (CN) type I individual was compared with that in a moderately hyperbilirubinemic CN II individual. The CN-I (CF) patient in this study sustained a TATA box insertional mutation which was paired with a coding defect at the second allele, unlike all coding defects previously seen in CN-I patients. The sequence of the mutant TATA box, [A(TA)8A], also seen in the CN-II patient, was compared with that at the wild-type box, [A(TA)7A]. Transcriptional activity with [A(TA)8A] was 10-15% that with the wild-type box when present in the -1.7 kb upstream regulatory region (URR) of the bilirubin transferase UGT1A1 gene which was fused to the chloramphenicol acetyl transferase reporter gene, pCAT 1.7H, and transfected into HepG2 cells. Also, a construct with a TA deletion, [A(TA)6A], was prepared and used as a control; transcriptional activity was 65% normal. The coding region defect, R336W, seen in CF (CN-I) was placed in the bilirubin transferase UGT1A1 [HUG-Br1] cDNA, and its corresponding protein was designated UGT1A1*32. The UGT1A1*32 protein supported 0-10% normal bilirubin glucuronidation when expressed in COS-1 cells. The I294T coding defect seen at the second allele in SM (CN-II) generated the UGT1A1*33 mutant protein which supported 40-55% normal activity with a normal Km (2.5 microM) for bilirubin. The hyperbilirubinemia seen in SM decreased in response to phenobarbital treatment, unlike that seen in CF. Parents of the patients were carriers of the respective mutations uncovered in the offspring. The TATA box mutation paired with a deleterious missense mutation is, therefore, completely repressive in the CN-I patient, and is responsible for a lethal genotype/phenotype; but when homozygous, i.e. paired with itself, as previously reported in the literature, it is far less repressive and generates the mild Gilbert's phenotype.

Gunn rat: a model for inherited deficiency of bilirubin glucuronidation.

Experiments in Gunn rats have provided important insights into physiological, biochemical, and molecular mechanisms of bilirubin conjugation and disposition. The Gunn rat is a natural model for bilirubin encephalopathy, and much of our knowledge of bilirubin toxicity and its treatment has come from studies performed in Gunn rats. The genetic lesion in Gunn rats closely parallel those in Crigler-Najjar syndrome, Type I. Presently, the Gunn rat model is being used to develop methods for gene therapy for inherited bilirubin-UGT deficiency. Thus, Gunn rats continue to be a valuable model for the investigation of inherited UGT deficiency and severe nonhemolytic unconjugated hyperbilirubinemia.

[Hyperbilirubinemia in liver diseases]. / Hyperbilirubinämie bei Leberekrankungen.

Jaundice is often the first and sometimes the only symptom of liver disease. Besides in parenchymal liver disease jaundice is also observed in chronic non-haemolytic hyperbilirubinemias (Crigler-Najjar type I and II, Gilbert's syndrome) and in hereditary conjugated hyperbilirubinaemias (Dubin-Johnson- and Rotor-syndrome). A specific therapy is only available for Crigler-Najjar type II which is treated with phenobarbitone.

Nonhemolytic hyperbilirubinemias.

The familial nonhemolytic hyperbilirubinemias include the syndromes of Gilbert, Crigler-Najjar, Dubin-Johnson and Rotor. Gilbert's syndrome is probably very common in occult form, and patients come to clinical attention partially owing to subtle coincidental hemolysis. The biochemical defect may lie not in microsomal glucuronyl transferase but rather in the plasma membrane enzyme which transglucuronidates bilirubin monoglucuronide to diglucuronide. Patients with Crigler-Najjar type I, a severe disease, exhibit virtual absence of glucuronyltransferase. Type II is milder and appears related to Gilbert's syndrome. Dubin-Johnson's syndrome and Rotor's syndrome, the conjugated hyperbilirubinemias, are separate entities. The former is a block in hepatic excretion, while the defect in the latter lies at least partially in uptake of bilirubin.

New insights into the classification and mechanisms of hereditary, chronic, non-haemolytic hyperbilirubinaemias.

Gilbert's syndrome is typically associated with a deficiency in hepatic bilirubin UDP-glucuronosyltransferase activity (B-GTA). The overproduction of bilirubin that is often found in this condition could be a fortuitous coincidence that leads to the unmasking of the disease, which otherwise often remains latent. Some cases of chronic unconjugated hyperbilirubinaemia could, however, be related to a defect in hepatic uptake, as reflected by alterations in BSP kinetics. Severe deficiencies of hepatic B-GTA exist in all types of Crigler-Najjar disease. An increased proportion of bilirubin monoglucuronide is always found in bile when a B-GTA deficiency is present. This observation strongly suggests a common biochemical defect in Gilbert's syndrome and in Crigler-Najjar disease, and thus renders the suggestion that the latter condition may be separated into two groups somewhat inappropriate. There is, however, no doubt that further knowledge of the conjugating enzyme, or enzymes, is required: such information may lead to the characterisation of several types of enzymic defects. Whereas little is new as far as the Dubin-Johnson syndrome is concerned, Rotor's syndrome can no longer be considered to be a variant of the former. The transport defect which is involved in most cases of Rotor's syndrome, if not in all, is an impairment of hepatic storage, thus distinguishing it from the impairment of excretion which is involved in the Dubin-Johnson syndrome. The distinct patterns of urinary coproporphyrin excretion, which were recently reported in Dubin-Johnson and Rotor's syndromes, offer additional evidence for a clear differentiation between these two entities.