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Wu M, Li A, Zhang T, Ding W, Wei Y, Wan C, Ke B, Cheng H, Jin C, Kong C. The novel prognostic analysis of AML based on ferroptosis and cuproptosis related genes. J Trace Elem Med Biol 2024; 86:127517. [PMID: 39270538 DOI: 10.1016/j.jtemb.2024.127517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/27/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a hematological malignancy. The aim of this research was to develop a ferroptosis and cuproptosis related novel prognostic signature associated with AML. METHODS The ferroptosis and cuproptosis related genes correlated with the prognosis of AML were identified by univariate Cox analysis. The consistent cluster analysis was performed for 150 AML patients in TCGA dataset. The key module genes associated with GSVA score of ferroptosis and cuproptosis were identified by WGCNA. univariate Cox and LASSO regression analysis were adopted to build a ferroptosis and cuproptosis AML prognostic signature. Finally, the expression of five prognostic genes in clinical tissue samples were verified by RT-qPCR. RESULTS A grand total of 27 FCRGs associated with AML prognosis were identified.Then, two AML sub-types with significantly different survival were obtained. We found 3 significantly differential expressed immune cells (naive CD4 cells, regulatory T cells and resting mast cells) between two risk sub-groups. Meanwhile, 'IL6 JAK STAT3 signaling' and 'P53 pathway' were enriched in low-risk group. A ferroptosis and cuproptosis related prognostic signature was build based on 8 prognostic genes. RT-qPCR results indicated that there was no significant difference in the expression of OLFML2A and CD109 between AML and normal samples. However, compared to the control group, LGALS1, SOCS1, and RHOC showed significantly lower expression in the AML group. CONCLUSION The prognostic signature comprised of OLFML2A, LGALS1, ABCB11, SOCS1, RHOC, CD109, RD3L and PTPN13 based on ferroptosis and cuproptosis was established, which provided theoretical basis for the research of AML.
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Affiliation(s)
- Mei Wu
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Anan Li
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Tingting Zhang
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Weirong Ding
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Yujing Wei
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Caishui Wan
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Bo Ke
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Hongbo Cheng
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Chenghao Jin
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China
| | - Chunfang Kong
- Department of Hematology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China; Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330006, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Soochow 215006, China.
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Verkade HJ, Felzen A, Keitel V, Thompson R, Gonzales E, Strnad P, Kamath B, van Mil S. EASL Clinical Practice Guidelines on genetic cholestatic liver diseases. J Hepatol 2024; 81:303-325. [PMID: 38851996 DOI: 10.1016/j.jhep.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 04/05/2024] [Indexed: 06/10/2024]
Abstract
Genetic cholestatic liver diseases are caused by (often rare) mutations in a multitude of different genes. While these diseases differ in pathobiology, clinical presentation and prognosis, they do have several commonalities due to their cholestatic nature. These Clinical Practice Guidelines (CPGs) offer a general approach to genetic testing and management of cholestatic pruritus, while exploring diagnostic and treatment approaches for a subset of genetic cholestatic liver diseases in depth. An expert panel appointed by the European Association for the Study of the Liver has created recommendations regarding diagnosis and treatment, based on the best evidence currently available in the fields of paediatric and adult hepatology, as well as genetics. The management of these diseases generally takes place in a tertiary referral centre, in order to provide up-to-date approaches and expertise. These CPGs are intended to support hepatologists (for paediatric and adult patients), residents and other healthcare professionals involved in the management of these patients with concrete recommendations based on currently available evidence or, if not available, on expert opinion.
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Al-Hussaini A, Alrashidi S, Hafez DH, Alkhalifah YS, Otayn B, Alrasheed M, Al Mufarreh S, AlKasim S. Patterns and unique features of infantile cholestasis among Arabs. Front Pediatr 2024; 12:1423657. [PMID: 39139600 PMCID: PMC11319143 DOI: 10.3389/fped.2024.1423657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/08/2024] [Indexed: 08/15/2024] Open
Abstract
Background Most of the literature on infantile cholestasis (IC) originated from Caucasian and Asian populations. The differential diagnosis of IC is very broad, and identification of etiology is challenging to clinicians because the list includes many entities with overlapping clinical, biochemical, and histological features. Thus, a structured, stepwise diagnostic approach is required to help early recognition and prompt evaluation and management of treatable causes of cholestasis. Objective (1) To determine the differential diagnosis of IC among Saudi population and (2) to evaluate the usefulness of a diagnostic algorithm that has been tailored by the authors to the local practice. Methods All infants with onset of cholestasis before 12 months of age (2007 and 2020) were identified and included if they underwent extensive work up to exclude infectious, structural, metabolic, endocrine, infiltrative, and familial causes. Results Our diagnostic pathway allowed a definite diagnosis in 373 of the included 533 cases; 160 (30%) were labelled as "idiopathic neonatal hepatitis" (INH) [i.e., overall 70% detection rate]. However, when considering the cases that underwent extensive investigations including advanced gene testing (415 of the 533), the yield of the diagnostic algorithm was 90% (373/415). Familial cholestasis group was the most common in 20% (107/533), and biliary atresia and neonatal-onset Dubin Johnson syndrome contributed to 6% each. The genetic/hereditary causes of cholestasis contributed to 58% of the diagnosed cases (217/373). No single case of alpha-1 antitrypsin deficiency was diagnosed. Forty-nine infants with cholestasis presented with liver failure (9%). Conclusion Our study highlights several unique features and causes of IC among Arabs which could have a great impact on the differential diagnosis process and the choice of laboratory tests used in the clinical setting.
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Affiliation(s)
- Abdulrahman Al-Hussaini
- Division of Pediatric Gastroenterology, Children’s Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Prince Abdullah bin Khalid Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Sami Alrashidi
- Division of Pediatric Gastroenterology, Children’s Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Deema H. Hafez
- Department of Pediatrics, Children’s Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Yasir S. Alkhalifah
- Department of Pediatrics, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Bashaer Otayn
- Intensive Care Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Majid Alrasheed
- Pediatric Endocrinology Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Sumayah Al Mufarreh
- Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Sultan AlKasim
- College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Khabou B, Kallabi F, Abdelaziz RB, Maaloul I, Aloulou H, Chehida AB, Kammoun T, Barbu V, Boudawara TS, Fakhfakh F, Khemakhem B, Sahnoun OS. Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low-GGT intrahepatic cholestasis: Genetic diagnosis and genotype-phenotype correlation assessment. Ann Hum Genet 2024; 88:194-211. [PMID: 38108658 DOI: 10.1111/ahg.12542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023]
Abstract
Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel-target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease-causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP-binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide-binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis-associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.
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Affiliation(s)
- Boudour Khabou
- Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia
| | - Fakhri Kallabi
- Molecular and Human Genetics Laboratory, Faculty of Medicine, University of Sfax, Sfax, Tunisia
| | - Rim Ben Abdelaziz
- Department of Pediatrics, Hospital La Rabta, Tunis, Tunisia
- Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Ines Maaloul
- Department of Pediatrics, University Hospital Hedi Chaker, Sfax, Tunisia
| | - Hajer Aloulou
- Department of Pediatrics, University Hospital Hedi Chaker, Sfax, Tunisia
| | | | - Thouraya Kammoun
- Department of Pediatrics, University Hospital Hedi Chaker, Sfax, Tunisia
| | - Veronique Barbu
- LCBGM, Medical Biology and Pathology Department, APHP, HUEP, St Antoine Hospital, Sorbonne University, Paris, France
| | | | - Faiza Fakhfakh
- Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia
| | - Bassem Khemakhem
- Plant Biotechnology Laboratory, Faculty of Sciences, Sfax University, Sfax, Tunisia
| | - Olfa Siala Sahnoun
- Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia
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Gonzales E, Gardin A, Almes M, Darmellah-Remil A, Seguin H, Mussini C, Franchi-Abella S, Duché M, Ackermann O, Thébaut A, Habes D, Hermeziu B, Lapalus M, Falguières T, Combal JP, Benichou B, Valero S, Davit-Spraul A, Jacquemin E. Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy. JHEP Rep 2023; 5:100844. [PMID: 37701337 PMCID: PMC10494458 DOI: 10.1016/j.jhepr.2023.100844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/16/2023] [Accepted: 06/22/2023] [Indexed: 09/14/2023] Open
Abstract
Background & Aims Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease caused by biallelic variations in ABCB4. Data reporting on the impact of genotype and of response to ursodeoxycholic acid (UDCA) therapy on long-term outcomes are scarce. Methods We retrospectively describe a cohort of 38 patients with PFIC3 with a median age at last follow-up of 19.5 years (range 3.8-53.8). Results Twenty patients presented with symptoms before 1 year of age. Thirty-one patients received ursodeoxycholic acid (UDCA) therapy resulting in serum liver test improvement in 20. Twenty-seven patients had cirrhosis at a median age of 8.1 years of whom 18 received a liver transplant at a median age of 8.5 years. Patients carrying at least one missense variation were more likely to present with positive (normal or decreased) canalicular MDR3 expression in the native liver and had prolonged native liver survival (NLS; median 12.4 years [range 3.8-53.8]). In contrast, in patients with severe genotypes (no missense variation), there was no detectable canalicular MDR3 expression, symptom onset and cirrhosis occurred earlier, and all underwent liver transplantation (at a median age of 6.7 years [range 2.3-10.3]). The latter group was refractory to UDCA treatment, whereas 87% of patients with at least one missense variation displayed an improvement in liver biochemistry in response to UDCA. Biliary phospholipid levels over 6.9% of total biliary lipid levels predicted response to UDCA. Response to UDCA predicted NLS. Conclusions Patients carrying at least one missense variation, with positive canalicular expression of MDR3 and a biliary phospholipid level over 6.9% of total biliary lipid levels were more likely to respond to UDCA and to exhibit prolonged NLS. Impact and implications In this study, data show that genotype and response to ursodeoxycholic acid therapy predicted native liver survival in patients with PFIC3 (progressive familial intrahepatic cholestasis type 3). Patients carrying at least one missense variation, with positive (decreased or normal) immuno-staining for canalicular MDR3, and a biliary phospholipid level over 6.9% of total biliary lipids were more likely to respond to ursodeoxycholic acid therapy and to exhibit prolonged native liver survival.
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Affiliation(s)
- Emmanuel Gonzales
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Antoine Gardin
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Marion Almes
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Amaria Darmellah-Remil
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
| | - Hanh Seguin
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
| | - Charlotte Mussini
- Pathology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Stéphanie Franchi-Abella
- Pediatric Radiology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Mathieu Duché
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Pediatric Radiology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Oanez Ackermann
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Alice Thébaut
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Dalila Habes
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Bogdan Hermeziu
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Martine Lapalus
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | | | | | | | | | - Anne Davit-Spraul
- Biochemistry; Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Emmanuel Jacquemin
- Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
- Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
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Chen R, Yang FX, Tan YF, Deng M, Li H, Xu Y, Ouyang WX, Song YZ. Clinical and genetic characterization of pediatric patients with progressive familial intrahepatic cholestasis type 3 (PFIC3): identification of 14 novel ABCB4 variants and review of the literatures. Orphanet J Rare Dis 2022; 17:445. [PMID: 36550572 PMCID: PMC9773540 DOI: 10.1186/s13023-022-02597-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/20/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disease caused by pathogenic variants of the gene ABCB4. This study aimed to investigate the ABCB4 genotypic and the clinical phenotypic features of PFIC3 patients. METHODS The clinical and molecular genetic data of 13 new pediatric patients with PFIC3 as well as 82 reported ones in the PubMed and CNKI databases were collected and analyzed. RESULTS The 13 new PFIC3 patients included six females and seven males, and the main presentations were hepatomegaly, splenomegaly, jaundice, and pruritus, as well as increased levels of gamma-glutamyl transpeptidase (GGT). Fourteen new ABCB4 variants were detected, including eight diagnosed to be likely-pathogenic and six, pathogenic. Among all the 95 PFIC3 cases, hepatomegaly was observed in 85.3% (81/95), pruritus in 67.4% (64/95), splenomegaly in 52.6% (50/95), jaundice in 48.4% (46/95), portal hypertension in 34.7% (33/95) and GGT elevation in 100% (88/88) of the patients. Positive responses at varied degrees to oral ursodeoxycholic acid (UDCA) treatment were observed in 66.1% (39/59) of the patients, among whom 38.5% (15/39) fully recovered in terms of the laboratory changes. Although the condition remained stable in 53 patients (58.9%, 53/90), the clinical outcomes were not promising in the rest 37 cases (41.1%, 37/90), including 7 died, 27 having undergone while another 3 waiting for liver transplantation. A total of 96 ABCB4 variants were detected in the 95 patients. PFIC3 patients with biallelic null variants exhibited earlier onset ages [10.5 (2, 18) vs. 19 (8, 60) months, p = 0.007], lower UDCA response rate [18.2% (2/11) vs. 77.1% (37/48), p = 0.001], and more unpromising clinical outcomes [80% (12/15) vs. 33.3% (25/75), p = 0.001], compared with those with non-biallelic null variants. CONCLUSIONS PFIC3 presented with hepatomegaly, pruritus, splenomegaly and jaundice with increased serum GGT level as a biochemistry hallmark. Although varying degrees of improvement in response to UDCA therapy were observed, 41.1% of PFIC3 patients exhibited unfavorable prognosis. ABCB4 genotypes of biallelic null variants were associated with severer PFIC3 phenotypes. Moreover, the 14 novel variants in this study expanded the ABCB4 mutation spectrum, and provided novel molecular biomarkers for diagnosis of PFIC3 patients.
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Affiliation(s)
- Rong Chen
- grid.258164.c0000 0004 1790 3548Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, 510630 China
| | - Feng-Xia Yang
- grid.413428.80000 0004 1757 8466Department of Infectious Diseases, Guangzhou Women and Children’s Medical Center, Guangzhou, 510120 China
| | - Yan-Fang Tan
- grid.440223.30000 0004 1772 5147Department of Hepatopathy, Hunan Children’s Hospital, Changsha, 410007 China
| | - Mei Deng
- grid.258164.c0000 0004 1790 3548Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, 510630 China
| | - Hua Li
- grid.258164.c0000 0004 1790 3548Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, 510630 China
| | - Yi Xu
- grid.413428.80000 0004 1757 8466Department of Infectious Diseases, Guangzhou Women and Children’s Medical Center, Guangzhou, 510120 China
| | - Wen-Xian Ouyang
- grid.440223.30000 0004 1772 5147Department of Hepatopathy, Hunan Children’s Hospital, Changsha, 410007 China
| | - Yuan-Zong Song
- grid.258164.c0000 0004 1790 3548Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, 510630 China
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Hou W, Xu D, Wang L, Chen Y, Chen Z, Zhou C, Chen Y. Plastic structures for diverse substrates: A revisit of human
ABC
transporters. Proteins 2022; 90:1749-1765. [DOI: 10.1002/prot.26406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 12/18/2022]
Affiliation(s)
- Wen‐Tao Hou
- School of Life Sciences University of Science and Technology of China Hefei People's Republic of China
| | - Da Xu
- School of Life Sciences University of Science and Technology of China Hefei People's Republic of China
| | - Liang Wang
- School of Life Sciences University of Science and Technology of China Hefei People's Republic of China
| | - Yu Chen
- School of Life Sciences University of Science and Technology of China Hefei People's Republic of China
| | - Zhi‐Peng Chen
- School of Life Sciences University of Science and Technology of China Hefei People's Republic of China
| | - Cong‐Zhao Zhou
- School of Life Sciences University of Science and Technology of China Hefei People's Republic of China
| | - Yuxing Chen
- School of Life Sciences University of Science and Technology of China Hefei People's Republic of China
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Sarma MS, Ravindranath A. Pediatric acute viral hepatitis with atypical variants: Clinical dilemmas and natural history. World J Hepatol 2022; 14:944-955. [PMID: 35721282 PMCID: PMC9157701 DOI: 10.4254/wjh.v14.i5.944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/20/2022] [Accepted: 05/07/2022] [Indexed: 02/06/2023] Open
Abstract
Classical acute viral hepatitis (AVH) has an uncomplicated outcome. Acute liver failure has a grave prognosis. Atypical manifestations of AVH are a group of disorders that causes significant morbidity and dilemmas in children. These include prolonged cholestasis, relapsing hepatitis, ascitic form of AVH, late-onset hepatic failure (LOHF), intravascular hemolysis, and provoking an autoimmune trigger leading to autoimmune hepatitis. These entities cause significant liver dysfunction or worsening and are often difficult to differentiate from chronic liver disease (CLD). Ascitic form of AVH, LOHF, decompensated CLD and acute-on-chronic liver failure have significant overlapping features that need to be carefully dissected out. In many cases, only on long-term follow-up, these clinical entities can be separately identified. Intravascular hemolysis is usually caused by associated glucose-6-phosphate dehydrogenase deficiency. Rarely CLD such as Wilson disease and autoimmune hepatitis can also present with hemolysis in the initial presentation, which can mimic AVH with hemolysis. Identifying deviations from typical manifestations aid in avoiding unnecessary investigations, allowing focused therapy and alleviating anxiety.
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Affiliation(s)
- Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Aathira Ravindranath
- Division of Pediatric Gastroenterology, Apollo BGS Hospitals, Mysuru 570023, Karnataka, India
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Alam S, Lal BB. Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies. World J Hepatol 2022; 14:98-118. [PMID: 35126842 PMCID: PMC8790387 DOI: 10.4254/wjh.v14.i1.98] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/17/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Recent evidence points towards the role of genotype to understand the phenotype, predict the natural course and long term outcome of patients with progressive familial intrahepatic cholestasis (PFIC). Expanded role of the heterozygous transporter defects presenting late needs to be suspected and identified. Treatment of pruritus, nutritional rehabilitation, prevention of fibrosis progression and liver transplantation (LT) in those with end stage liver disease form the crux of the treatment. LT in PFIC has its own unique issues like high rates of intractable diarrhoea, growth failure; steatohepatitis and graft failure in PFIC1 and antibody-mediated bile salt export pump deficiency in PFIC2. Drugs inhibiting apical sodium-dependent bile transporter and adenovirus-associated vector mediated gene therapy hold promise for future.
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Affiliation(s)
- Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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Al-Hussaini A, Abanemai M, Alhebbi H, Saadah O, Bader R, Al Sarkhy A, Alhatlani M, Halabi H, Aladsani A, AlEdreesi M, Wali S, Alguofi T, Al-Drees K, Arain Z, Al Saleem B, Asery A, Holdar S, Alrashidi S, Alsayed F, Aldhalan S, NasserAllah A, Alghamdi R, Alhaffaf F, AlAwfi A, AlSweed A, Alshamrani A, AlShaikh M, Saeed A, Assiri H, Bashir MS. The Epidemiology and Outcome of Biliary Atresia: Saudi Arabian National Study (2000-2018). Front Pediatr 2022; 10:921948. [PMID: 35923790 PMCID: PMC9339784 DOI: 10.3389/fped.2022.921948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/27/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The epidemiology and outcomes of biliary atresia (BA) have been well-documented in national cohorts from two main ethnicities, namely, the Asian Orientals and Caucasians, with incidence ranging from 1 in 5,000 to 1 in 9,000 live births in East Asia and 1 in 15,000 to 19,000 live births in Europe and North America. OBJECTIVE We report the first nationwide BA study outside North America, Europe, and East Asia to describe the epidemiology and outcomes of BA in Saudi Arabia. METHODS A national database of BA cases diagnosed between 2000 and 2018 was analyzed. We assessed clearance of jaundice (bilirubin <20 μmol/L) in all cases that underwent Kasai portoenterostomy (KPE). We then estimated survival using the Kaplan-Meier method with endpoints of liver transplantation (LT), death, or survival with native liver (SNL). RESULTS BA was diagnosed in 204 infants (106 females; 10% pre-term). The incidence of BA was 1 in 44,365, or 2.254 in 100,000 live births (range, 0.5-4 in 100,000). Polysplenia was diagnosed in 22 cases (11%). The median age at referral was 65 days. A total of 146 children (71.5%) underwent KPE at a median age of 70 days. Clearance of jaundice was achieved in 66 of the 146 (45%) infants. The 10-year SNL after KPE was 25.5%, and the overall 10-year estimated survival was 72.5%. The Kaplan-Meier survival curves for patients undergoing KPE at the age of <60, 61-90, and >90 days showed a SNL rate at 51.6, 33, and 12.5%, respectively, at 5 years (P < 0.001). The 2-, 5-, and 10-year post-LT survival rates were 92.5, 90.6, and 90%, respectively. Undergoing an initial KPE did not impact negatively on the overall LT survival rate when compared to BA cases that underwent primary LT (P = 0.88). CONCLUSION The incidence rate of BA in Saudi Arabia is lower than the incidence reported elsewhere. Late referral of BA cases remains a problem in Saudi Arabia; as a result, the SNL rate was lower than reported by other national registries. Hence, national policies devoted to timely referral and earlier age at KPE are needed.
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Affiliation(s)
- Abdulrahman Al-Hussaini
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.,Prince Abdullah Bin Khaled Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Abanemai
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Homoud Alhebbi
- Division of Pediatric Gastroenterology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Omar Saadah
- Division of Pediatric Gastroenterology, Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Razan Bader
- Multi-Organ Transplant Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia.,King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Ahmed Al Sarkhy
- Gastroenterology Division, Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Maher Alhatlani
- Al Imam Abdulrahman Bin Faisal Hospital, Ministry of National Guard Health Affairs, Dammam, Saudi Arabia
| | - Hana Halabi
- Maternity and Children's Hospital, Makkah, Saudi Arabia
| | - Ahmed Aladsani
- Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mohammed AlEdreesi
- Specialty Pediatrics Division, Women and Children's Health Institute, Pediatric Gastroenterology, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
| | - Sami Wali
- Division of Pediatric Gastroenterology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Talal Alguofi
- Organs Transplant Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Khalid Al-Drees
- Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Zahid Arain
- Multi-Organ Transplant Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia.,King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Badr Al Saleem
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Ali Asery
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Sinan Holdar
- Division of Pediatric Gastroenterology, Department of Pediatrics, Royal Commission Hospital, Jubail, Saudi Arabia
| | - Sami Alrashidi
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Fahad Alsayed
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Sulaiman Aldhalan
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Rawabi Alghamdi
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Faisal Alhaffaf
- Division of Pediatric Gastroenterology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Ahmed AlAwfi
- Division of Pediatric Gastroenterology, King Saud Medical City, Riyadh, Saudi Arabia
| | - Abdulrahman AlSweed
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Manal AlShaikh
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Anjum Saeed
- Gastroenterology Division, Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Heba Assiri
- Gastroenterology Division, Department of Pediatrics, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Muhammed Salman Bashir
- Department of Biostatistics, Research Services Administration, Research Center, King Fahad Medical City, Riyadh, Saudi Arabia
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Zhou JL, Zhao YZ, Wang SS, Chen MX, Zhou S, Chen C. RNA Splicing: A Versatile Regulatory Mechanism in Pediatric Liver Diseases. Front Mol Biosci 2021; 8:725308. [PMID: 34651015 PMCID: PMC8505697 DOI: 10.3389/fmolb.2021.725308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/23/2021] [Indexed: 12/03/2022] Open
Abstract
With the development of high-throughput sequencing technology, the posttranscriptional mechanism of alternative splicing is becoming better understood. From decades of studies, alternative splicing has been shown to occur in multiple tissues, including the brain, heart, testis, skeletal muscle, and liver. This regulatory mechanism plays an important role in physiological functions in most liver diseases. Currently, due to the absence of symptoms, chronic pediatric liver diseases have a significant impact on public health. Furthermore, the progression of the disease is accelerated in children, leading to severe damage to their liver tissue if no precautions are taken. To this end, this review article summarizes the current knowledge of alternative splicing in pediatric liver diseases, paying special attention to liver damage in the child stage. The discussion of the regulatory role of splicing in liver diseases and its potential as a new therapeutic target is also included.
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Affiliation(s)
- Jian-Li Zhou
- Division of Gastroenterology, Shenzhen Children's Hospital, Shenzhen, China
| | - Yu-Zhen Zhao
- Division of Gastroenterology, Shenzhen Children's Hospital, Shenzhen, China
| | - Shan-Shan Wang
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Mo-Xian Chen
- Co-Innovation Center for Sustainable Forestry in Southern China, College of Biology and the Environment, Nanjing Forestry University, Nanjing, China
| | - Shaoming Zhou
- Division of Gastroenterology, Shenzhen Children's Hospital, Shenzhen, China
| | - Chen Chen
- Department of Infectious Disease, Nanjing Second Hospital, Nanjing University of Chinese Medicine, Nanjing, China
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