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1.
Clinics (Sao Paulo) ; 79: 100383, 2024.
Article in English | MEDLINE | ID: mdl-38797123

ABSTRACT

BACKGROUND: Neonatal Intrahepatic Cholestasis (NICCD), as the early-age stage of Citrin deficiency involving liver dysfunction, lacks efficient diagnostic markers. Procalcitonin (PCT) has been identified as a biomarker for infection as well as various organ damage. This study aimed to explore the potential of PCT as a biomarker for NICCD. METHODS: In a single-center retrospective case-control study. Serum PCT concentrations before and after treatment of 120 NICCD patients, as the study group, were compared to the same number of cholestatic hepatitis patients, as the control group. The potential value of PCT to discriminate NICCD from control disease was further explored using Receiver Operating Characteristic (ROC) curve analysis and compared to those of other inflammatory markers. RESULTS: There was a significantly higher level of PCT in NICCD patients than in the control group. PCT concentrations were only weakly correlated with neutrophil counts and CRP levels (p ˂ 0.05). At a cut-off value of 0.495 ng/mL, PCT exhibited a significantly higher diagnostic value compared to other inflammatory markers for discriminating NICCD from the control, with a sensitivity of 90.8 % and specificity of 98.3 %. CONCLUSION: PCT might be used as an initial biomarker to discriminate children with NICCD from another hepatitis disease.


Subject(s)
Biomarkers , Cholestasis, Intrahepatic , Citrullinemia , Procalcitonin , ROC Curve , Humans , Procalcitonin/blood , Biomarkers/blood , Retrospective Studies , Male , Female , Case-Control Studies , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/diagnosis , Citrullinemia/blood , Citrullinemia/complications , Citrullinemia/diagnosis , Infant , Infant, Newborn , Sensitivity and Specificity , C-Reactive Protein/analysis , Reference Values
2.
Zhonghua Fu Chan Ke Za Zhi ; 59(4): 270-278, 2024 Apr 25.
Article in Chinese | MEDLINE | ID: mdl-38644273

ABSTRACT

Objective: To analyze serum bile acid profiles in pregnant women with normal pregnancy, intrahepatic cholestasis of pregnancy (ICP) and asymptomatic hypercholanemia of pregnancy (AHP), and to evaluate the application value of serum bile acid profiles in the diagnosis of ICP and AHP. Methods: The clinical data of 122 pregnant women who underwent prenatal examination in Xuzhou Maternal and Child Health Care Hospital from June 2022 to May 2023 were collected, including 54 cases of normal pregnancy group, 28 cases of ICP group and 40 cases of AHP group. Ultraperformance liquid chromatography-tandem mass spectrometry was used to measure the levels of 15 serum bile acids in each group, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), glycolcholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), glycoursodeoxycholic acid (GUDCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA) and tauroursodeoxycholic acid (TUDCA). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to screen differential bile acids. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy of differential bile acids and combined indicators between groups. Results: (1) Compared with normal pregnancy group, the serum levels of LCA, GCA, GCDCA, GDCA, GLCA, UDCA, TCA, TCDCA, TDCA, TLCA, GUDCA and TUDCA in ICP group were significantly different (all P<0.05), while the levels of LCA, DCA, GCA, GCDCA, GDCA, GLCA, TCA, TCDCA, TDCA, TLCA, GUDCA and TUDCA in AHP group were significantly different (all P<0.05). Compared with ICP group, the serum levels of CDCA, DCA, UDCA, TDCA, GUDCA and TUDCA in AHP group were significantly different (all P<0.05). (2) In the OPLS-DA model, the differential bile acids between ICP group and AHP group were TUDCA, TCA, UDCA, GUDCA and GCA, and their variable importance in projection (VIP) were 1.489, 1.345, 1.344, 1.184 and 1.111, respectively. TCA, GCDCA, GCA, TDCA, GDCA and TCDCA were the differentially expressed bile acids between AHP group and normal pregnancy group, and their VIP values were 1.236, 1.229, 1.197, 1.145, 1.139 and 1.138, respectively. (3) ROC analysis showed that the area under the curve (AUC) of TUDCA, TCA, UDCA, GUDCA and GCA in the differential diagnosis of ICP and AHP was 0.860, and the sensitivity and specificity were 67.9% and 95.0%, respectively. The AUC of TCA, GCDCA, GCA, TDCA, GDCA and TCDCA in the diagnosis of AHP was 0.964, and the sensitivity and specificity were 95.0% and 93.1%, respectively. Conclusions: There are differences in serum bile acid profiles among normal pregnant women, ICP and AHP. The serum bile acid profiles of pregnant women have potential application value in the differential diagnosis of ICP and AHP and the diagnosis of AHP.


Subject(s)
Bile Acids and Salts , Cholestasis, Intrahepatic , Pregnancy Complications , Humans , Female , Pregnancy , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/diagnosis , Bile Acids and Salts/blood , Pregnancy Complications/blood , Pregnancy Complications/diagnosis , Adult , Tandem Mass Spectrometry/methods , Sensitivity and Specificity , ROC Curve
3.
Zhonghua Er Ke Za Zhi ; 62(5): 462-466, 2024 May 02.
Article in Chinese | MEDLINE | ID: mdl-38623015

ABSTRACT

Objective: To analyze the clinical manifestations, pathology, and gene variant characteristics in children with progressive familial intrahepatic cholestasis type 3 (PFIC3). Methods: This retrospective study assessed the clinical manifestations, pathological features, gene variants, and prognosis data of 11 children with PFIC3 hospitalized in the Department of Hepatology, Fifth Medical Center, PLA General Hospital, from January 2015 to December 2022. Panel or whole exome sequencing was performed on the probands, followed by Sanger sequencing for verification within the family. Detected pathogenic variants were compared with known disease databases. Additionally, the new variants were predicted the deleteriousness and protein structure using relevant software to evaluate their pathogenicity. Results: Among the 11 PFIC3 children, 8 were boys and 3 were girls. The age of onset was 3.1 (0.2, 15.6) years. The main complaint of onset was different in the 11 patients;5 of them were abnormal liver function, 3 of them were liver and spleen enlargement, 2 of them were abdominal distension, and 1 of them was jaundice. Alanine aminotransferase, asparate aminotransferase and γ-glutamyltransferase increased in all the patients, which were(113±40), (150±44) and (270±156) U/L respectively. Moreover, direct bilirubin increased in 9 patients, and cholestasis was showed in 8 patients. All patients showed liver fibrosis on imaging, and 8 patients had cirrhosis. The pathological features of 8 cases by liver biopsy were as follows: 8 cases of fibrosis in the portal area, 7 cases of small bile duct hyperplasia, 4 cases of positive copper staining, and 5 cases of cirrhosis. A total of 17 ABCB4 gene variants were detected, including 9 new variants: c.589C>T(p.Q197X), c.1230+1G>A(Splicing), c.2914G>A(P.D972N), c.1058G>A(p.C353Y), c.956G>T(p.G319V), c.473T>A(p.L158Q), c.164T>C(p.L55S), c.2493G>C(p.R831S), and c.1150G>C(p.G384R). All 11 patients were treated with ursodeoxycholic acid and followed up for 5.1(0.6, 7.4) years. Among them, 4 cases of cirrhosis progressed continuously, 3 cases had liver transplantations, and the remaining 4 cases were stable after medical treatment. Conclusions: Children with PFIC3 have early onset, diverse clinical manifestations, rapid progression of fibrotic and cholestasis, as well as poor prognosis. Genetic testing helps to confirm the diagnosis.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/deficiency , Cholestasis, Intrahepatic , Exome Sequencing , Humans , Male , Female , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/diagnosis , Retrospective Studies , Child , Child, Preschool , Infant , Adolescent , Mutation , Liver/pathology , gamma-Glutamyltransferase/blood , Alanine Transaminase/blood , ATP Binding Cassette Transporter, Subfamily B/genetics , Prognosis , Aspartate Aminotransferases/blood
4.
Orphanet J Rare Dis ; 19(1): 171, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38641832

ABSTRACT

BACKGROUND: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. METHODS: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. RESULTS: Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. CONCLUSIONS: We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.


Subject(s)
Cholestasis, Intrahepatic , Cholestasis , Humans , Infant, Newborn , Infant , Retrospective Studies , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/therapy , Cholestasis/genetics
5.
Clin Chim Acta ; 557: 117854, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38513931

ABSTRACT

Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of cesarean section and adverse fetal outcomes. Currently, ICP diagnosis depends largely on serum levels of bile acids and lacks sensitivity and specificity for accurate diagnosis. Tongue diagnosis is an important diagnostic tool in traditional Chinese medicine (TCM) and is used in our clinic as complementary treatment and personalized medicine for ICP. However, the molecular basis of the manifestation of greasy white tongue coatings in ICP remains unknown. In this study, we performed untargeted metabolomic profiling of the serum, tongue coating, and saliva of 66 pregnant women, including 22 with ICP. The metabolomic profiles of the serum and tongue coatings showed marked differences between the two clinical groups. Forty-six differentially abundant metabolites were identified, and their relative concentrations correlated with total bile acid levels. These differential metabolites included bile acids, lipids, microbiota- and diet-related metabolites, and exposomes. Conventional biochemical markers, including serum aminotransferases and bilirubin, were not significantly increased in the ICP group, whereas the total cholesterol and triglyceride levels were significantly increased as early as the first trimester. Our data provide insights into the pathophysiology of ICP and implicate the gut-liver axis and environmental exposure. Tongue coating has the potential to be a non-invasive diagnostic approach. Further studies are required to validate the clinical utility of these findings.


Subject(s)
Cholestasis, Intrahepatic , Pregnancy Complications , Pregnancy , Female , Humans , Pregnant Women , Cesarean Section , Bile Acids and Salts , Pregnancy Complications/diagnosis , Cholestasis, Intrahepatic/diagnosis , Tongue
7.
Ann Hepatol ; 29(3): 101490, 2024.
Article in English | MEDLINE | ID: mdl-38403070

ABSTRACT

INTRODUCTION AND OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications. MATERIALS AND METHODS: Retrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration. RESULTS: Neonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p<0.001). The group of neonates that were exposed to full UDCA dose had the highest rate of unfavorable composite neonatal outcome (53% for full dose, 30% for gradually increasing dose, 24% for the no treatment group, p=0.006). CONCLUSIONS: Compared to the administration of a full UDCA dose, the administration of a gradually increasing dose of UDCA may be associated with a greater gestational age at delivery and fewer events of unfavorable composite neonatal outcomes. These novel findings should be retested prospectively in a large cohort of patients.


Subject(s)
Cholagogues and Choleretics , Cholestasis, Intrahepatic , Gestational Age , Pregnancy Complications , Ursodeoxycholic Acid , Humans , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/therapeutic use , Female , Pregnancy , Cholestasis, Intrahepatic/drug therapy , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/blood , Retrospective Studies , Pregnancy Complications/drug therapy , Pregnancy Complications/blood , Infant, Newborn , Cholagogues and Choleretics/administration & dosage , Cholagogues and Choleretics/adverse effects , Cholagogues and Choleretics/therapeutic use , Adult , Treatment Outcome , Pregnancy Outcome
8.
J Gastroenterol Hepatol ; 39(5): 964-974, 2024 May.
Article in English | MEDLINE | ID: mdl-38323732

ABSTRACT

BACKGROUND AND AIM: Advances in molecular genetics have uncovered causative genes responsible for neonatal cholestasis. Panel-based next-generation sequencing has been used clinically in infants with neonatal cholestasis. We aimed to evaluate the clinical application of single-gene testing and next-generation sequencing and to develop a diagnostic algorithm for neonatal intrahepatic cholestasis. METHODS: From January 2010 to July 2021, patients suspected of having neonatal intrahepatic cholestasis were tested at the Seoul National University Hospital. If there was a clinically suspected disease, single-gene testing was performed. Alternatively, if it was clinically difficult to differentiate, a neonatal cholestasis gene panel test containing 34 genes was performed. RESULTS: Of the total 148 patients examined, 49 (33.1%) were received a confirmed genetic diagnosis, including 14 with Alagille syndrome, 14 with neonatal intrahepatic cholestasis caused by citrin deficiency, 7 with Dubin-Johnson syndrome, 5 with arthrogryposis-renal dysfunction-cholestasis syndrome, 5 with progressive familial intrahepatic cholestasis type II, 1 with Rotor syndrome, 1 with Niemann-Pick disease type C, 1 with Kabuki syndrome, and 1 with Phenylalanyl-tRNA synthetase subunit alpha mutation. Sixteen novel pathogenic or likely pathogenic variants of neonatal cholestasis were observed in this study. Based on the clinical characteristics and laboratory findings, we developed a diagnostic algorithm for neonatal intrahepatic cholestasis by integrating single-gene testing and next-generation sequencing. CONCLUSIONS: Alagille syndrome and neonatal intrahepatic cholestasis caused by citrin deficiency were the most common diseases associated with genetic neonatal cholestasis. Single-gene testing and next-generation sequencing are important and complementary tools for the diagnosis of genetic neonatal cholestasis.


Subject(s)
Algorithms , Cholestasis, Intrahepatic , Genetic Testing , High-Throughput Nucleotide Sequencing , Humans , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/diagnosis , High-Throughput Nucleotide Sequencing/methods , Infant, Newborn , Genetic Testing/methods , Male , Female , Alagille Syndrome/genetics , Alagille Syndrome/diagnosis , Infant
9.
Orphanet J Rare Dis ; 19(1): 57, 2024 Feb 10.
Article in English | MEDLINE | ID: mdl-38341604

ABSTRACT

BACKGROUND: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an ultra-rare disease caused by mutations in the ABCB11 gene. This study aimed to understand the course of PFIC2 during the native liver period. METHODS: From November 2014 to October 2015, a survey to identify PFIC2 patients was conducted in 207 hospitals registered with the Japanese Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Investigators retrospectively collected clinical data at each facility in November 2018 using pre-specified forms. RESULTS: Based on the biallelic pathogenic variants in ABCB11 and/or no hepatic immunohistochemical detection of BSEP, 14 Japanese PFIC2 patients were enrolled at seven facilities. The median follow-up was 63.2 [47.7-123.3] months. The median age of disease onset was 2.5 [1-4] months. Twelve patients underwent living donor liver transplantation (LDLT), with a median age at LDLT of 9 [4-57] months. Two other patients received sodium 4-phenylbutyrate (NaPB) therapy and survived over 60 months with the native liver. No patients received biliary diversion. The cases that resulted in LDLT had gradually deteriorated growth retardation, biochemical tests, and liver histology since the initial visit. In the other two patients, jaundice, growth retardation, and most of the biochemical tests improved after NaPB therapy was started, but pruritus and liver fibrosis did not. CONCLUSIONS: Japanese PFIC2 patients had gradually worsening clinical findings since the initial visit, resulting in LDLT during infancy. NaPB therapy improved jaundice and growth retardation but was insufficient to treat pruritus and liver fibrosis.


Subject(s)
Cholestasis, Intrahepatic , Jaundice , Liver Transplantation , Child , Humans , Infant , Retrospective Studies , ATP-Binding Cassette Transporters/genetics , Living Donors , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/pathology , Liver Cirrhosis/pathology , Pruritus , Growth Disorders
10.
J Pediatr Gastroenterol Nutr ; 78(2): 178-187, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38374571

ABSTRACT

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.


Subject(s)
Cholestasis, Intrahepatic , Cholestasis , Citrullinemia , Gastroenterology , Infant, Newborn, Diseases , Organic Anion Transporters , Adolescent , Child , Humans , Infant , Infant, Newborn , Cholestasis/diagnosis , Cholestasis/etiology , Cholestasis/therapy , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/etiology , Cholestasis, Intrahepatic/therapy , Citrullinemia/complications , Citrullinemia/diagnosis , Citrullinemia/genetics , Mitochondrial Membrane Transport Proteins/genetics , Mutation , Organic Anion Transporters/genetics
12.
Reprod Sci ; 31(6): 1573-1585, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38177949

ABSTRACT

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, which can lead to adverse fetal outcomes, including preterm labor and intrauterine death. The pathogenesis of ICP is still unclear. We hypothesized that pathological index leads to abnormal placenta changes in ICP. Investigation of these differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying ICP. The present study screened differentially expressed proteins (DEPs) as novel diagnostic markers for ICP. Proteomic profiles of placental tissues from 32 ICP patients and 24 healthy volunteers (controls) were analyzed. Our founding was valid by following western blotting and immunohistochemistry staining, respectively. The association of the key protein expression with clinicopathological features of ICP was further analyzed. A total of 178 DEPs were identified between the ICP and control groups. Functional enrichment analysis showed these proteins were significantly enriched in the PPAR singling pathway by KEGG and PPARα/RXRα activation by IPA. Apolipoprotein A2 (APOA2) was the only upregulated protein, which uniquely identified in ICP groups and related to both pathways. Validation of western blotting and immunohistochemical staining analysis showed significantly higher APOA2 expression in the ICP group than in the control group. Furthermore, the expression of APOA2 is associated with clinicopathological features in ICP groups. Receiver operating characteristic (ROC) curve analyses showed that the AUC of APOA2 was 0.8984 (95% confidence interval (CI): 0.772-1.000). This study has identified up-regulated APOA2 associated with PPAR singling pathway and PPARα/RXRα activation in ICP. Thus, APOA2 may be involved in ICP pathogenesis, serving as a novel biomarker for its diagnosis.


Subject(s)
Biomarkers , Cholestasis, Intrahepatic , Pregnancy Complications , Proteomics , Humans , Female , Cholestasis, Intrahepatic/metabolism , Cholestasis, Intrahepatic/diagnosis , Pregnancy , Proteomics/methods , Biomarkers/metabolism , Adult , Pregnancy Complications/metabolism , Pregnancy Complications/diagnosis , Placenta/metabolism , Apolipoprotein A-II/metabolism , Case-Control Studies
13.
Gastroenterol. hepatol. (Ed. impr.) ; 47(1): 24-31, ene. 2024. ilus, tab, graf
Article in English | IBECS | ID: ibc-229083

ABSTRACT

Background MicroRNAs (miRNAs) are a group of small non-coding RNAs that bind to the target mRNA and regulate gene expression. Recently circulating microRNAs were investigated as markers of diseases and therapeutic targets. Although various studies analyze the miRNA expression in liver disease, these studies on PFIC are few. Progressive familial intrahepatic cholestasis (PFIC) is a rare liver disease with autosomal recessive inheritance. Most children with PFIC progress to cirrhosis and liver failure and consequently need to have a liver transplant. The aim of this study is the investigation of the miR-19b and miR-let7b expression levels in Iranian PFIC children. Methods 25 PFIC patients, 25 healthy children and 25 Biliary Atresia patients were considered as case and two control groups respectively. Blood samples were obtained and Liver function tests (LFTs) were measured. After RNA extraction and cDNA synthesis, quantitative PCR was performed using specific primers for miR-19b and miR-let7b. The U6 gene is used as an internal control. Results qPCR on PFIC patients’ samples demonstrated that the miR-19b and the miR-let7b expression were significantly decreased in patients compared to the control groups, with a p-value<0.0001 and p-value=0.0006 receptively. Conclusion In conclusion, circulating micro-RNA like miR-19b and miR-let7b have a potential opportunity to be a non-invasive diagnostic marker or therapeutic target for PFIC in the future (AU)


Antecedentes Los microRNA (miRNA) son un grupo de pequeños RNA no codificantes que se unen al ARNm diana y regulan la expresión génica. Recientemente se han investigado los microRNA circulantes como marcadores de enfermedades y dianas terapéuticas. Aunque varios estudios analizan la expresión de miRNA en enfermedades hepáticas, estos estudios sobre PFIC son escasos. La colestasis intrahepática familiar progresiva (PFIC) es una enfermedad hepática rara con herencia autosómica recesiva. La mayoría de los niños con PFIC progresan a cirrosis e insuficiencia hepática y, en consecuencia, requieren de un trasplante de hígado. El objetivo de este trabajo es la investigación de los niveles de expresión de miR-19b y miR-17b en niños iraníes con PFIC. Métodos Se consideraron 25 pacientes con PFIC, 25 niños sanos y 25 pacientes con atresia biliar como grupos de casos y controles. Se obtuvieron muestras de sangre y se midieron las pruebas de función hepática (LFT). Después de la extracción de RNA y la síntesis de cDNA, se realizó PCR cuantitativa usando cebadores específicos para miR-19b y miR-17b. El gen U6 se utiliza como control interno. Resultados La qPCR en muestras de pacientes con PFIC demostró que la expresión de miR-19b y miR-17b disminuyó significativamente en los pacientes en comparación con dos grupos de control, con un valor de p<0,0001 y un valor de p=0,0006, receptivamente. Conclusión En conclusión, los micro-RNA circulantes, como miR-19b y miR-let7b, tienen una oportunidad potencial de ser un marcador de diagnóstico no invasivo o un objetivo terapéutico para PFIC en el futuro (AU)


Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Child , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/genetics , Hepatic Insufficiency , Fibrosis , MicroRNAs/genetics
14.
Gastroenterol Hepatol ; 47(1): 24-31, 2024 Jan.
Article in English, Spanish | MEDLINE | ID: mdl-36934840

ABSTRACT

BACKGROUND: MicroRNAs (miRNAs) are a group of small non-coding RNAs that bind to the target mRNA and regulate gene expression. Recently circulating microRNAs were investigated as markers of diseases and therapeutic targets. Although various studies analyze the miRNA expression in liver disease, these studies on PFIC are few. Progressive familial intrahepatic cholestasis (PFIC) is a rare liver disease with autosomal recessive inheritance. Most children with PFIC progress to cirrhosis and liver failure and consequently need to have a liver transplant. The aim of this study is the investigation of the miR-19b and miR-let7b expression levels in Iranian PFIC children. METHODS: 25 PFIC patients, 25 healthy children and 25 Biliary Atresia patients were considered as case and two control groups respectively. Blood samples were obtained and Liver function tests (LFTs) were measured. After RNA extraction and cDNA synthesis, quantitative PCR was performed using specific primers for miR-19b and miR-let7b. The U6 gene is used as an internal control. RESULTS: qPCR on PFIC patients' samples demonstrated that the miR-19b and the miR-let7b expression were significantly decreased in patients compared to the control groups, with a p-value<0.0001 and p-value=0.0006 receptively. CONCLUSION: In conclusion, circulating micro-RNA like miR-19b and miR-let7b have a potential opportunity to be a non-invasive diagnostic marker or therapeutic target for PFIC in the future.


Subject(s)
Cholestasis, Intrahepatic , MicroRNAs , Child , Humans , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/diagnosis , Iran , MicroRNAs/genetics
15.
Hepatol Int ; 18(2): 661-672, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37314652

ABSTRACT

BACKGROUND AND AIMS: Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first month of life. METHODS: We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis, and re-analyzed phenotype and whole-exome sequencing (WES) data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. RESULTS: Overall, we identified disease-causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) had metabolic liver diseases, 9 (17%) had syndromic cholestasis, 9 (17%) had progressive familial intrahepatic cholestasis, 3 (6%) had bile acid synthesis defects, 3(6%) had infantile liver failure and 10 (19%) had a phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G > A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By re-analyzing WES data, two patients were newly solved, who had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved WES families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice models. CONCLUSIONS: In a single-center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Our findings suggest that re-evaluating existing WES data from well-phenotyped patients on a regular basis can increase the diagnostic yield for cholestatic liver disease in children.


Subject(s)
Cholestasis, Intrahepatic , Cholestasis , Membrane Transport Proteins , Child , Humans , Animals , Mice , Retrospective Studies , High-Throughput Nucleotide Sequencing , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/diagnosis , Mutation , Kinesins/genetics , Ubiquitin Thiolesterase/genetics , Ubiquitin-Specific Proteases/genetics , Cell Cycle Proteins/genetics , Adenosine Triphosphatases/genetics
16.
Reprod Sci ; 31(2): 341-351, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37626275

ABSTRACT

Intrahepatic cholestasis of pregnancy (ICP) is a hepatic disorder in pregnancy linked with adverse fetal outcomes, which primarily manifests in the late second and third trimesters of pregnancy. This review aims to recapitulate the existing evidence on factors that can predict detrimental perinatal outcomes in pregnant women diagnosed with intrahepatic cholestasis of pregnancy. We searched PubMed, Web of Science, Cochrane Library, Scopus, Medline, and Embase databases and selected studies related to predictors of fetal outcome in intrahepatic cholestasis of pregnancy. Studies of the articles showed that predictors of an adverse fetal outcome include in vitro fertilization (IVF) pregnancy, multifetal pregnancy, biochemical markers, gestational age of ICP onset, presence of comorbidities (preeclampsia and gestational diabetes mellitus), maternal history of ICP, and hepatobiliary disease.Intrahepatic cholestasis of pregnancy (ICP) complicates the pregnancy. Hence, early assessment of low-risk and high-risk groups will help to administer definite management protocols and strategies to prevent adverse neonatal outcomes. Further research should concentrate on the number of conditions/factors and the predictive power of different factors to determine the most reliable predictors and biomarkers that can predict adverse fetal outcomes and improve the assessment of risk in pregnancy complicated with ICP.


Subject(s)
Cholestasis, Intrahepatic , Pregnancy Complications , Infant, Newborn , Pregnancy , Female , Humans , Pregnancy Outcome , Pregnancy Complications/diagnosis , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/therapy , Prenatal Care , Biomarkers
17.
Int J Gynaecol Obstet ; 164(2): 656-661, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37493015

ABSTRACT

OBJECTIVE: To evaluate the aspartate aminotransferase to platelet ratio (APRI) score as a predictive and prognostic test in intrahepatic cholestasis of pregnancy (ICP). METHODS: This study was conducted in 198 patients diagnosed with ICP and 204 healthy pregnant women who presented to a tertiary center between 2019 and 2022. APRI scores; laboratory findings in the first, second, and third trimesters; and perinatal outcomes were compared between the two groups. The ICP group was evaluated for correlation between APRI scores and composite adverse outcomes. Two different receiver operating characteristic analyses were performed to determine optimal cutoff values of predictive APRI score of ICP and composite adverse outcomes in patients with ICP. RESULTS: Aspartate aminotransferase values and APRI scores were significantly higher in the ICP group in all trimesters (P < 0.001). The optimal cutoff values of APRI scores to predict ICP for the first, second, and third trimesters were 0.101 (79.7% sensitivity, 79.6% specificity), 0.103 (78.4% sensitivity, 76.3% specificity), and 0.098 (72.5% sensitivity, 72% specificity), respectively. APRI scores were statistically higher in patients with ICP with composite adverse outcomes in all trimesters (P values of 0.03, 0.04, and 0.01, respectively). CONCLUSION: APRI score was found to be a valuable predictor of ICP and its adverse outcomes during the entire pregnancy.


Subject(s)
Cholestasis, Intrahepatic , Pregnancy Complications , Humans , Pregnancy , Female , Case-Control Studies , Aspartate Aminotransferases , Prognosis , Cholestasis, Intrahepatic/diagnosis , Pregnancy Complications/diagnosis
18.
Mol Genet Genomic Med ; 12(1): e2291, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37787087

ABSTRACT

BACKGROUND: ABCB4 gene (OMIM *171060) variant is associated with a wide clinical spectrum of hepatobiliary diseases, including familial intrahepatic cholestasis of pregnancy (ICP), progressive familial intrahepatic cholestasis type 3 (PFIC3), and neonatal hyperbilirubinemia due to impaired protection of the bile duct. The majority of reported cases, however, were missense or nonsense variants, with few deletion variant findings in the Chinese population. METHOD: We performed whole genome sequencing and confirmed it with Sanger sequencing of the proband infant and his families. Clinical courses and laboratory results were documented and collected from the proband infant and his mother. We also reviewed other published cases related to genetic variants in ABCB4 in the Chinese population. RESULTS: A 26-year-old Chinese female (II.2) who had recurrent intrahepatic cholestasis of pregnancy and her 49-day-old son (III.4) who had hyperbilirubinemia, both presented with extremely elevated total bile acid, cholestatic dominant pattern liver function abnormalities. They were able to stay relatively stable with mild pruritus on ursodeoxycholic acid treatment. After ruling out other possibilities, genetic sequencing revealed a diagnosis of heterozygous deletion variant NM_018849.3:c.1452_1454del (NP_061337.1:p.Thr485del) in ABCB4, which was not reported before, in the symptomatic mother (II.2), index patient (III.4), and the symptomatic grandmother (I.2). This variant resulted in clinical spectrums of ICP, neonatal hyperbilirubinemia, and cholelithiasis in our pedigree. CONCLUSION: We reported a novel heterozygous deletion variant of the ABCB4 gene in a Chinese family, as well as a literature review of ABCB4-related disorders. We aim to facilitate healthcare professionals to better understand genetic factors as an uncommon cause of hepatobiliary diseases, as well as improve therapeutic strategies in challenging clinical situations such as pregnancy and neonatal care.


Subject(s)
Cholelithiasis , Cholestasis, Intrahepatic , Hyperbilirubinemia, Neonatal , Pregnancy Complications , Adult , Female , Humans , Infant, Newborn , Pregnancy , China , Cholelithiasis/genetics , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/diagnosis
19.
Int J Gynaecol Obstet ; 164(3): 979-984, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37680091

ABSTRACT

OBJECTIVE: This study aimed to investigate maternal serum vascular endothelial growth factor (VEGF) C and D levels in patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: A total of 83 patients, including 41 patients with ICP and 42 healthy pregnant women, were included in the study. We first compared the maternal serum VEGF-C and VEGF-D levels between the ICP and control groups and then examined the correlation between the serum VEGF-C level and the bile acid level in patients with severe ICP. RESULTS: We observed statistically significantly higher serum VEGF-C levels and lower VEGF-D levels in the ICP group compared with the healthy controls (P < 0.001 and P = 0.015, respectively). According to receiver operating characteristic analysis, the optimal cutoff value for ICP was 147 ng/mL in the determination of the VEGF-C level (specificity and sensitivity: 76%). In patients with severe ICP, the serum VEGF-C statistically significantly correlated with the bile acid level (P = 0.019). CONCLUSION: This study showed that the maternal serum VEGF-C level was higher and the VEGF-D level was lower in patients with ICP compared with healthy pregnant women. We also found that the VEGF-C level was correlated with the serum bile acid level in patients with severe ICP. Serum VEGF-C level can be used in the diagnosis and follow-up of intrahepatic pregnancy cholestasis.


Subject(s)
Cholestasis, Intrahepatic , Pregnancy Complications , Vascular Endothelial Growth Factor C , Vascular Endothelial Growth Factor D , Female , Humans , Pregnancy , Bile Acids and Salts , Case-Control Studies , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/diagnosis , Pregnancy Complications/diagnosis , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor C/blood , Vascular Endothelial Growth Factor D/blood
20.
J Obstet Gynaecol Res ; 50(2): 196-204, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37994385

ABSTRACT

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) manifests in late pregnancy. Elevated serum bile acid is a diagnostic criterion: however, its measurement is troublesome. Prediction of ICP by blood markers is not established. Serum bile acid level is associated with liver damage and inflammation. We hypothesized that the following markers could predict the occurrence of ICP and have diagnostic value for it: Liver damage-indicating scores (albumin-bilirubin [ALBI], Model for End-Stage Liver Disease [MELD], aspartate aminotransferase-to-platelet ratio [APRI]) and inflammatory markers (platelet-to-lymphocyte ratio [PLR] and neutrophil-to-lymphocyte ratio [NLR]). METHODS: Eighty ICP patients and 200 controls were studied. The values of MELD, APRI, ALBI, PLR, and NLR were measured in the 1st trimester and at the time of diagnosis. RESULTS: Patients with ICP had significantly higher ALBI, MELD, and APRI scores both in the first trimester and at diagnosis. Multivariate logistic regression (MLR) showed that age, ALBI, MELD, and APRI scores were statistically significant (p < 0.05). By receiver operating characteristic (ROC) analysis, the sensitivity of MELD, ALBI, APRI, and NLR in the first trimester was 62%, 73%, 58%, and 29%, respectively, and MELD, ALBI, APRI, and PLR at diagnosis was 28%, 38%, 57%, and 8%, respectively, with a fixed false-positive rate of 10%. CONCLUSION: This study has demonstrated the usability of the MELD, ALBI, and APRI scores in predicting and diagnosing ICP. They are easy to obtain and might be used in routine practice.


Subject(s)
Cholestasis, Intrahepatic , End Stage Liver Disease , Pregnancy Complications , Female , Humans , Pregnancy , Prognosis , Serum Albumin/analysis , Severity of Illness Index , Cholestasis, Intrahepatic/diagnosis , Bile Acids and Salts , Retrospective Studies , ROC Curve
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