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Translational Pediatrics Apr 2021Sodium-taurocholate cotransporting polypeptide (NTCP) deficiency is a newly reported hereditary bile acid metabolic disease. Here we describe the clinical...
Sodium-taurocholate cotransporting polypeptide (NTCP) deficiency is a newly reported hereditary bile acid metabolic disease. Here we describe the clinical characteristics of 12 cases of pediatric NTCP deficiency, as well as review 60 previously reported cases in the literature in order to provide better guidance for pediatricians. The clinical records, laboratory and imaging data were collected of 12 cases who were treated at the pediatric infectious disease department of the West China Second University Hospital of Sichuan University, China, from December 2018 to July 2020. PubMed and Wanfang databases were searched and 11 studies including 60 pediatric NTCP deficiency patients from January 2015 to November 2020 were retrieved. In our center, there were 4 girls and 8 boys, with a median age at admission of 9.9 months (range, 2.2 to 70 months). Six patients (50%) had prolonged neonatal jaundice. All of the patients (12/12; 100%) had normal growth and development. The reason for the first visit was prolonged neonatal jaundice (4/12, 33.3%), non-liver related diseases (6/12, 50%) and routine checkup (2/12, 16.7%). Hypercholanemia was documented in 12/12 (100%), elevated aspartate aminotransferase (AST) in 6/12 (50%), and elevated alanine aminotransferase (ALT) in 1/12 (8.3%). All of the patients (12/12; 100%) had homozygous mutations of c.800C>T in SLC10A1. Sixty patients (22 girls and 38 boys) were included in the literature review; 36 (60%) had hyperbilirubinemia after 1 month. The reasons for testing for hypercholanemia were identified in 47/60 cases, and included prolonged neonatal jaundice and neonatal transient cholestasis in 26 (26/47, 55.3%); non-liver related diseases in 14 (14/47, 29.8%); routine medical examination in 3 (3/14, 6.4%); volunteer recruitment in 1 (1/14, 7.1%); dark urine in 1 (1/47, 2.1%). Hypercholanemia was confirmed in 60/60 (100%); 31 (51.7%) had elevated AST, and 10 (16.7%) had elevated ALT. Among 59 Chinese patients, 52 (88.1%) had homozygous mutations of c.800C>T in SLC10A1. The most common symptom of pediatric NTCP deficiency is jaundice. NTCP deficiency can also be detected during routine check-ups. The common biochemical features are hypercholanemia and elevated AST. Screening for c.800C>T mutation in SLC10A1 is useful for primary genetic screening in Chinese infants with persistent hypercholanemia after infectious, structural, and immunological factors are excluded.
PubMed: 34012853
DOI: 10.21037/tp-20-360 -
PloS One 2021In contrast to AAV, Simian Virus 40 (rSV40) not inducing neutralizing antibodies (NAbs) allowing re-treatment seems a promising vector for neonatal treatment of...
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.
Topics: Animals; Antibodies, Neutralizing; Cell Line, Tumor; Genetic Therapy; Genetic Vectors; Glucuronosyltransferase; Humans; Hyperbilirubinemia, Hereditary; Liver; Mice; Mice, Knockout; Promoter Regions, Genetic; Simian virus 40; Tissue Distribution; Transcriptional Activation
PubMed: 33891666
DOI: 10.1371/journal.pone.0250605 -
Hepatology Communications Apr 2021Organic anion transporting polypeptide (OATP) 1B1 (gene, solute carrier organic anion transporter family member 1B1 []) and OATP1B3 () serve as transporters for hepatic...
Organic anion transporting polypeptide (OATP) 1B1 (gene, solute carrier organic anion transporter family member 1B1 []) and OATP1B3 () 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 []) 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. Detailed BA analysis revealed glucuronidated bile acidemia in patients with Rotor syndrome. Further exploration of the physiologic role of glucuronidated BAs is necessary.
Topics: Aged; Aged, 80 and over; Bile Acids and Salts; Child; Female; Hepatocytes; Humans; Hyperbilirubinemia, Hereditary; Infant; Male; Middle Aged; Organic Anion Transporters; Solute Carrier Organic Anion Transporter Family Member 1B3
PubMed: 33860121
DOI: 10.1002/hep4.1660 -
Trends in Psychiatry and Psychotherapy 2021Gilbert's syndrome (GS) is a benign genetic disorder that is characterized by intermittent mild jaundice in which the liver doesn't process bilirubin properly. The aim...
OBJECTIVE
Gilbert's syndrome (GS) is a benign genetic disorder that is characterized by intermittent mild jaundice in which the liver doesn't process bilirubin properly. The aim of this study was to determine whether GS patients have a different personality structure and if there are associations between properties of temperament and character and total bilirubin levels.
METHODS
A total of 1665 young male individuals aged from 19 to 30 who were admitted for occupational examinations were included in this study. Careful patient history was taken, a detailed physical examination was conducted, and hematologic and biochemical tests and abdominal ultrasonography were performed. The Turkish version of the Temperament and Character Inventory (TCI) was administered to all participants. 81 patients diagnosed with GS and 150 randomly chosen healthy individuals (control group) were investigated with comparison and correlation analyses.
RESULTS
GS patients had higher scores than healthy controls for disorderliness (NS4) (p = 0.018), sentimentality (RD1) (p = 0.042), and fatigability (HA4) (p = 0.03). Moreover, Gilbert syndrome patients scored lower than controls for empathy (C2) (p = 0.041) and transpersonal identification (ST2) (p = 0.044). Bilirubin levels were positively associated with disorderliness (NS4) (r = 0.141, p = 0.032) and fatigability (HA4) (r = 0.14, p = 0.033).
CONCLUSIONS
GS patients may have some different personality characteristics from healthy individuals. This study is an initial exploration of the personality structure of GS patients and the findings should be interpreted with caution. Further prospective studies are needed to identify the relationship between Gilbert disease and personality characteristics.
Topics: Bilirubin; Gilbert Disease; Humans; Male; Personality; Personality Disorders
PubMed: 33844900
DOI: 10.47626/2237-6089-2020-0003 -
Diabetology International Apr 2021Glycated hemoglobin (HbA1c) is an important indicator of glycemic control in patients with diabetes. High-performance liquid chromatography (HPLC) is the most commonly...
Glycated hemoglobin (HbA1c) is an important indicator of glycemic control in patients with diabetes. High-performance liquid chromatography (HPLC) is the most commonly used method for measuring HbA1c levels; as HPLC measures all hemoglobin types, the values can be influenced by hemoglobin variants. Moreover, as HPLC-HbA1c levels are low in some diseases, including hemolytic anemia, it may be difficult to differentiate hemoglobin variants from these diseases based on HPLC-HbA1c levels alone. Similar HbA1c values using both HPLC and immunoassays (IAs) are noted for these diseases, while discrepancies are noted in the case of hemoglobin variants. Herein, we describe our process of differential diagnosis for hereditary spherocytosis, the most common inherited hemolytic anemia, in a 56-year-old man presenting with a low HPLC-HbA1c level compared to the glucose concentration, concomitant with anemia, jaundice, hyperbilirubinemia, cholelithiasis, and splenomegaly. There was a discrepancy between HbA1c levels measured with HPLC and IAs and glycated albumin levels. The possibility of hemoglobin variants was unlikely, based on the chromatography and isoelectric focusing results. The haptoglobin levels and reticulocyte counts were low and high, respectively. The direct and indirect Coomb's tests were negative. The presence of spherocytes on blood smears and flow cytometric analysis of the eosin-5-maleimide binding test supported a diagnosis of hereditary spherocytosis. We recommend that when a discrepancy between HPLC-HbA1c levels and glucose concentrations is noted, clinicians should consider hemolysis or hemoglobin variants as the diagnosis. It should be considered that a discrepancy between HbA1c levels measured with HPLC and IAs does not specifically exclude hemolysis.
PubMed: 33786277
DOI: 10.1007/s13340-020-00456-4 -
Frontiers in Pharmacology 2021Unconjugated bilirubin (UCB) is more than the final product of heme catabolism. Mildly elevated systemic bilirubin concentrations, such as in Gilbert syndrome (GS),...
Unconjugated bilirubin (UCB) is more than the final product of heme catabolism. Mildly elevated systemic bilirubin concentrations, such as in Gilbert syndrome (GS), protect against various oxidative stress-mediated and metabolic diseases, including cardiovascular disease, type 2 diabetes mellitus, metabolic syndrome, cancer, and age-related disease. The Gunn rat is an animal model of hereditary hyperbilirubinemia widely used in assessing the effect of high serum bilirubin concentration in various organs. The present work aims to understand if life-long hyperbilirubinemia and bilirubin-priming might contribute to protection against atherosclerosis and diabetic nephropathy (DN) at the cellular level. Primary aortic endothelial cells and podocytes obtained from hyperbilirubinemic homozygous jj and normobilirubinemic heterozygous Nj Gunn rats were exposed to Palmitic Acid (PA) and Angiotensin II (Ang II), respectively, and the effects on cell viability and the activation of damage-related metabolic pathways evaluated. Results were validated on immortalized H5V and HK2 cells exposed to damage after UCB pretreatment. In both primary cell models, cells obtained from jj Gunn rats showed as significantly higher than Nj Gunn rats at any dose of the toxic agent. Reduction in CHOP expression and IL-6 release was observed in jj primary aortic endothelial cells exposed to PA compared to Nj cells. The same occurred on H5V pretreated with Unconjugated bilirubin. Upon Ang II treatment, primary podocytes from jj Gunn rats showed lower DNA fragmentation, cleaved caspase-3, and cleaved PARP induction than primary podocytes from Nj Gunn rats. In HK2 cells, the induction by Ang II of HIF-1α and LOXl2 was significantly reduced by UCB pretreatment. Our data suggest that in models of atherosclerosis and DN life-long hyperbilirubinemia exposure or bilirubin-priming significantly contribute to decrease the injury by enhancing thecellular defensive response.
PubMed: 33776779
DOI: 10.3389/fphar.2021.646953 -
Medicine Mar 2021The etiology of non-immune hydrops fetalis is complex, and its prognosis is poor. One of its main causes is anemia. There are few reports on hydrops fetalis due to...
RATIONALE
The etiology of non-immune hydrops fetalis is complex, and its prognosis is poor. One of its main causes is anemia. There are few reports on hydrops fetalis due to anemia caused by hereditary spherocytosis (HS), especially regarding its occurrence in the neonatal period. Thus, we report on a case of neonatal HS caused by a new SPTB gene mutation that was characterized by hydrops fetalis.
PATIENT CONCERNS
A neonate with intrauterine hydrops fetalis showed severe hyperbilirubinemia and anemia, reticulocytosis, and hepatosplenomegaly. Laboratory examination findings were normal.
DIAGNOSES
Gene sequencing of the patient and his parents showed a de novo frameshift mutation in the patient's SPTB gene. Ultimately, the patient was diagnosed with HS.
INTERVENTIONS
Exchange and red blood cell transfusions were performed in the neonatal period.
OUTCOMES
The child was discharged from the hospital 14 days postnatal because his hemoglobin and bilirubin levels were stable. Red blood cell transfusion was performed once in infancy; however, no further red blood cell transfusions were required within 2 years of age.
LESSONS
Hydrops fetalis can be a manifestation of HS. Genetic detection can help confirm the diagnosis of suspected neonatal HS undocumented by other laboratory examinations.
Topics: DNA Mutational Analysis; Erythrocyte Transfusion; Frameshift Mutation; Hemoglobins; Humans; Hydrops Fetalis; Infant, Newborn; Male; Spectrin; Spherocytosis, Hereditary; Treatment Outcome
PubMed: 33761640
DOI: 10.1097/MD.0000000000024804 -
Journal of Nuclear Medicine Technology Jun 2021Rotor syndrome (RS) is a benign, inherited, commonly misdiagnosed cause of conjugated hyperbilirubinemia whose identification prevents unnecessary invasive...
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.
Topics: Child, Preschool; Diagnosis, Differential; Humans; Hyperbilirubinemia, Hereditary; Liver; Male; Radionuclide Imaging
PubMed: 33722924
DOI: 10.2967/jnmt.120.257618 -
Revista Espanola de Enfermedades... Aug 2021We present the case of a 35-year-old female with a history of polycystic ovary syndrome, treated with oral contraceptives. She was under study due to nine months...
We present the case of a 35-year-old female with a history of polycystic ovary syndrome, treated with oral contraceptives. She was under study due to nine months evolution of pain in the right iliac fossa, associated with hyporexia and mild hyperbilirubinemia with a predominance of the conjugated fraction (total Bi 3.7 mg/dl, conjugated Bi 2.9 mg/dl). An abdominal computed tomography (CT) was performed showing homogeneous hepatosplenomegaly and adenopathies in both iliac chains, the largest in the right external iliac chain of 1.6 x 3.6 cm.
Topics: Adult; Female; Humans; Hyperbilirubinemia; Jaundice, Chronic Idiopathic; Laparoscopy; Tomography, X-Ray Computed
PubMed: 33657825
DOI: 10.17235/reed.2021.7866/2021 -
Gene May 2021Gilbert's syndrome (GS) is a mild condition characterized by periods of hyperbilirubinemia, which results in variations in the UDP-glucuronosyltransferase 1 (UGT1A1)...
Gilbert's syndrome (GS) is a mild condition characterized by periods of hyperbilirubinemia, which results in variations in the UDP-glucuronosyltransferase 1 (UGT1A1) gene. Variant genotypes of UGT1A1 vary in different populations in the world. The present study aimed to determine the genotype of the UGT1A1 promoter and exon that are related to the serum total bilirubin (STB) level in the Chinese Han population. A total of 120 individuals diagnosed with GS (GS group) and 120 healthy individuals (non-GS group) were enrolled. Routine blood, liver function tests, and antibodies associated with autoimmune liver diseases were assessed. Blood samples were collected for DNA purification. Sequencing of the UGT1A1 promoter and exons was conducted for post segment amplification by PCR. Compound heterozygous UGT1A1*28 and UGT1A1*6 (25/120, 20.83%), single homozygous UGT1A1*28 (24/120, 20.00%) and single heterozygous UGT1A1*6 (18/120, 15.00%) were the most frequent genotypes in the GS group. However, single heterozygous UGT1A1*6 (30/120, 25.00%) and single heterozygous UGT1A1*28 (19/120, 15.83%) were the most frequent genotypes in the non-GS group. Further, the frequencies of single homozygous UGT1A1*28, compound heterozygous UGT1A1*28 and UGT1A1*6, and compound heterozygous UGT1A1*28, UGT1A1*6 and UGT1A1*27 were significantly higher in the GS group than those in the non-GS group. The STB levels of GS patients with the homozygous UGT1A1*28 genotype were remarkably higher than those of patients with other genotypes. Homozygous UGT1A1*28 and heterozygous UGT1A1*6 variants were associated with the highest and lowest risks of hyperbilirubinemia, respectively. Our study revealed that compound heterozygous UGT1A1*28 and UGT1A1*6, or single homozygous UGT1A1*28 are major genotypes associated with GS in Chinese Han people. These findings might facilitate the precise genomic diagnosis of Gilbert's syndrome.
Topics: Adult; Asian People; Bilirubin; China; Female; Genotype; Gilbert Disease; Glucuronosyltransferase; Heterozygote; Homozygote; Humans; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Promoter Regions, Genetic
PubMed: 33631237
DOI: 10.1016/j.gene.2021.145526