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Buyuker F, Sermet M, Ozsoy MS, Tosun S, Ekinci Ö, Baysal H, Alimoglu O. The effect of ursodeoxycholic acid in dissolving gallstones formed after laparoscopic sleeve gastrectomy: retrospective cohort study. Langenbecks Arch Surg 2025; 410:91. [PMID: 40050567 PMCID: PMC11885402 DOI: 10.1007/s00423-025-03656-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/20/2025] [Indexed: 03/09/2025]
Abstract
PURPOSE Rapid weight loss that often occurs after laparoscopic sleeve gastrectomy (LSG) has been linked to an increased risk of gallstone formation. This study aimed to investigate whether ursodeoxycholic acid could be an effective alternative treatment for gallstone dissolution, potentially offering a nonsurgical option for patients requiring gallstone removal. METHODS This retrospective study analyzed 88 patients who underwent LSG and subsequently developed gallstones between 2017 and 2023. Fifty-one patients who received UDCA treatment were compared to 37 patients who did not receive UDCA. Demographic and clinical characteristics and gallstone dissolution rates were analyzed using SPSS v25.0. RESULTS Gallstones dissolved in 60% of patients who received UDCA treatment, and symptoms such as dyspepsia decreased. A stone diameter of less than 5 mm was associated with a higher treatment success rate. The number of hospitalizations and admissions due to gallstone symptoms has decreased. The side effects were mild and did not require treatment discontinuation. CONCLUSIONS UDCA treatment is an effective option for the resolution of gallstones after LSG. However, surgery may be more appropriate for treating larger stones. The results of this study suggest that UDCA is an effective intervention for reducing gallstone-related complications following LSG.
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Affiliation(s)
- Fatih Buyuker
- Istanbul Medeniyet University Faculty of Medicine Goztepe Prof. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Medeni Sermet
- Istanbul Medeniyet University Faculty of Medicine Goztepe Prof. Suleyman Yalcin City Hospital, Istanbul, Turkey.
| | - Mehmet Sait Ozsoy
- Istanbul Medeniyet University Faculty of Medicine Goztepe Prof. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Salih Tosun
- Istanbul Medeniyet University Faculty of Medicine Goztepe Prof. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Özgür Ekinci
- Istanbul Medeniyet University Faculty of Medicine Goztepe Prof. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Hakan Baysal
- Istanbul Medeniyet University Faculty of Medicine Goztepe Prof. Suleyman Yalcin City Hospital, Istanbul, Turkey
| | - Orhan Alimoglu
- Istanbul Medeniyet University Faculty of Medicine Goztepe Prof. Suleyman Yalcin City Hospital, Istanbul, Turkey
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Arteaga I, Chacón C, Martínez-Escudé A, Rojano IR, Diez-Fadrique G, Carmona-Cervelló M, Torán-Monserrat P. Evaluating Pediatric NAFLD with Controlled Attenuation Parameter: A Comprehensive Narrative Review. Diagnostics (Basel) 2025; 15:299. [PMID: 39941229 PMCID: PMC11816681 DOI: 10.3390/diagnostics15030299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/09/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) in the pediatric population has emerged as a significant health concern due to its alarming rise in prevalence. In children, the characteristics of the disease differ from those seen in adults. NAFLD may progress to more severe liver disease in children compared to adults with similar profiles. Liver biopsy remains the gold standard for diagnosis; its invasive nature and high cost limit its use as a first-line tool. Alternatively, magnetic resonance imaging (MRI) techniques, such as magnetic resonance imaging-estimated liver proton density fat fraction (MRI-PDFF), have shown a good correlation with the degree of histological steatosis, although their use is limited by high costs and limited accessibility. Controlled attenuation parameter (CAP), integrated with vibration-controlled transient elastography (VCTE) (FibroScan®), is a novel non-invasive, accessible, and effective method for diagnosing hepatic steatosis. In this article, we reviewed the existing literature on the diagnostic accuracy of CAP in pediatric NAFLD. The PubMed and EMBASE databases were searched. Seven relevant studies were identified, conducted in pediatric hospital populations with specific demographic characteristics. Two of these studies compared CAP with liver biopsy, one compared CAP with liver biopsy and MRI-PDFF, and the remaining four compared CAP with MRI. Overall, CAP proved to be accurate in detecting the presence or absence of fatty infiltration, positioning it as a promising tool to simplify the diagnosis of NAFLD in children. However, further studies in larger populations are needed to confirm these findings and facilitate its implementation in routine clinical practice.
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Affiliation(s)
- Ingrid Arteaga
- Unitat de Suport a la Recerca (USR) Metropolitana Nord, Fundació Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), 08303 Mataró, Spain; (I.A.); (C.C.); (A.M.-E.); (I.R.R.); (G.D.-F.); (M.C.-C.)
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, 08303 Mataró, Spain
- Primary Healthcare Center Vall del Tenes, Gerència d’Àmbit d’Atenció Primària Metropolitana Nord, Institut Català de la Salut, 08186 Llicà d’Amunt, Spain
| | - Carla Chacón
- Unitat de Suport a la Recerca (USR) Metropolitana Nord, Fundació Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), 08303 Mataró, Spain; (I.A.); (C.C.); (A.M.-E.); (I.R.R.); (G.D.-F.); (M.C.-C.)
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, 08303 Mataró, Spain
- Ph.D. Programme in Medicine and Translational Research, Faculty of Medicine, University of Barcelona, 08193 Barcelona, Spain
| | - Alba Martínez-Escudé
- Unitat de Suport a la Recerca (USR) Metropolitana Nord, Fundació Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), 08303 Mataró, Spain; (I.A.); (C.C.); (A.M.-E.); (I.R.R.); (G.D.-F.); (M.C.-C.)
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, 08303 Mataró, Spain
- Primary Healthcare Center La Llagosta, Gerència d’Àmbit d’Atenció Primària Metropolitana Nord, Institut Català de la Salut, 08120 La Llagosta, Spain
- Department of Medicine, Faculty of Medicine, Autonomous University of Barcelona, 08193 Bellaterra, Spain
| | - Irene Ruiz Rojano
- Unitat de Suport a la Recerca (USR) Metropolitana Nord, Fundació Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), 08303 Mataró, Spain; (I.A.); (C.C.); (A.M.-E.); (I.R.R.); (G.D.-F.); (M.C.-C.)
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, 08303 Mataró, Spain
- Primary Healthcare Center Dr. Barraquer, Gerència d’Àmbit d’Atenció Primària Metropolitana Nord, Institut Català de la Salut, 08930 Sant Adrià del Besos, Spain
| | - Galadriel Diez-Fadrique
- Unitat de Suport a la Recerca (USR) Metropolitana Nord, Fundació Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), 08303 Mataró, Spain; (I.A.); (C.C.); (A.M.-E.); (I.R.R.); (G.D.-F.); (M.C.-C.)
| | - Meritxell Carmona-Cervelló
- Unitat de Suport a la Recerca (USR) Metropolitana Nord, Fundació Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), 08303 Mataró, Spain; (I.A.); (C.C.); (A.M.-E.); (I.R.R.); (G.D.-F.); (M.C.-C.)
| | - Pere Torán-Monserrat
- Unitat de Suport a la Recerca (USR) Metropolitana Nord, Fundació Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), 08303 Mataró, Spain; (I.A.); (C.C.); (A.M.-E.); (I.R.R.); (G.D.-F.); (M.C.-C.)
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, 08303 Mataró, Spain
- Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
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Giraudi PJ, Pascut D, Banfi C, Ghilardi S, Tiribelli C, Bondesan A, Caroli D, Minocci A, Sartorio A. Serum proteome signatures associated with liver steatosis in adolescents with obesity. J Endocrinol Invest 2025; 48:213-225. [PMID: 39017916 PMCID: PMC11729140 DOI: 10.1007/s40618-024-02419-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 06/19/2024] [Indexed: 07/18/2024]
Abstract
PURPOSE Childhood obesity, a pressing global health issue, significantly increases the risk of metabolic complications, including metabolic dysfunction associated with steatotic liver disease (MASLD). Accurate non-invasive tests for early detection and screening of steatosis are crucial. In this study, we explored the serum proteome, identifying proteins as potential biomarkers for inclusion in non-invasive steatosis diagnosis tests. METHODS Fifty-nine obese adolescents underwent ultrasonography to assess steatosis. Serum samples were collected and analyzed by targeted proteomics with the Proximity Extension Assay technology. Clinical and biochemical parameters were evaluated, and correlations among them, the individuated markers, and steatosis were performed. Receiver operating characteristic (ROC) curves were used to determine the steatosis diagnostic performance of the identified candidates, the fatty liver index (FLI), and their combination in a logistic regression model. RESULTS Significant differences were observed between subjects with and without steatosis in various clinical and biochemical parameters. Gender-related differences in the serum proteome were also noted. Five circulating proteins, including Cathepsin O (CTSO), Cadherin 2 (CDH2), and Prolyl endopeptidase (FAP), were identified as biomarkers for steatosis. CDH2, CTSO, Leukocyte Immunoglobulin Like Receptor A5 (LILRA5), BMI, waist circumference, HOMA-IR, and FLI, among others, significantly correlated with the steatosis degree. CDH2, FAP, and LDL combined in a logit model achieved a diagnostic performance with an AUC of 0.91 (95% CI 0.75-0.97, 100% sensitivity, 84% specificity). CONCLUSIONS CDH2 and FAP combined with other clinical parameters, represent useful tools for accurate diagnosis of fatty liver, emphasizing the importance of integrating novel markers into diagnostic algorithms for MASLD.
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Affiliation(s)
- P J Giraudi
- Metabolic Liver Disease Unit, Fondazione Italiana Fegato-ONLUS, Trieste, Italy.
| | - D Pascut
- Liver Cancer Unit, Fondazione Italiana Fegato-ONLUS, Trieste, Italy
| | - C Banfi
- Unit of Functional Proteomics, Metabolomics, and Network Analysis, Centro Cardiologico Monzino, IRCCS, Milan, Italy
| | - S Ghilardi
- Unit of Functional Proteomics, Metabolomics, and Network Analysis, Centro Cardiologico Monzino, IRCCS, Milan, Italy
| | - C Tiribelli
- Metabolic Liver Disease Unit, Fondazione Italiana Fegato-ONLUS, Trieste, Italy
- Liver Cancer Unit, Fondazione Italiana Fegato-ONLUS, Trieste, Italy
| | - A Bondesan
- Istituto Auxologico Italiano IRCCS, Experimental Laboratory for Auxo-endocrinological Research, Piancavallo-Verbania, Italy
| | - D Caroli
- Istituto Auxologico Italiano IRCCS, Experimental Laboratory for Auxo-endocrinological Research, Piancavallo-Verbania, Italy
| | - A Minocci
- Division of Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Piancavallo-Verbania, Italy
| | - A Sartorio
- Istituto Auxologico Italiano IRCCS, Experimental Laboratory for Auxo-endocrinological Research, Piancavallo-Verbania, Italy
- Istituto Auxologico Italiano IRCCS, Experimental Laboratory for Auxo-endocrinological Research, Milan, Italy
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Jin HY, Noh ES, Jeong H, Hwang IIT. Prediction of hepatic fibrosis using the aspartate transaminase-to-platelet ratio index in children and adolescents with metabolic dysfunction-associated steatotic liver disease. BMC Pediatr 2024; 24:788. [PMID: 39614232 DOI: 10.1186/s12887-024-05263-3] [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: 09/03/2024] [Accepted: 11/19/2024] [Indexed: 12/01/2024] Open
Abstract
BACKGROUND Aspartate transaminase-to-platelet ratio index (APRI) is an easy and useful predictor of hepatic fibrosis in patients with chronic hepatic disease, and it significantly correlates with the degree of hepatic fibrosis in adult patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to evaluate the use of APRI in assessing the severity of MASLD in children and adolescents. METHODS Medical records of 115 patients (males: 78; females: 37) with MASLD were retrospectively reviewed. The correlations between the APRI and clinical parameters that indicate the severity of MASLD were analyzed. Their ages ranged between 7.3 and 18.8 years old. Patients with hepatitis B or C infections were excluded from the study. The APRI score was calculated, and transient elastography for liver stiffness measurement (LSM) was performed for all the patients. RESULTS The mean APRI score was 0.46 ± 0.26, ranging between 0.16 and 1.57. The LSM values ranged between 2.94 and 7.72 kPa. Body mass index-standard deviation score, transaminase levels, and HbA1c levels were higher in a group with abnormal LSM when divided into two groups according to LSM. The APRI score was greater in the group with abnormal LSM (0.40 ± 0.17 vs. 0.64 ± 0.40, P < 0.001). The APRI score was associated with LSM (r = 0.354, P < 0.001). Area under the curve of APRI for predicting abnormal LSM was 0.650 (95% confidence interval, 0.517-0.784) with a cutoff value of 0.74. CONCLUSIONS APRI score showed weak correlation with LSM. Further study encompassing various severity of hepatic fibrosis is needed for identifying better and sensitive non-invasive indicators in pediatric MASLD.
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Affiliation(s)
- Hye Young Jin
- Department of Pediatrics, Kangdong Sacred Heart hospital, Hallym University College of Medicine, 150, Seongan-ro, Gangdong-gu, Seoul, 05355, Republic of Korea
| | - Eu Seon Noh
- Department of Pediatrics, Kangdong Sacred Heart hospital, Hallym University College of Medicine, 150, Seongan-ro, Gangdong-gu, Seoul, 05355, Republic of Korea
| | - Hwalrim Jeong
- Department of Pediatrics, Soonchunhyang University, Cheonan hospital, Cheonan, Korea
| | - I I Tae Hwang
- Department of Pediatrics, Kangdong Sacred Heart hospital, Hallym University College of Medicine, 150, Seongan-ro, Gangdong-gu, Seoul, 05355, Republic of Korea.
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Kim MN, Han JW, An J, Kim BK, Jin YJ, Kim SS, Lee M, Lee HA, Cho Y, Kim HY, Shin YR, Yu JH, Kim MY, Choi Y, Chon YE, Cho EJ, Lee EJ, Kim SG, Kim W, Jun DW, Kim SU, on behalf of The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for noninvasive tests to assess liver fibrosis in chronic liver disease. Clin Mol Hepatol 2024; 30:S5-S105. [PMID: 39159947 PMCID: PMC11493350 DOI: 10.3350/cmh.2024.0506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 08/21/2024] Open
Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Ji Won Han
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jihyun An
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Seung-seob Kim
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Minjong Lee
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
| | - Hee Yeon Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yu Rim Shin
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jung Hwan Yu
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Young Eun Chon
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Joo Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - on behalf of The Korean Association for the Study of the Liver (KASL)
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
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Wang A, Blackford AL, Behling C, Wilson LA, Newton KP, Xanthakos SA, Fishbein MH, Vos MB, Mouzaki M, Molleston JP, Jain AK, Hertel P, Harlow Adams K, Schwimmer JB. Development of Fibro-PeN, a clinical prediction model for moderate-to-severe fibrosis in children with nonalcoholic fatty liver disease. Hepatology 2024; 79:1381-1392. [PMID: 37870272 PMCID: PMC11035485 DOI: 10.1097/hep.0000000000000644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 09/23/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND AND AIMS Liver fibrosis is common in children with NAFLD and is an important determinant of outcomes. High-performing noninvasive models to assess fibrosis in children are needed. The objectives of this study were to evaluate the performance of existing pediatric and adult fibrosis prediction models and to develop a clinical prediction rule for identifying moderate-to-severe fibrosis in children with NAFLD. APPROACH AND RESULTS We enrolled children with biopsy-proven NAFLD in the Nonalcoholic Steatohepatitis Clinical Research Network within 90 days of liver biopsy. We staged liver fibrosis in consensus using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. We evaluated existing pediatric and adult models for fibrosis and developed a new pediatric model using the least absolute shrinkage and selection operator with linear and spline terms for discriminating moderate-to-severe fibrosis from none or mild fibrosis. The model was internally validated with 10-fold cross-validation. We evaluated 1055 children with NAFLD, of whom 26% had moderate-to-severe fibrosis. Existing models performed poorly in classifying fibrosis in children, with area under the receiver operator curves (AUC) ranging from 0.57 to 0.64. In contrast, our new model, fibrosis in pediatric NAFLD was derived from fourteen common clinical variables and had an AUC of 0.79 (95% CI: 0.77-0.81) with 72% sensitivity and 76% specificity for identifying moderate-to-severe fibrosis. CONCLUSION Existing fibrosis prediction models have limited clinical utility in children with NAFLD. Fibrosis in pediatric NAFLD offers improved performance characteristics for risk stratification by identifying moderate-to-severe fibrosis in children with NAFLD.
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Affiliation(s)
- Andrew Wang
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California, USA
- Department of Gastroenterology, Rady Children's Hospital, San Diego, California, USA
| | - Amanda L Blackford
- Department of Oncology, Division of Quantitative Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Cynthia Behling
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California, USA
| | - Laura A Wilson
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Kimberly P Newton
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California, USA
- Department of Gastroenterology, Rady Children's Hospital, San Diego, California, USA
| | - Stavra A Xanthakos
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Mark H Fishbein
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Miriam B Vos
- Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Marialena Mouzaki
- Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Jean P Molleston
- Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ajay K Jain
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Saint Louis University, St. Louis, Missouri, USA
| | - Paula Hertel
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Kathryn Harlow Adams
- Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jeffrey B Schwimmer
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California, USA
- Department of Gastroenterology, Rady Children's Hospital, San Diego, California, USA
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7
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Bacha F, Gupta R, Jenkins TM, Brandt ML, Inge TH, Kleiner DE, Xanthakos SA. Prognostic factors in resolution of nonalcoholic fatty liver disease post bariatric surgery in adolescents. Surg Obes Relat Dis 2024; 20:367-375. [PMID: 38155077 DOI: 10.1016/j.soard.2023.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/31/2023] [Accepted: 11/12/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND The long-term effect of bariatric surgery on adolescent non-alcoholic fatty liver disease is not clear. OBJECTIVES To evaluate longitudinal change in serum alanine aminotransferase (ALT) levels and to determine the factors independently associated with this change over 2 years after bariatric surgery in adolescents with severe obesity. SETTING An observational prospective cohort from the Teen-LABS Consortium. METHODS We examined the relationship of longitudinal change in serum ALT (% change and normalization) to change in body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), high- (HDL) and low-density lipoprotein cholesterol, A1C and fasting glucose, accounting for age, sex, race-ethnicity, blood pressure, and baseline BMI in 219 adolescents during the first 2 years post-surgery. RESULTS Mean BMI declined from a baseline of 52.6 to 37.2 kg/m2 at 2 years (P < .01). Alanine aminotransferase decreased significantly from baseline (36.5 [95% CI: 31.4, 41.7]) to 6 months (30.5 [95% CI: 25.4, 35.6]), and remained stable at 12 and 24 months, all P < .01 versus baseline. After adjustment, improvement in BMI, fasting glucose, HOMA-IR, triglycerides, TG/HDL ratio, and HDL were independently associated with reduced ALT at 6 months. These remained significantly associated with a decline in ALT after adjusting for BMI change. The %participants with elevated ALT decreased from 71% at baseline to 42% and 36% at 1 and 2 years post-surgery. CONCLUSIONS Bariatric surgery resulted in significant and sustained improvement in ALT levels over 2 years. Although associated with weight loss, this decline was also associated with improved metabolic indices, independent of weight loss.
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Affiliation(s)
- Fida Bacha
- Children's Nutrition Research Center and Division of Pediatric Diabetes and Endocrinology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
| | - Resmi Gupta
- Department of Internal Medicine, Division of Clinical and Translational Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Todd M Jenkins
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Mary L Brandt
- Department of Surgery, Tulane University School of Medicine and Children's Hospital New Orleans, New Orleans, Louisiana
| | - Thomas H Inge
- Department of Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stavra A Xanthakos
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
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8
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Kalveram L, Baumann U, De Bruyne R, Draijer L, Janczyk W, Kelly D, Koot BG, Lacaille F, Lefere S, Lev HM, Lubrecht J, Mann JP, Mosca A, Rajwal S, Socha P, Vreugdenhil A, Alisi A, Hudert CA. Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease. J Pediatr Gastroenterol Nutr 2024; 78:27-35. [PMID: 38291699 DOI: 10.1002/jpn3.12068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/01/2023] [Accepted: 10/25/2023] [Indexed: 02/01/2024]
Abstract
OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. METHODS The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). RESULTS Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. CONCLUSIONS Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.
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Affiliation(s)
- Laura Kalveram
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität zu Berlin and Humboldt-Universität zu, Berlin, Germany
| | - Ulrich Baumann
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases Hannover, Hannover Medical School, Hanover, Germany
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Ruth De Bruyne
- Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University, Ghent, Belgium
| | - Laura Draijer
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Netherlands
| | - Wojciech Janczyk
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Deirdre Kelly
- Liver unit, Birmingham Children's Hospital, University of Birmingham, Birmingham, UK
| | - Bart G Koot
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Netherlands
| | - Florence Lacaille
- Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants maladies, Paris, France
| | - Sander Lefere
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Hadar Moran Lev
- Pediatric Gastroenterology Unit, Dana Dwek Children's Hospital, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Judith Lubrecht
- Department of Pediatrics, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Jake P Mann
- Liver unit, Birmingham Children's Hospital, University of Birmingham, Birmingham, UK
| | - Antonella Mosca
- Hepatology, Gastroenterology, Nutrition, and Liver Transplantation Unit, Bambino Gesu' Children's Hospital, IRCCS, Rome, Italy
| | - Sanjay Rajwal
- Children's Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK
| | - Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Anita Vreugdenhil
- Department of Pediatrics, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Anna Alisi
- Genetics of Complex Phenotypes Research Unit, Bambino Gesu' Children's Hospital, IRCCS, Rome, Italy
| | - Christian A Hudert
- Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität zu Berlin and Humboldt-Universität zu, Berlin, Germany
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9
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Bodewes FAJA, Freeman AJ, Weymann A, Debray D, Scheers I, Verkade HJ, Narkewicz MR. Towards a Standardized Classification of the Hepatobiliary Manifestations in Cystic Fibrosis (CFHBI): A Joint ESPGHAN/NASPGHAN Position Paper. J Pediatr Gastroenterol Nutr 2024; 78:153-165. [PMID: 38291686 DOI: 10.1097/mpg.0000000000003944] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/08/2023] [Indexed: 02/01/2024]
Abstract
The broad spectrum of hepatobiliary involvement in cystic fibrosis (CF) has been commonly referred to as cystic fibrosis liver disease (CFLD). However, differences in the definitions of CFLD have led to variations in reported prevalence, incidence rates, and standardized recommendations for diagnosis and therapies. Harmonizing the description of the spectrum of hepatobiliary involvement in all people with CF (pwCF) is deemed essential for providing a reliable account of the natural history, which in turn supports the development of meaningful clinical outcomes in patient care and research. Recognizing this necessity, The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) commissioned and tasked a committee to develop and propose a systematic classification of the CF hepatobiliary manifestations to increase uniformity, accuracy, and comparability for clinical, registry, and research purposes. This report describes the committee's combined expert position statement on hepatobiliary involvement in CF, which has been endorsed by NASPGHAN and ESPGHAN. We recommend using CFHBI (Cystic Fibrosis Hepato-Biliary Involvement) as the updated term to describe and classify all hepatobiliary manifestations in all pwCF. CFHBI encompasses the current extensive spectrum of phenotypical, clinical, or diagnostic expressions of liver involvement observed in pwCF. We present a schematic categorization of CFHBI, which may also be used to track and classify the changes and development of CFHBI in pwCF over time. The proposed classification for CFHBI is based on expert consensus and has not been validated for clinical practice and research purposes. Achieving validation should be an important aim for future research.
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Affiliation(s)
- Frank A J A Bodewes
- Division of Pediatric Gastroenterology/Hepatology, Beatrix Children's Hospital/University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Alvin Jay Freeman
- Division of Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Alexander Weymann
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Nationwide Children's Hospital/The Ohio State University College of Medicine, Columbus, OH
| | - Dominique Debray
- Pediatric Hepatology Unit, Assistance Publique-Hôpitaux de Paris (APHP)-Hôpital Necker-Enfants maladies, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Isabelle Scheers
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Henkjan J Verkade
- Division of Pediatric Gastroenterology/Hepatology, Beatrix Children's Hospital/University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Michael R Narkewicz
- Digestive Health Institute, Children's Hospital Colorado and Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
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10
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Chacón C, Arteaga I, Martínez-Escudé A, Ruiz Rojano I, Lamonja-Vicente N, Caballeria L, Ribatallada Diez AM, Schröder H, Montraveta M, Bovo MV, Ginés P, Pera G, Diez-Fadrique G, Pachón-Camacho A, Alonso N, Graupera I, Torán-Monserrat P, Expósito C. Clinical epidemiology of non-alcoholic fatty liver disease in children and adolescents. The LiverKids: Study protocol. PLoS One 2023; 18:e0286586. [PMID: 37831682 PMCID: PMC10575486 DOI: 10.1371/journal.pone.0286586] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 05/18/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is rapidly increasing alongside overweight and obesity, not only in adults but also in children and adolescents. It is unknown what impact the development of NAFLD in childhood may have in later life. The importance of early detection and treatment lies in its potential for progression to cirrhosis, liver cancer and liver-related death, as well as its associated extrahepatic comorbidities. Vibration-Controlled Transient Elastography (VCTE) with Controlled Attenuation Parameter (CAP) is an effective, non-invasive and safe diagnostic method to estimate the degree of fibrosis and steatosis in the liver, but little is known about its applicability in the paediatric population. AIMS 1) To assess the prevalence of significant liver fibrosis (Liver Stiffness Measurement (LSM) ≥6.5 kPa) using VCTE, and that of non-alcoholic fatty liver disease (≥225 dB/m) using CAP in children and adolescents. 2) To determine the optimal cut-off points of the CAP to achieve maximum concordance with the Magnetic Resonance Imaging (MRI) findings in the diagnosis of mild, moderate and severe NAFLD in children and adolescents. METHODS Cross-sectional population-based study which will include 2,866 subjects aged between 9 and 16 years. Participants will undergo: anamnesis, physical examination, blood extraction, VCTE, MRI and questionnaires on socio-demographic data, personal and family medical history and lifestyle assessment. APPLICABILITY AND RELEVANCE The study aims to establish the foundations for the use of VCTE in children and adolescents in order to achieve early diagnosis of NAFLD. Moreover, it will serve to understand in further detail the disease and to identify the risk groups of children and adolescents who may be at risk of developing it. Ultimately, this will help determine to which subgroups of the population we need to target resources for prevention and early detection of this entity, as well as possible intervention for its treatment. TRIAL REGISTRATION The LiverKids study is registered on Clinicaltrials.gov (NCT05526274).
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Affiliation(s)
- Carla Chacón
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, Mataró, Barcelona, Spain
- PhD Programme in Medicine and Translational Research, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Ingrid Arteaga
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, Mataró, Barcelona, Spain
- Centre d’Atenció Primària Palaudàries, Institut Català de la Salut, Lliçà d’Amunt, Barcelona, Spain
| | - Alba Martínez-Escudé
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, Mataró, Barcelona, Spain
- Centre d’Atenció Primària La Llagosta, Institut Català de la Salut, La Llagosta, Barcelona, Spain
| | - Irene Ruiz Rojano
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, Mataró, Barcelona, Spain
- Centre d’Atenció Primària Dr. Barraquer, Institut Català de la Salut, Sant Adrià del Besos, Barcelona, Spain
| | - Noemí Lamonja-Vicente
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
| | - Llorenç Caballeria
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, Mataró, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
| | - Ana María Ribatallada Diez
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, Mataró, Barcelona, Spain
- Centre d’Atenció Primària Serraparera, Institut Català de la Salut, Cerdanyola del Vallès, Barcelona, Spain
| | - Helmut Schröder
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
- CIBER Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Montserrat Montraveta
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Maria Victoria Bovo
- Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Pere Ginés
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
- Liver Unit, Hospital Clínic de Barcelona, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Guillem Pera
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
| | - Galadriel Diez-Fadrique
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
| | - Alba Pachón-Camacho
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
| | - Núria Alonso
- Department of Endocrinology and Nutrition, Hospital Universitario Germans Trias I Pujol, Badalona, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Center for Biomedical Research on Diabetes and Associated Metabolic diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Graupera
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
- Liver Unit, Hospital Clínic de Barcelona, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Pere Torán-Monserrat
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, Mataró, Barcelona, Spain
- Direcció d’Atenció Primària Metropolitana Nord Institut Català de Salut, Mataró, Spain
| | - Carmen Expósito
- Unitat de Suport a la Recerca Metropolitana Nord (USR Metro-Nord), Institut Universitari d’Investigació en Atenció Primària Jordi Gol i Gurina (IDIAP Jordi Gol), Mataró, Barcelona, Spain
- Grup de Recerca en Malalties Hepàtiques a l’Atenció Primària (GRemHAp), IDIAP Jordi Gol, USR Metro-Nord, Mataró, Barcelona, Spain
- Centre d’Atenció Primària Badia del Vallès, Institut Català de la Salut, Badia del Vallès, Barcelona, Spain
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11
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Garibay-Nieto N, Pedraza-Escudero K, Omaña-Guzmán I, Garcés-Hernández MJ, Villanueva-Ortega E, Flores-Torres M, Pérez-Hernández JL, León-Hernández M, Laresgoiti-Servitje E, Palacios-González B, López-Alvarenga JC, Lisker-Melman M, Vadillo-Ortega F. Metabolomic Phenotype of Hepatic Steatosis and Fibrosis in Mexican Children Living with Obesity. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1785. [PMID: 37893503 PMCID: PMC10608521 DOI: 10.3390/medicina59101785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 10/29/2023]
Abstract
Background and Objectives: Metabolic-dysfunction-associated steatotic liver disease or MASLD is the main cause of chronic liver diseases in children, and it is estimated to affect 35% of children living with obesity. This study aimed to identify metabolic phenotypes associated with two advanced stages of MASLD (hepatic steatosis and hepatic steatosis plus fibrosis) in Mexican children with obesity. Materials and Methods: This is a cross-sectional analysis derived from a randomized clinical trial conducted in children and adolescents with obesity aged 8 to 16 years. Anthropometric and biochemical data were measured, and targeted metabolomic analyses were carried out using mass spectrometry. Liver steatosis and fibrosis were estimated using transient elastography (Fibroscan® Echosens, Paris, France). Three groups were studied: a non-MASLD group, an MASLD group, and a group for MASLD + fibrosis. A partial least squares discriminant analysis (PLS-DA) was performed to identify the discrimination between the study groups and to visualize the differences between their heatmaps; also, Variable Importance Projection (VIP) plots were graphed. A VIP score of >1.5 was considered to establish the importance of metabolites and biochemical parameters that characterized each group. Logistic regression models were constructed considering VIP scores of >1.5, and the receiver operating characteristic (ROC) curves were estimated to evaluate different combinations of variables. Results: The metabolic MASLD phenotype was associated with increased concentrations of ALT and decreased arginine, glycine, and acylcarnitine (AC) AC5:1, while MASLD + fibrosis, an advanced stage of MASLD, was associated with a phenotype characterized by increased concentrations of ALT, proline, and alanine and a decreased Matsuda Index. Conclusions: The metabolic MASLD phenotype changes as this metabolic dysfunction progresses. Understanding metabolic disturbances in MASLD would allow for early identification and the development of intervention strategies focused on limiting the progression of liver damage in children and adolescents.
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Affiliation(s)
- Nayely Garibay-Nieto
- Pediatric Obesity Clinic and Wellness Unit, General Hospital of Mexico, Mexico City 06720, Mexico; (N.G.-N.); (K.P.-E.); (I.O.-G.); (M.J.G.-H.); (E.V.-O.)
| | - Karen Pedraza-Escudero
- Pediatric Obesity Clinic and Wellness Unit, General Hospital of Mexico, Mexico City 06720, Mexico; (N.G.-N.); (K.P.-E.); (I.O.-G.); (M.J.G.-H.); (E.V.-O.)
| | - Isabel Omaña-Guzmán
- Pediatric Obesity Clinic and Wellness Unit, General Hospital of Mexico, Mexico City 06720, Mexico; (N.G.-N.); (K.P.-E.); (I.O.-G.); (M.J.G.-H.); (E.V.-O.)
| | - María José Garcés-Hernández
- Pediatric Obesity Clinic and Wellness Unit, General Hospital of Mexico, Mexico City 06720, Mexico; (N.G.-N.); (K.P.-E.); (I.O.-G.); (M.J.G.-H.); (E.V.-O.)
| | - Eréndira Villanueva-Ortega
- Pediatric Obesity Clinic and Wellness Unit, General Hospital of Mexico, Mexico City 06720, Mexico; (N.G.-N.); (K.P.-E.); (I.O.-G.); (M.J.G.-H.); (E.V.-O.)
| | - Mariana Flores-Torres
- Unidad de Vinculación de la Facultad de Medicina, UNAM, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico;
| | - José Luis Pérez-Hernández
- Hepatology Clinic, Gastroenterology Department, General Hospital of Mexico, Mexico City 06720, Mexico;
| | | | | | - Berenice Palacios-González
- Laboratorio de Envejecimiento Saludable, Centro de Investigación Sobre el Envejecimiento, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico;
| | - Juan Carlos López-Alvarenga
- Department of Population Health & Biostatistics, University of Texas Rio Grande Valley, Edinburg, TX 78539, USA;
| | - Mauricio Lisker-Melman
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Felipe Vadillo-Ortega
- Unidad de Vinculación de la Facultad de Medicina, UNAM, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico;
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12
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Jayasekera D, Hartmann P. Noninvasive biomarkers in pediatric nonalcoholic fatty liver disease. World J Hepatol 2023; 15:609-640. [PMID: 37305367 PMCID: PMC10251277 DOI: 10.4254/wjh.v15.i5.609] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/14/2023] [Accepted: 04/10/2023] [Indexed: 05/24/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide among children and adolescents. It encompasses a spectrum of disease, from its mildest form of isolated steatosis, to nonalcoholic steatohepatitis (NASH) to liver fibrosis and cirrhosis, or end-stage liver disease. The early diagnosis of pediatric NAFLD is crucial in preventing disease progression and in improving outcomes. Currently, liver biopsy is the gold standard for diagnosing NAFLD. However, given its invasive nature, there has been significant interest in developing noninvasive methods that can be used as accurate alternatives. Here, we review noninvasive biomarkers in pediatric NAFLD, focusing primarily on the diagnostic accuracy of various biomarkers as measured by their area under the receiver operating characteristic, sensitivity, and specificity. We examine two major approaches to noninvasive biomarkers in children with NAFLD. First, the biological approach that quantifies serological biomarkers. This includes the study of individual circulating molecules as biomarkers as well as the use of composite algorithms derived from combinations of biomarkers. The second is a more physical approach that examines data measured through imaging techniques as noninvasive biomarkers for pediatric NAFLD. Each of these approaches was applied to children with NAFLD, NASH, and NAFLD with fibrosis. Finally, we suggest possible areas for future research based on current gaps in knowledge.
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Affiliation(s)
- Dulshan Jayasekera
- Department of Internal Medicine and Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, United States
| | - Phillipp Hartmann
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of California San Diego, La Jolla, CA 92093, United States.
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13
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Dybbro E, Vos MB, Kohli R. Special Population: Pediatric Nonalcoholic Fatty Liver Disease. Clin Liver Dis 2023; 27:471-482. [PMID: 37024219 DOI: 10.1016/j.cld.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Pediatric nonalcoholic fatty liver disease represents the most common liver disease in children and has been shown to carry significant morbidity. Widespread heterogeneity of disease, as well as the limitation of indirect screening modalities, has made true prevalence of disease difficult to estimate as well as hindered ability to identify optimal prognostic factors in the pediatric population. Current therapeutic options are limited in pediatric patients with current mainstay of therapy, lifestyle modifications, has proven to have a limited efficacy in current clinical application. Current research remains needed in improved screening modalities, prognosticating techniques, and therapeutic options in the pediatric population.
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Affiliation(s)
- Eric Dybbro
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Miriam B Vos
- Division of Gastroenterology, Hepatology, and Nutrition, Emory School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Rohit Kohli
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA.
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14
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Klepper C, Crimmins NA, Orkin S, Sun Q, Fei L, Xanthakos S, Mouzaki M. Nonalcoholic Fatty Liver Disease in Young Children with Obesity. Child Obes 2023; 19:179-185. [PMID: 35639419 PMCID: PMC10122212 DOI: 10.1089/chi.2022.0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Background: To evaluate the prevalence of suspected nonalcoholic fatty liver disease (NAFLD) in young children with obesity and determine associated risk factors. Methods: Retrospective single-center study of children with obesity, ages 2-6 years. Suspected NAFLD was defined as an alanine aminotransferase (ALT) >30 U/L. Multivariable analyses were performed to determine predictors of elevated ALT. Results: Among 237 children 2-6 years old, 35% had elevated ALT. Multivariable analysis showed that higher BMI z score [odds ratio (OR): 1.5 confidence interval (95% CI: 1.04-1.92)] and higher gamma-glutamyl transferase (GGT) [OR: 21.3 (95% CI: 3.7-121.1)] predicted elevated ALT. Of those with ≥2 ALT levels, 38% (n = 33/86) had a persistently elevated ALT (median ALT >30 U/L). Only 7% of patients with ALT >30 U/L underwent further testing to evaluate for alternative causes of liver disease. Conclusion: Suspected NAFLD is common in young children with obesity and predicted by obesity severity and GGT. Other cardiometabolic markers were equivalent between those with normal vs. elevated ALT, suggesting NAFLD onset may precede development of comorbidities. Earlier screening will enable prompt diagnosis and intervention, which may prevent or delay the onset of cardiometabolic diseases commonly associated with NAFLD in adolescence and adulthood.
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Affiliation(s)
- Corie Klepper
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Nancy A. Crimmins
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Sarah Orkin
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Qin Sun
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Lin Fei
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Stavra Xanthakos
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Marialena Mouzaki
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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15
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Muacevic A, Adler JR, Farhat H, Irfan H, Muthiah K, Pallipamu N, Taheri S, Thiagaraj SS, Hamid P. The Usefulness of Combining Noninvasive Methods for Early Identification and Potential Prevention of Cystic Fibrosis-Associated Liver Disease. Cureus 2022; 14:e32340. [PMID: 36628032 PMCID: PMC9826601 DOI: 10.7759/cureus.32340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/09/2022] [Indexed: 12/13/2022] Open
Abstract
Cystic fibrosis-associated liver disease is the third leading cause of morbidity and mortality in patients with cystic fibrosis (CF). Liver damage in the course of CF ranges from biochemical abnormalities to full-blown cirrhosis and may involve complicated processes like inflammation, fibrogenesis, remodeling, apoptosis, and cholestasis. Despite robust research in the field of CF, its complex pathogenesis is not fully understood. Because of the unknown pathogenesis, it is difficult to develop a highly sensitive and specific test or technology that is standardized, acceptable, and available at most pediatric institutions. The Cystic Fibrosis Foundation (CFF) recommends annual blood tests to screen for liver pathology, which often fails to identify early-onset liver disease. In this review article, we present the use of different liver indices and imaging modalities that can help identify liver disease at the onset and may help in its prevention. Although the disease is commonly diagnosed in the pediatric population, due to increased life expectancy, there is increasing evidence of liver disease in adults too. We believe that the tools we present in this review will help in the prevention of liver disease and thereby reduce the associated morbidity and mortality.
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16
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Roeb E, Canbay A, Bantel H, Bojunga J, de Laffolie J, Demir M, Denzer UW, Geier A, Hofmann WP, Hudert C, Karlas T, Krawczyk M, Longerich T, Luedde T, Roden M, Schattenberg J, Sterneck M, Tannapfel A, Lorenz P, Tacke F. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:1346-1421. [PMID: 36100202 DOI: 10.1055/a-1880-2283] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- E Roeb
- Gastroenterologie, Medizinische Klinik II, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - A Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - H Bantel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - J Bojunga
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin., Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - J de Laffolie
- Allgemeinpädiatrie und Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - M Demir
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
| | - U W Denzer
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Marburg, Deutschland
| | - A Geier
- Medizinische Klinik und Poliklinik II, Schwerpunkt Hepatologie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - W P Hofmann
- Gastroenterologie am Bayerischen Platz - Medizinisches Versorgungszentrum, Berlin, Deutschland
| | - C Hudert
- Klinik für Pädiatrie m. S. Gastroenterologie, Nephrologie und Stoffwechselmedizin, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - T Karlas
- Klinik und Poliklinik für Onkologie, Gastroenterologie, Hepatologie, Pneumologie und Infektiologie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - M Krawczyk
- Klinik für Innere Medizin II, Gastroent., Hepat., Endokrin., Diabet., Ern.med., Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - T Longerich
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - T Luedde
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - M Roden
- Klinik für Endokrinologie und Diabetologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - J Schattenberg
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| | - M Sterneck
- Klinik für Hepatobiliäre Chirurgie und Transplantationschirurgie, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - A Tannapfel
- Institut für Pathologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - P Lorenz
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - F Tacke
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
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17
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Authors, Collaborators:. Updated S2k Clinical Practice Guideline on Non-alcoholic Fatty Liver Disease (NAFLD) issued by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) - April 2022 - AWMF Registration No.: 021-025. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:e733-e801. [PMID: 36100201 DOI: 10.1055/a-1880-2388] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
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18
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Habash N, Ezaizi Y, Kak I, Conjeevaram Selvakumar PK, Lopez R, Alkhouri N, Kabbany MN. Accuracy of noninvasive fibrosis scores in predicting advanced fibrosis in pediatric patients after liver transplantation. Pediatr Transplant 2022; 26:e14279. [PMID: 35393654 DOI: 10.1111/petr.14279] [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: 12/03/2021] [Revised: 02/11/2022] [Accepted: 03/23/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Liver biopsy is the gold standard to stage fibrosis in liver disease. Several scoring systems have been studied to predict advanced fibrosis in liver disease. Those scores have not been validated in pediatric liver transplant patients. AIM Evaluate the performance of three fibrosis scores (FSc) in assessing the presence of advanced fibrosis (AF) in children after orthotopic liver transplantation (OLT). METHODS Patients < 20 years of age who underwent liver biopsy post-OLT with laboratory values within 1 month of the biopsy were included. Fibrosis was determined by an experienced pathologist (F0-4). We defined AF as F3-4. The following FSc were calculated: AST/ALT ratio, APRI, and FIB-4 index. Receiver operating characteristic curve analysis was done to assess the FSc performance in predicting AF. RESULTS A total of 232 biopsies were analyzed, of those 42 (18.1%) showed AF (F3-4). FIB-4 was significantly higher in patients with AF compared to those without AF [median value of 1.1 [0.7, 3.0] and 0.6 [0.2, 1.4], respectively (p = .02)]; however, FIB-4 had satisfactory accuracy to diagnose AF with significant overlap and AUC of 0.68 (CI 0.56-0.81). Cutoff points of 0.2 and 3.03 were used to rule in and rule out AF, respectively. AST/ALT and APRI were not significantly different between patients with and without AF. CONCLUSION Even though FIB-4 had satisfactory accuracy in detecting AF in pediatric transplant patients, noninvasive hepatic FSc developed in adults still performed poorly. Our results highlight the need to develop a reliable pediatric FSc.
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Affiliation(s)
- Nawras Habash
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Pediatrics Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Yamen Ezaizi
- Department of Pediatrics Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ibrahim Kak
- Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Rocio Lopez
- Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Mohammad Nasser Kabbany
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
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19
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Rose PC, Nel ED, Cotton MF, Pitcher RD, Otwombe K, Browne SH, Innes S. Prevalence and Risk Factors for Hepatic Steatosis in Children With Perinatal HIV on Early Antiretroviral Therapy Compared to HIV-Exposed Uninfected and HIV-Unexposed Children. Front Pediatr 2022; 10:893579. [PMID: 35757117 PMCID: PMC9218275 DOI: 10.3389/fped.2022.893579] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/13/2022] [Indexed: 11/13/2022] Open
Abstract
Objectives We evaluated the prevalence and risk factors for hepatic steatosis in South African children with perinatally acquired HIV (PHIV) who started treatment early and remain on long-term antiretroviral therapy (ART) compared to HIV-uninfected children. Design A cross-sectional study from April 2019 to October 2021. PHIV, HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled from an ongoing cohort study. Methods All children had transient elastography (TE) with controlled attenuation parameter (CAP). Liver enzymes, lipogram, insulin and glucose were sent after an overnight fast. Multivariable linear regression analyses identified predictors of CAP. Hepatic steatosis was defined as CAP>248kPa. Results 215 children (111 [52%] male; median age 14.1 years; IQR 12.7-14.9) participated in the study, 110 PHIV, 105 HIV-uninfected (36 HEU, 69 HU). PHIV initiated ART at a median age of 2.7 months (IQR 1.8-8.5). Hepatic steatosis prevalence was 9% in PHIV, 3% in HEU and 1% in HU children (p = 0.08). However, 8% of lean (body mass index z-score ≤ +1) PHIV had hepatic steatosis compared to zero lean HEU or HU children (p = 0.03). In multivariable linear regression analysis of all PHIV, body mass index (BMI) z-score was positively associated with CAP (p = 0.001) while CD4 count (p = 0.02) and duration of suppression of HIV viraemia (p = 0.009) were negatively associated with CAP, adjusting for age, sex and ethnicity. Conclusions Hepatic steatosis prevalence was higher in lean PHIV than lean HIV-uninfected South African children. Longer suppression of HIV viraemia and higher CD4 count were associated with lower CAP and might be protective factors for hepatic steatosis in PHIV children.
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Affiliation(s)
- Penelope C. Rose
- Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa
| | - Etienne D. Nel
- Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa
| | - Mark F. Cotton
- Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa
- Family Center for Research With Ubuntu (FAMCRU), Cape Town, South Africa
| | - Richard D. Pitcher
- Division of Radiodiagnosis, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Kennedy Otwombe
- Perinatal HIV Research Unit, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Sara H. Browne
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Steve Innes
- Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa
- Family Center for Research With Ubuntu (FAMCRU), Cape Town, South Africa
- Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa
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20
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Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, Kashyap S, Mechanick JI, Mouzaki M, Nadolsky K, Rinella ME, Vos MB, Younossi Z. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract 2022; 28:528-562. [PMID: 35569886 DOI: 10.1016/j.eprac.2022.03.010] [Citation(s) in RCA: 537] [Impact Index Per Article: 179.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/11/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To provide evidence-based recommendations regarding the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to endocrinologists, primary care clinicians, health care professionals, and other stakeholders. METHODS The American Association of Clinical Endocrinology conducted literature searches for relevant articles published from January 1, 2010, to November 15, 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RECOMMENDATION SUMMARY This guideline includes 34 evidence-based clinical practice recommendations for the diagnosis and management of persons with NAFLD and/or NASH and contains 385 citations that inform the evidence base. CONCLUSION NAFLD is a major public health problem that will only worsen in the future, as it is closely linked to the epidemics of obesity and type 2 diabetes mellitus. Given this link, endocrinologists and primary care physicians are in an ideal position to identify persons at risk on to prevent the development of cirrhosis and comorbidities. While no U.S. Food and Drug Administration-approved medications to treat NAFLD are currently available, management can include lifestyle changes that promote an energy deficit leading to weight loss; consideration of weight loss medications, particularly glucagon-like peptide-1 receptor agonists; and bariatric surgery, for persons who have obesity, as well as some diabetes medications, such as pioglitazone and glucagon-like peptide-1 receptor agonists, for those with type 2 diabetes mellitus and NASH. Management should also promote cardiometabolic health and reduce the increased cardiovascular risk associated with this complex disease.
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Affiliation(s)
- Kenneth Cusi
- Guideine and Algorithm Task Forces Co-Chair, Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
| | - Scott Isaacs
- Guideline and Algorithm Task Forces Co-Chair, Division of Endocrinology, Emory University School of Medicine, Atlanta, Georgia
| | - Diana Barb
- University of Florida, Gainesville, Florida
| | - Rita Basu
- Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Sonia Caprio
- Yale University School of Medicine, New Haven, Connecticut
| | - W Timothy Garvey
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama
| | | | - Jeffrey I Mechanick
- The Marie-Josee and Henry R. Kravis Center for Cardiovascular Health at Mount Sinai Heart, Icahn School of Medicine at Mount Sinai
| | | | - Karl Nadolsky
- Michigan State University College of Human Medicine, Grand Rapids, Michigan
| | - Mary E Rinella
- AASLD Representative, University of Pritzker School of Medicine, Chicago, Illinois
| | - Miriam B Vos
- Center for Clinical and Translational Research, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia
| | - Zobair Younossi
- AASLD Representative, Inova Medicine, Inova Health System, Falls Church, Virginia
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21
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Ciardullo S, Perseghin G. Advances in fibrosis biomarkers in nonalcoholic fatty liver disease. Adv Clin Chem 2022; 106:33-65. [PMID: 35152974 DOI: 10.1016/bs.acc.2021.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult world population and the degree of liver fibrosis represents the best predictor of the development of liver-related outcomes. Easily applicable and well performing non-invasive fibrosis tests can overcome the limitations of liver biopsy and are of paramount importance to identify at-risk subjects in clinical practice. While tests with optimal performance and ease of use do not exist at this stage, available markers can be divided in three broad groups: simple serum tests, complex serum tests and elastographic methods. Simple scores (such as Fibrosis-4 and NAFLD Fibrosis Score) are based on readily available biochemical data and clinical features, while complex/proprietary tests (such as Fibrotest, Enhanced Liver Fibrosis and Hepascore) directly measure markers of fibrogenesis and fibrolysis, but have higher costs. Elastography techniques estimate the degree of fibrosis from liver stiffness and are based on either ultrasound or magnetic resonance (MR) imaging. MR elastography has better performance compared with sonographic techniques and is not affected by obesity and inflammation, but is highly costly and less available. In general, non-invasive tests are able to exclude the presence of fibrosis, but their positive predictive value is low to moderate and they lead to a high number of indeterminate results. In this context, a combination of different tests might increase accuracy while reducing gray-zone results. Their ability to predict future events and response to treatment is suboptimal and needs to be studied further. Finally, recent studies have tried different approaches, spanning from "omics" to the microbiome and micro-RNAs, with some promising results.
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Affiliation(s)
- Stefano Ciardullo
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy; School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Gianluca Perseghin
- Department of Medicine and Rehabilitation, Policlinico di Monza, Monza, Italy; School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy.
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22
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Yang A, Jung N, Kim S, Lee JE. Association Between Non-invasive Diagnostic Methods of Liver Fibrosis and Type 2 Diabetes in Pediatric Patients With Non-alcoholic Fatty Liver Disease. Front Pediatr 2022; 10:825141. [PMID: 35223701 PMCID: PMC8866638 DOI: 10.3389/fped.2022.825141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/10/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND AND PURPOSE The prevalence of non-alcoholic fatty liver disease (NAFLD) in children has been increasing associated with insulin resistance. However, there is a scarcity of related studies in children with NAFLD with type 2 diabetes mellitus (T2DM) compared to adults. We conducted this study to investigate the association between non-invasive diagnostic methods of liver fibrosis and T2DM in pediatric patients with NAFLD. METHODS We enrolled a total of 152 patients aged <18 years with NAFLD, and compared their data according to the presence of T2DM. We evaluated fibrosis by transient elastography (TE, FibroScan®), and calculated the following fibrosis scores for each patient: NAFLD fibrosis score (NFS), AST: platelet ratio index (APRI), Fibrosis-4 (FIB-4) index, and pediatric NAFLD fibrosis index (PNFI). RESULTS In the NAFLD-T2DM group, the NFS and mean controlled attenuation parameter in FibroScan were significantly higher than those in the nondiabetic group. The receiver operating characteristic (ROC) curve values for predicting the presence of T2DM were 0.78 for NFS, 0.64 for FIB-4, 0.62 for PNFI, and 0.61 for APRI. The cutoff HbA1c levels for predicting fibrosis progression in APRI, NFS, and PNFI were 5.7% [area under the curve (AUC) 0.74], 6.4% (AUC 0.71), and 6.4% (AUC 0.55), respectively. In the multivariate analysis, hepatosteatosis on abdomen sonography, NFS, FibroScan F, and APRI were independently associated with T2DM risk. CONCLUSIONS We significantly characterized non-invasive fibrosis markers and elastography in pediatric NAFLD with T2DM compared with the nondiabetic group. We suggest evaluating the progression of fibrosis in the prediabetic stage in children using a combination of these non-invasive methods.
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Affiliation(s)
- Aram Yang
- Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Nayoung Jung
- Department of Pediatrics, Inha University Hospital, Inha University College of Medicine, Incheon, South Korea
| | - Sinae Kim
- Division of Biostatistics, Department of R&D Management, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ji-Eun Lee
- Department of Pediatrics, Inha University Hospital, Inha University College of Medicine, Incheon, South Korea
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Mosca A, Della Volpe L, Alisi A, Veraldi S, Francalanci P, Maggiore G. Non-Invasive Diagnostic Test for Advanced Fibrosis in Adolescents With Non-Alcoholic Fatty Liver Disease. Front Pediatr 2022; 10:885576. [PMID: 35558366 PMCID: PMC9086671 DOI: 10.3389/fped.2022.885576] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is a multifaceted disease that includes a wide spectrum of liver damage. The presence and the degree of fibrosis are considered important factors for the prognosis of NAFLD and in predicting the risk of developing cirrhosis. Our aim was to evaluate the usefulness of four fibrosis scores (aspartate aminotransferase/Platelet Index [APRI], FIB-4, NAFLD Fibrosis Score [NFS], and Hepamet) in predicting different degrees of fibrosis among children with biopsy-proven NAFLD. METHODS About 286 adolescents [mean age 14.3 years ± 2.5; 154 (53.6%) males], referred between January 2014 and December 2019, with biopsy-proven NAFLD were enrolled. RESULTS About 173 (60.4%) patients presented fibrosis at histological analysis. In particular: 140 (49.3%) patients had F = 1, 31 (10.8%), had F = 2 and 2 (0.66%) had F = 3. APRI (AUROC 0.619, 95% CI 0.556-0.679) and Hepamet (AUROC 0.778, 95% CI 0.722-0.828) scores had significant (p < 0.001) accuracy to distinguish subjects with fibrosis; while NFS and FIB-4 had not. APRI had a positive predictive value (PPV) of 62.77% (95% CI 57.96-67.35) and an negative predictive value (NPV) of 52.01% (95% CI 46.54-57.43); Hepamet a PPV of 63.24% (95% CI 59.95-66.41) and an NPV of 61.29% (52.9-69.01). CONCLUSIONS Our study showed that Hepamet and APRI perform better than NFS and FIB-4 for identifying fibrosis in patients with NAFLD, but do not have PPVs so high to be considered diagnostic. Therefore, they cannot be employed, in children, for a certain diagnosis of fibrosis or its progression and cannot replace liver biopsy as the gold diagnostic standard. It is, therefore, necessary to continue to research and develop new markers of exclusive fibrosis.
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Affiliation(s)
- Antonella Mosca
- Hepatogastroenterology, Nutrition, Digestive Endoscopy and Liver Transplant Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Luca Della Volpe
- Hepatogastroenterology, Nutrition, Digestive Endoscopy and Liver Transplant Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Silvio Veraldi
- Hepatogastroenterology, Nutrition, Digestive Endoscopy and Liver Transplant Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Paola Francalanci
- Pathology Unit, Department of Diagnostic and Laboratory Medicine, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Giuseppe Maggiore
- Hepatogastroenterology, Nutrition, Digestive Endoscopy and Liver Transplant Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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24
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Chen BR, Pan CQ. Non-invasive assessment of fibrosis and steatosis in pediatric non-alcoholic fatty liver disease. Clin Res Hepatol Gastroenterol 2022; 46:101755. [PMID: 34311134 DOI: 10.1016/j.clinre.2021.101755] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Non-Alcoholic Fatty Liver Disease (NAFLD) has become one of the most common causes of chronic liver disease in the pediatric population. Recent advances have been made in developing non-invasive measures for NAFLD assessment. This review presents an analysis of these latest developments and also proposes an algorithm for screening pediatric patients at risk for NAFLD. METHODS A systematic literature search on PUBMED and EMBASE was conducted. Guidelines for clinical care of pediatric NAFLD were also reviewed. RESULTS In imaging tests, transient elastography (TE) combined with controlled attenuation parameter (CAP) is a promising, relatively low-cost method offering an intermediate level of accuracy on accessing patient's fibrosis and steatosis in a singular package. Liver biopsy remains the gold standard for diagnosis and/or evaluation of NAFLD, but with our proposed algorithm on utilizing non-invasive testing, the number of liver biopsies required could decrease. The current evidence supports the implementation of TE and CAP in an evaluation algorithm for pediatric NAFLD. CONCLUSIONS Current data support the use of TE and CAP as a first-line tool in the diagnosis and evaluation of adolescent NAFLD, to better stratify high-risk patients and cut down on the number of liver biopsies needed.
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Affiliation(s)
- Bryan R Chen
- University of California, Los Angeles, Los Angeles, CA 90025 USA.
| | - Calvin Q Pan
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Division of Gastroenterology and Hepatology, Department of Medicine, NYU Langone Health, New York University Grossman School of Medicine, New York, NY, USA.
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25
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Metabolic Associated Fatty Liver Disease in Children-From Atomistic to Holistic. Biomedicines 2021; 9:biomedicines9121866. [PMID: 34944682 PMCID: PMC8698557 DOI: 10.3390/biomedicines9121866] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease has become the most common chronic liver disease in children due to the alarmingly increasing incidence of pediatric obesity. It is well-documented that MAFLD prevalence is directly related to an incremental increase in BMI. The multiple hits theory was designed for providing insights regarding the pathogenesis of steatohepatitis and fibrosis in MAFLD. Recent evidence suggested that the microbiome is a crucial contributor in the pathogenesis of MAFLD. Aside from obesity, the most common risk factors for pediatric MAFLD include male gender, low-birth weight, family history of obesity, MAFLD, insulin resistance, type 2 diabetes mellitus, obstructive sleep apnea, and polycystic ovarium syndrome. Usually, pediatric patients with MAFLD have nonspecific symptoms consisting of fatigue, malaise, or diffuse abdominal pain. A wide spectrum of biomarkers was proposed for the diagnosis of MAFLD and NASH, as well as for quantifying the degree of fibrosis, but liver biopsy remains the key diagnostic and staging tool. Nevertheless, elastography-based methods present promising results in this age group as potential non-invasive replacers for liver biopsy. Despite the lack of current guidelines regarding MAFLD treatment in children, lifestyle intervention was proven to be crucial in the management of these patients.
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Relationship of Enhanced Liver Fibrosis Score with Pediatric Nonalcoholic Fatty Liver Disease Histology and Response to Vitamin E or Metformin. J Pediatr 2021; 239:161-167.e5. [PMID: 34400208 PMCID: PMC8922020 DOI: 10.1016/j.jpeds.2021.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/02/2021] [Accepted: 08/09/2021] [Indexed: 12/19/2022]
Abstract
OBJECTIVES To study the diagnostic performance of the enhanced liver fibrosis score (ELF) for detecting different stages of fibrosis and its usefulness in detecting histologic response to vitamin E or metformin in children with nonalcoholic fatty liver disease who participated in the Vitamin E or Metformin for the Treatment Of NAFLD In Children (TONIC) trial. STUDY DESIGN ELF was measured at baseline and weeks 24, 48, and 96 on sera from 166 TONIC participants. Associations between ELF with baseline and end of trial (EOT) fibrosis stages and other histologic features were assessed using χ2 tests and logistic regression models. RESULTS ELF was significantly associated with severity of fibrosis at baseline and EOT. ELF areas under the curve for discriminating patients with clinically significant and advanced fibrosis were 0.70 (95% CI, 0.60-0.80) and 0.79 (95% CI, 0.69-0.89), respectively. A 1-unit decrease in ELF at EOT was associated with overall histologic improvement (OR, 1.86; 95% CI, 1.11-3.14; P = .02), resolution of steatohepatitis (OR, 1.88; 95% CI, 1.09-3.25; P = .02), improvement in steatosis grade (OR, 1.76; 95% CI, 1.06-2.82; P = .03), and hepatocellular ballooning (OR, 1.79; 95% CI, 1.06-3.00; P = .03), but not with improvement in fibrosis stage (OR, 1.26; 95% CI, 0.78-2.03; P = .34). CONCLUSIONS ELF was associated with fibrosis stage in children who participated in TONIC. Although not associated with improvement in fibrosis, a decrease in ELF at EOT was associated with Nonalcoholic Steatohepatitis resolution and improvement in nonalcoholic fatty liver disease histology. ELF may be a useful noninvasive test to monitor treatment response in children with nonalcoholic fatty liver disease.
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27
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Cohen CC, Castillo-Leon E, Farris AB, Caltharp SA, Cleeton RL, Sinclair EM, Shevell DE, Karsdal MA, Nielsen MJF, Leeming DJ, Vos MB. PRO-C3, a Serological Marker of Fibrosis, During Childhood and Correlations With Fibrosis in Pediatric NAFLD. Hepatol Commun 2021; 5:1860-1872. [PMID: 34558828 PMCID: PMC8557318 DOI: 10.1002/hep4.1766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/07/2021] [Accepted: 05/08/2021] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease in children and may lead to cirrhosis requiring liver transplant. Thus, prompt diagnosis of advanced fibrosis is essential. Our objectives were to examine PRO-C3 (a neo-epitope pro-peptide of type III collagen formation) levels across childhood/adolescence and associations with advanced fibrosis in pediatric NAFLD. This cross-sectional study included 88 children and adolescents with biopsy-proven NAFLD (mean age: 13.9 ± 2.9 years, 71% male) and 65 healthy participants (11.8 ± 4.5 years, 38% male). PRO-C3, and the bone remodeling biomarkers C-terminal telopeptide of type I collagen (CTX-I; bone resorption) and osteocalcin (N-MID; bone formation), were measured in serum by enzyme-linked immunosorbent assay. Fibrosis was assessed by liver biopsy in participants with NAFLD, who were categorized as having advanced (Ishak score ≥ 3) or none/mild fibrosis (Ishak score ≤ 2). Overall, PRO-C3 was similar in participants with NAFLD (median [interquartile range]: 20.6 [15.8, 25.9] ng/mL) versus healthy participants (19.0 [13.8, 26.0] ng/mL), but was significantly lower in older adolescents ≥ 15 years old (16.4 [13.0, 21.2] ng/mL) compared with children ≤ 10 years old (22.9 [18.1, 28.4] ng/mL; P < 0.001) or 11-14 years old (22.4 [18.3, 31.2] ng/mL; P < 0.001). PRO-C3 was also directly correlated with levels of CTX-I and N-MID (r = 0.64 and r = 0.62, respectively; both P < 0.001). Among participants with NAFLD, PRO-C3 was higher in those with advanced fibrosis (median [IQR]: 28.5 [21.6, 37.6]) compared with none/mild fibrosis (20.3 [18.2, 22.8]; P = 0.020) in models adjusted for age, sex, and body mass index z-score. However, associations were attenuated after additionally adjusting for bone-remodeling CTX-I (P = 0.09) or N-MID (P = 0.08). Conclusion: Collectively, these findings show that PRO-C3 levels are higher in children with advanced fibrosis in NAFLD, but are also influenced by age and pubertal growth spurt, assessed by bone remodeling biomarkers, and therefore may not be a reliable biomarker for liver fibrosis in pediatric NAFLD until late adolescence.
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Affiliation(s)
- Catherine C Cohen
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA.,Department of PediatricsUniversity of Colorado Denver Anschutz Medical CampusAuroraCOUSA
| | | | - Alton B Farris
- Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlantaGAUSA
| | - Shelley A Caltharp
- Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlantaGAUSA.,Children's Healthcare of AtlantaAtlantaGAUSA
| | - Rebecca L Cleeton
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA
| | - Elizabeth M Sinclair
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA.,Children's Healthcare of AtlantaAtlantaGAUSA
| | - Diane E Shevell
- Translational MedicineBristol Myers SquibbLawrencevilleNJUSA
| | | | | | - Diana J Leeming
- Nordic BioscienceFibrosis Biology and BiomarkersHerlevDenmark
| | - Miriam B Vos
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA.,Children's Healthcare of AtlantaAtlantaGAUSA
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Kulkarni S, Naz N, Gu H, Stoll JM, Thompson MD, DeBosch BJ. A clinical model to predict fibrosis on liver biopsy in paediatric subjects with nonalcoholic fatty liver disease. Clin Obes 2021; 11:e12472. [PMID: 34106515 PMCID: PMC8928096 DOI: 10.1111/cob.12472] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/09/2021] [Accepted: 05/28/2021] [Indexed: 12/19/2022]
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) in children is rapidly increasing. Liver fibrosis is a poor prognostic feature that independently predicts cirrhosis. The time that intercedes the first medical encounter and biopsy is rate-limiting to multi-modal treatment. This study aimed to identify non-invasive parameters to predict advanced NAFLD and fibrosis. We conducted a single-center, retrospective 10-year analysis of 640 paediatric patients who underwent liver biopsy. 55 patients, age 3-21 years, had biopsy-confirmed NAFLD. We assessed primary outcomes, NAFLD activity score (NAS) and fibrosis scores, against non-invasive parameters by linear regression, by using binary cutoff values, and by a multivariate logistic regression fibrosis prediction model. NAS correlated with platelets and female sex. Fibrosis scores correlated with platelet counts, gamma glutamyl transferase (GGT), and ultrasound shear wave velocity. 25-hydroxy-vitamin D and GGT differentiated mild versus moderate-to-advanced fibrosis. Our multivariate logistical regression model-based scoring system predicted F2 or higher (parameters: BMI%, vitamin D, platelets, GGT), with sensitivity and specificity of 0.83 and 0.95 (area under the ROC curve, 0.944). We identify a clinical model to identify high-risk patients for expedited biopsy. Stratifying patients to abbreviate time-to-biopsy can attenuate delays in aggressive therapy for high-risk patients.
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Affiliation(s)
- Sakil Kulkarni
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Nadia Naz
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Hongjie Gu
- Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
| | - Janis M. Stoll
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Michael D. Thompson
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Digestive Diseases Research Center (DDRCC), Washington University School of Medicine, St. Louis, MO, USA
| | - Brian J. DeBosch
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
- Digestive Diseases Research Center (DDRCC), Washington University School of Medicine, St. Louis, MO, USA
- Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
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29
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Hwang J, Yoon HM, Kim KM, Oh SH, Namgoong JM, Kim DY, Cho YA. Assessment of native liver fibrosis using ultrasound elastography and serological fibrosis indices in children with biliary atresia after the Kasai procedure. Acta Radiol 2021; 62:1088-1096. [PMID: 32811156 DOI: 10.1177/0284185120948489] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Validated non-invasive examinations are necessary to monitor liver fibrosis in children with biliary atresia (BA) after the Kasai procedure. PURPOSE To evaluate the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE), transient elastography (TE), and the serologic biomarkers of aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for evaluating native liver fibrosis in children with BA. MATERIAL AND METHODS We retrospectively reviewed same-day 2D-SWE and TE liver stiffness (LS) measurements of 63 patients with BA who underwent the Kasai procedure. The APRI and FIB-4 score were computed. Hepatic fibrosis was categorized into three clinical categories based on the ultrasound (US) hepatic morphology and clinical manifestations of liver cirrhosis: I, pre-cirrhotic liver state (n = 15); II, US and/or clinical signs of liver cirrhosis with compensated liver function (n = 27); and III, liver cirrhosis with decompensated liver function (n = 21). We compared area under the receiver operating characteristic curve (AUC) data among 2D-SWE, TE, APRI, and FIB-4 score. Combined evaluation of serologic fibrosis indices and US elastography was conducted and AUCs of combinations were analyzed. RESULTS 2D-SWE, TE, APRI, and FIB-4 score showed good to excellent diagnostic accuracy for differentiating clinical categories (AUCs 0.779-0.955). AUC values were significantly increased after adding TE to FIB-4 score for detecting liver cirrhosis (P = 0.02). CONCLUSION 2D-SWE, TE, APRI, and FIB-4 score are accurate non-invasive markers for monitoring native liver fibrosis in patients with BA. Combined use of serologic markers and US elastography could yield more accurate diagnoses of liver fibrosis than serologic markers alone.
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Affiliation(s)
- Jisun Hwang
- Department of Radiology, Dongtan Sacred Heart Hospital, Hallym University Medical Center, Hwaseong, Republic of Korea
| | - Hee Mang Yoon
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jung-Man Namgoong
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dae Yeon Kim
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Ah Cho
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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30
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Lee S, Choi YH, Cho YJ, Lee SB, Cheon JE, Kim WS, Ko JS, Koh J, Kang GH. The usefulness of noninvasive liver stiffness assessment using shear-wave elastography for predicting liver fibrosis in children. BMC Med Imaging 2021; 21:68. [PMID: 33845776 PMCID: PMC8040233 DOI: 10.1186/s12880-021-00601-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/01/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Pediatric patients with liver disease require noninvasive monitoring to evaluate the risk of fibrosis progression. This study aimed to identify the significant factors affecting liver stiffness values using two-dimensional shear-wave elastography (2D-SWE), and determine whether liver stiffness can predict the fibrosis stage of various childhood liver diseases. METHODS This study included 30 children (22 boys and 8 girls; mean age, 5.1 ± 6.1 years; range, 7 days-17.9 years) who had undergone biochemical evaluation, 2D-SWE examination, histopathologic analysis of fibrosis grade (F0 to F3), assessment of necroinflammatory activity, and steatosis grading between August 2016 and March 2020. The liver stiffness from 2D-SWE was compared between fibrosis stages using Kruskal-Wallis analysis. Factors that significantly affected liver stiffness were evaluated using univariate and multivariate linear regression analyses. The diagnostic performance was determined from the area under the receiver operating curve (AUC) values of 2D-SWE liver stiffness. RESULTS Liver stiffness at the F0-1, F2, and F3 stages were 7.9, 13.2, and 21.7 kPa, respectively (P < 0.001). Both fibrosis stage and necroinflammatory grade were significantly associated with liver stiffness (P < 0.001 and P = 0.021, respectively). However, in patients with alanine aminotransferase (ALT) levels below 200 IU/L, the only factor affecting liver stiffness was fibrosis stage (P = 0.030). The liver stiffness value could distinguish significant fibrosis (≥ F2) with an AUC of 0.950 (cutoff value, 11.3 kPa) and severe fibrosis (F3 stage) with an AUC of 0.924 (cutoff value, 18.1 kPa). The 2D-SWE values for differentiating significant fibrosis were 10.5 kPa (≥ F2) and 18.1 kPa (F3) in patients with ALT levels below 200 IU/L. CONCLUSION The liver stiffness values on 2D-SWE can be affected by both fibrosis and necroinflammatory grade and can provide excellent diagnostic performance in evaluating the fibrosis stage in various pediatric liver diseases. However, clinicians should be mindful of potential confounders, such as necroinflammatory activity or transaminase level, when performing 2D-SWE measurements for liver fibrosis staging.
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Affiliation(s)
- Seunghyun Lee
- Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Young Hun Choi
- Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. .,Department of Radiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
| | - Yeon Jin Cho
- Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Seul Bi Lee
- Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jung-Eun Cheon
- Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Department of Radiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Institute of Radiation Medicine, Seoul National University Medical Research Center, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Woo Sun Kim
- Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Department of Radiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.,Institute of Radiation Medicine, Seoul National University Medical Research Center, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jaemoon Koh
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
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31
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Performance Characteristics, Intra- and Inter-operator Agreement of Transient Elastography in Pediatric Nonalcoholic Fatty Liver Disease. J Pediatr Gastroenterol Nutr 2021; 72:430-435. [PMID: 33230078 DOI: 10.1097/mpg.0000000000002991] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Transient elastography (TE) is a valuable tool in assessment of hepatic steatosis and fibrosis using liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), respectively. Although widely used in adults, little is known about performance characteristics and reproducibility of TE (using Fibroscan device) in evaluation of pediatric nonalcoholic fatty liver disease (NAFLD). METHODS We prospectively recruited children with NAFLD. Three consecutive Fibroscan examinations were performed during the same visit-twice by a single expert operator and once by a different novice operator. Intra and inter-operator agreement was calculated using concordance correlation coefficient (CCC). Failure was defined as inability to obtain 10 valid measurements and examination was considered unreliable if LSM interquartile range/median was greater 30%. RESULTS Fifty-one children (34 boys; median age 15 years) were recruited. Failure rates for expert and novice operator were 10% (5/51) and 12% (6/51) while unreliable readings were obtained in 2% (1/46) and 4% (2/45) of patients, respectively. Patients with failed/unreliable measurements were significantly more obese (median BMI 46.2 vs 33.1 kg/m2, P = 0.002) compared with those with reliable measurements. The intra-operator agreement was almost perfect for LSM and substantial for CAP values (CCC = 0.85 and 0.73, respectively). Inter-operator agreement was substantial for LSM and moderate for CAP values (CCC = 0.76 and 0.58, respectively). The inter-operator agreement in LSM did not vary significantly over time but showed an inverse correlation with BMI and CAP. CONCLUSION Our study demonstrated that use of TE in assessment of hepatic fibrosis and steatosis in children with NAFLD is highly reliable with low failure rate and highly reproducible with high intra- and inter-operator reproducibility.
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Suri A, Song E, van Nispen J, Voigt M, Armstrong A, Murali V, Jain A. Advances in the Epidemiology, Diagnosis, and Management of Pediatric Fatty Liver Disease. Clin Ther 2021; 43:438-454. [PMID: 33597074 DOI: 10.1016/j.clinthera.2021.01.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/28/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Nonalcoholic fatty liver (NAFL) is a major contributor to pediatric liver disease. This review evaluated the current literature on prevalence, screening, diagnosis, and management of NAFL in children and explored recent advances in the field of pediatric NAFL. METHODS A PubMed search was performed for manuscripts describing disease burden, diagnosis, and management strategies in pediatric NAFL published within the past 15 years. Systematic reviews, clinical practice guidelines, randomized controlled trials, and cohort and case-control studies were reviewed for the purpose of this article. FINDINGS The prevalence of NAFL in children is increasing. It is a leading cause of liver-related morbidity and mortality in children. Screening and diagnosis of NAFL in children are a challenge. Lifestyle changes and exercise are the cornerstones of the management of NAFL. IMPLICATIONS Further research is needed to develop better screening and diagnostic tools for pediatric NAFL, including noninvasive diagnostics. NAFL therapeutics is another area of much-needed, ongoing research.
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Affiliation(s)
- Anandini Suri
- Department of Pediatrics, School of Medicine, St. Louis University, St. Louis, Missouri, USA.
| | - Eric Song
- Department of Pediatrics, School of Medicine, St. Louis University, St. Louis, Missouri, USA
| | - Johan van Nispen
- Department of Pediatrics, School of Medicine, St. Louis University, St. Louis, Missouri, USA
| | - Marcus Voigt
- Department of Pediatrics, School of Medicine, St. Louis University, St. Louis, Missouri, USA
| | - Austin Armstrong
- Department of Pediatrics, School of Medicine, St. Louis University, St. Louis, Missouri, USA
| | - Vidul Murali
- Department of Pediatrics, School of Medicine, St. Louis University, St. Louis, Missouri, USA
| | - Ajay Jain
- Department of Pediatrics, School of Medicine, St. Louis University, St. Louis, Missouri, USA
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33
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Al-Baiaty FDR, Ismail A, Abdul Latiff Z, Muhammad Nawawi KN, Raja Ali RA, Mokhtar NM. Possible Hepatoprotective Effect of Tocotrienol-Rich Fraction Vitamin E in Non-alcoholic Fatty Liver Disease in Obese Children and Adolescents. Front Pediatr 2021; 9:667247. [PMID: 34307250 PMCID: PMC8295474 DOI: 10.3389/fped.2021.667247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 06/09/2021] [Indexed: 12/23/2022] Open
Abstract
Obesity has become a worldwide health concern among the pediatric population. The prevalence of non-alcoholic fatty liver disease (NAFLD) is growing rapidly, alongside the high prevalence of obesity. NAFLD refers to a multifactorial disorder that includes simple steatosis to non-alcoholic steatohepatitis (NASH) with or devoid of fibrosis. NAFLD is regarded as a systemic disorder that influences glucose, lipid, and energy metabolism with hepatic manifestations. A sedentary lifestyle and poor choice of food remain the major contributors to the disease. Prompt and timely diagnosis of NAFLD among overweight children is crucial to prevent the progression of the condition. Yet, there has been no approved pharmacological treatment for NAFLD in adults or children. As indicated by clinical evidence, lifestyle modification plays a vital role as a primary form of therapy for managing and treating NAFLD. Emphasis is on the significance of caloric restriction, particularly macronutrients (fats, carbohydrates, and proteins) in altering the disease consequences. A growing number of studies are now focusing on establishing a link between vitamins and NAFLD. Different types of vitamin supplements have been shown to be effective in treating NAFLD. In this review, we elaborate on the potential role of vitamin E with a high content of tocotrienol as a therapeutic alternative in treating NAFLD in obese children.
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Affiliation(s)
- Farah D R Al-Baiaty
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Aziana Ismail
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Zarina Abdul Latiff
- Department of Pediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Khairul Najmi Muhammad Nawawi
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.,GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Raja Affendi Raja Ali
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.,GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.,GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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34
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Shaunak M, Byrne CD, Davis N, Afolabi P, Faust SN, Davies JH. Non-alcoholic fatty liver disease and childhood obesity. Arch Dis Child 2021; 106:3-8. [PMID: 32409495 DOI: 10.1136/archdischild-2019-318063] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) in children and adolescents has an estimated prevalence of 36.1% in the context of obesity. This figure is anticipated to increase in conjunction with the global obesity epidemic. Worryingly, NAFLD in childhood persisting into adulthood is likely to be harmful, contributing to significant hepatic and extrahepatic morbidities. Early disease detection is required, although the optimum timing, frequency and mode of screening remains undetermined. While the efficacy of several medications, antioxidants, fatty acid supplements and probiotics has been investigated in children, healthy eating and physical activity remain the only prevention and treatment strategies for paediatric NAFLD. This short review discusses the epidemiology, diagnosis, pathogenesis and management of NAFLD in childhood obesity.
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Affiliation(s)
- Meera Shaunak
- Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Christopher D Byrne
- Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.,NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Nikki Davis
- Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.,Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK
| | - Paul Afolabi
- Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.,NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Saul N Faust
- Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.,NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.,NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Justin Huw Davies
- Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK .,Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK
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35
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Mosca A, Panera N, Crudele A, Alisi A. Noninvasive diagnostic tools for pediatric NAFLD: where are we now? Expert Rev Gastroenterol Hepatol 2020; 14:1035-1046. [PMID: 32715793 DOI: 10.1080/17474124.2020.1801413] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in the pediatric population. It is a significant liver complication of obesity that also prominently affects children. Over the past decade, several noninvasive methods have been investigated for replacing liver biopsy to identify which children with NAFLD have nonalcoholic steatohepatitis (NASH) and fibrosis. These methods that aim to differentiate the type and extent of liver damage are based on two main different methodologies: a 'biological' approach centered on the quantification of circulating biomarkers; and a 'physical' approach established by analyzing different imaging data. AREAS COVERED In this review, we illustrate the state of the art and recent discoveries on noninvasive methods for the diagnosis of NAFLD, NASH, and advanced fibrosis. EXPERT OPINION Currently, noninvasive tests cannot diagnose NASH or determine the degree of fibrosis. However, several lines of evidence have suggested that if these tests are used in a complementary way with other laboratory tests and imaging they have the potential to be used to monitor progression of disease and response to therapy in pediatric NAFLD. Future scientific research will focus on combining these methods with multiple potential predictors of genetic susceptibility.
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Affiliation(s)
- Antonella Mosca
- Hepatology Gastroenterology and Nutrition, Bambino Gesù Children's Hospital , Rome, Italy
| | - Nadia Panera
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
| | - Annalisa Crudele
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
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Sandhu S, Orsi C, Francis GL, Wang Z, Fernandez R, Alkhouri N. Shear wave elastography reveals a high prevalence of liver fibrosis in overweight or obese Hispanic youth. J Ultrason 2020; 20:e162-e168. [PMID: 33365151 PMCID: PMC7705483 DOI: 10.15557/jou.2020.0027] [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: 03/09/2020] [Accepted: 07/07/2020] [Indexed: 12/05/2022] Open
Abstract
Background: Obesity, prediabetes, and type 2 diabetes are risk factors for nonalcoholic fatty liver disease. Inflammation and hepatocellular damage associated with nonalcoholic fatty liver disease lead to progressive non-alcoholic steatohepatitis, fibrosis and cirrhosis. Current tests to identify fibrosis (liver biopsy) are invasive and not conducive to serial examination. For that reason, we used the newer technique of shear wave elastogrophy (SWE) to detect fibrosis in overweight or obese Hispanic youth and sought to determine if carbohydrate tolerance or insulin resistance were associated with fibrosis in this high risk population. Methods: A total of 67 Hispanic youth (8-18 years of age) with overweight or obesity who were referred for multidisciplinary evaluation were included. SWE was used to identify those with suspected fibrosis. Results of SWE were then compared with glycohemoglobin (A1c), insulin resistance (homeostatic model of insulin resistance), and biochemical parameters. Results: The prevalence of suspected fibrosis (SWE >5.10 kPa) in overweight or obese Hispanic youth was 62.7% (42/67). Patients with suspected fibrosis (SWE ≥5.10 kPa) had significantly higher levels of serum aspartate aminotransferase, alanine aminotransferase and the aminotransferase to platelet ratio index when compared to patients without significant fibrosis (SWE <5.01 kPa). However, there were no significant differences between the groups in body mass index, A1c, or homeostatic model of insulin resistance. Conclusions: SWE detected a high prevalence (62.7%) of suspected hepatic fibrosis in a group of high risk, overweight or obese Hispanic youth suggesting that SWE is a useful tool for surveillance and longitudinal studies.
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Affiliation(s)
- Sanjeet Sandhu
- University of Texas Health and Science Center, Department of Pediatric Endocrinology, San Antonio, TX, United States
| | - Carisse Orsi
- University of Texas Health and Science Center, Department of Pediatric Endocrinology, San Antonio, TX, United States
| | - Gary L Francis
- University of Texas Health and Science Center, Department of Pediatric Endocrinology, San Antonio, TX, United States
| | - Zhu Wang
- University of Texas Health and Science Center Department of Population Health Sciences, San San Antonio TX, United States
| | - Roman Fernandez
- University of Texas Health and Science Center Department of Population Health Sciences, San San Antonio TX, United States
| | - Naim Alkhouri
- Texas Liver Institute and University of Texas Health, Department of Pediatric Gastroenterology, San Antonio, TX, United States
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Castillo‐Leon E, Cioffi CE, Vos MB. Perspectives on youth-onset nonalcoholic fatty liver disease. Endocrinol Diabetes Metab 2020; 3:e00184. [PMID: 33102800 PMCID: PMC7576279 DOI: 10.1002/edm2.184] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/07/2020] [Accepted: 07/11/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The prevalence and incidence of youth-onset nonalcoholic fatty liver disease (NAFLD) far exceeds other paediatric chronic liver diseases and represents a considerable public health issue globally. METHODS Here, we performed a narrative review of current knowledge regarding the epidemiology of paediatric NAFLD, selected concepts in pathogenesis, comorbidities, diagnosis, and management, and issues related to the transition to adulthood. RESULTS Paediatric NAFLD has become increasingly more prevalent, especially in certain subgroups, such as children with obesity and certain races/ethnicities. The pathophysiology of paediatric NAFLD is complex and multifactorial, driven by an interaction of environmental and genetic factors. Once developed, NAFLD in childhood is associated with type 2 diabetes, hypertension, increased cardiovascular disease risk, and end-stage liver disease. This predicts an increased burden of morbidity and mortality in adolescents and young adults. Early screening and diagnosis are therefore crucial, and the development of noninvasive biomarkers remains an active area of investigation. Currently, treatment strategies are focused on lifestyle changes, but there is also research interest in pharmacological and surgical options. In the transition from paediatric to adult care, there are several potential challenges/barriers to treatment and research is needed to understand how best to support patients during this time. CONCLUSIONS Our understanding of the epidemiology and pathophysiology of paediatric NAFLD has increased considerably over recent decades, but several critical knowledge gaps remain and must be addressed in order to better mitigate the short-term and long-term risks of youth-onset NAFLD.
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Affiliation(s)
| | - Catherine E. Cioffi
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA
- Nutrition & Health Sciences Doctoral ProgramLaney Graduate SchoolEmory UniversityAtlantaGAUSA
| | - Miriam B. Vos
- Department of PediatricsEmory University School of MedicineAtlantaGAUSA
- Children's Healthcare of AtlantaAtlantaGAUSA
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38
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Estimation of the risk of fibrosis in children with nonalcoholic fatty liver disease. Clin Exp Hepatol 2020; 6:220-227. [PMID: 33145428 PMCID: PMC7592087 DOI: 10.5114/ceh.2020.99515] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 04/29/2020] [Indexed: 01/02/2023] Open
Abstract
Aim of the study Assessment of liver fibrosis as a predictive factor of liver-related mortality in children with nonalcoholic fatty liver disease (NAFLD) is crucial. This study aims to estimate the risk of fibrosis using noninvasive markers. Material and methods The study group of 49 children with NAFLD (age range 3-16, mean 10.51 ±3.18 years) was created. The diagnosis was based on clinical picture, abdominal ultrasound, and laboratory tests; four children underwent liver biopsy. Then homeostatic model assessment (HOMA-IR) and noninvasive hepatic fibrosis scores were calculated, and patients were divided into four groups depending on body mass index (BMI, obese vs. lean) and aminotransferases. Results 71.43% of patients were obese, and 14.29% were overweight. We found that overweight children had lower mean corpuscular volume (MCV) than lean patients. In a group of patients with a high risk of fibrosis or significant fibrosis due to pediatric NAFLD fibrosis score (PNFS), higher alanine aminotransferase (ALT) to platelet ratio (APRI) values were observed. The highest values of APRI were found in a group of lean patients with elevated aminotransferases and the highest value of PNFS – among obese patients with elevated aminotransferases. A strong significant correlation between APRI and PNFS was found (r = 0.88). Conclusions Apart from aminotransferase activity, complete blood count should be assessed looking for lower MCV caused by iron deficiency. In contrast to FIB-4 (fibrosis score), PNFS and APRI proved to be more accurate in our group. PNFS seems to be appropriate to evaluate fibrosis in a noninvasive diagnostic algorithm.
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Shiau H, Guffey D, Loomes KM, Seidman C, Ragozzino E, Molleston JP, Schady D, Leung DH. Biopsy Validated Study of Biomarkers for Liver Fibrosis and Transplant Prediction in Inherited Cholestasis. Hepatol Commun 2020; 4:1516-1526. [PMID: 33024920 PMCID: PMC7527690 DOI: 10.1002/hep4.1569] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/29/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are inherited cholestatic disorders with risk of developing end‐stage liver disease requiring liver transplantation (LT). We investigated aspartate aminotransferase‐to‐platelet ratio index (APRI), Fibrosis‐4 score (FIB‐4), and conjugated bilirubin as biomarkers to assess fibrosis severity and risk for LT among children with ALGS and PFIC. This multicenter, cross‐sectional study included 64 children with ALGS or PFIC (per genetics or strict clinical criteria) with APRI, FIB‐4, and conjugated bilirubin levels collected within ±90 days of their most recent liver biopsy. A single, blinded pathologist staged all biopsies (metavir; F0‐F2: nonsevere, F3‐F4: severe). Logistic regression and area under the receiver operating characteristic curve analysis (AUC) were used to assess biomarker associations with fibrosis severity and risk for LT. In ALGS, only APRI distinguished F3‐F4 (AUC 0.72, P = 0.012), with a cutoff greater than 2.97 demonstrating a sensitivity of 61.5% (95% confidence interval 0.32, 0.86) and specificity of 81.5% (0.62, 0.94). In ALGS, a 50% increase of APRI increased the odds of F3‐F4 by 1.31‐fold (1.04, 1.65; P = 0.023). In ALGS, APRI (AUC 0.87; P < 0.001) and FIB‐4 (AUC 0.84; P < 0.001) were able to predict risk for LT. In PFIC, only APRI distinguished F3‐4 (AUC 0.74, P = 0.039), with a cutoff greater than 0.99 demonstrating a sensitivity of 80% (0.44, 0.98) and specificity of 64.3% (0.35, 0.87). In PFIC, only FIB‐4 was able predict risk for LT (AUC 0.80; P = 0.002). In ALGS or PFIC, conjugated bilirubin could not distinguish F3‐F4 or predict risk for LT. Conclusion: This liver biopsy–validated study suggests that APRI is able to distinguish F3‐F4 from F0‐F2 in ALGS and PFIC. APRI and FIB‐4 may also serve as predictors of risk for LT in ALGS (APRI and FIB‐4) and PFIC (FIB‐4).
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Affiliation(s)
- Henry Shiau
- Pediatric Gastroenterology, Hepatology, and Nutrition Baylor College of Medicine Houston TX.,Texas Children's Hospital Houston TX
| | - Danielle Guffey
- Institute for Clinical and Translational Research Baylor College of Medicine Houston TX
| | - Kathleen M Loomes
- Pediatric Gastroenterology, Hepatology, and Nutrition University of Pennsylvania Perelman School of Medicine Philadelphia PA.,Children's Hospital of Philadelphia Philadelphia PA
| | | | | | - Jean P Molleston
- Pediatric Gastroenterology, Hepatology, and Nutrition Indiana University-Riley Hospital for Children Indianapolis IN
| | - Deborah Schady
- Pathology and Immunology Baylor College of Medicine Houston TX
| | - Daniel H Leung
- Pediatric Gastroenterology, Hepatology, and Nutrition Baylor College of Medicine Houston TX.,Texas Children's Hospital Houston TX
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40
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Peña-Vélez R, Garibay-Nieto N, Cal-Y-Mayor-Villalobos M, Laresgoiti-Servitje E, Pedraza-Escudero K, García-Blanco MDC, Heredia-Nieto OA, Villanueva-Ortega E. Association between neck circumference and non-alcoholic fatty liver disease in Mexican children and adolescents with obesity. J Pediatr Endocrinol Metab 2020; 33:205-213. [PMID: 31846425 DOI: 10.1515/jpem-2019-0204] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 11/05/2019] [Indexed: 12/20/2022]
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disorder in the pediatric population and has grown along with the obesity pandemic in which we live today. Adipose tissue storage in the upper body segment has been positively correlated with visceral adiposity and metabolic disease, which suggests that neck circumference could represent an easily accessible and replicable anthropometric measurement to identify patients with a higher risk of developing NAFLD. The main purpose of this study is to determine if there is an association between neck circumference and NAFLD. The secondary objectives are to establish cutoff values based on gender and puberty staging. Methods We included a sample pediatric population of 112 patients diagnosed with obesity aged between 6 and 18 years. We performed anthropometric and metabolic measurements on every patient, and NAFLD diagnosis was determined with hepatic ultrasound. Results The neck circumference was larger in NAFLD pediatric patients compared to those without NAFLD (p = 0.001). In a multivariate analysis, the neck circumference was associated with NAFLD as an independent risk factor (odds ratio [OR] = 1.172; 95% CI = 1.008-1.362; p = 0.038). Tanner 2-3 = 35 cm and Tanner 4-5 = 38 cm were established as risk cutoff values to develop NAFLD in the male adolescent population. Conclusions There is an association between the neck circumference and NAFLD in pediatric patients with obesity, particularly in the male population.
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Affiliation(s)
- Rubén Peña-Vélez
- Children and Adolescent Obesity Clinic, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico.,School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Nayely Garibay-Nieto
- Children and Adolescent Obesity Clinic, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico.,School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico.,Department of Human Genetics, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | | | | | - Karen Pedraza-Escudero
- Children and Adolescent Obesity Clinic, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico.,School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | | | - Eréndira Villanueva-Ortega
- Children and Adolescent Obesity Clinic, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico.,School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
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41
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Wang Y, Pan W, Zhao D, Chen Y, Chen X, Xia H. Diagnostic Value of Serum Procollagen III N-Terminal Peptide for Liver Fibrosis in Infantile Cholestasis. Front Pediatr 2020; 8:131. [PMID: 32296668 PMCID: PMC7136468 DOI: 10.3389/fped.2020.00131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 03/10/2020] [Indexed: 01/29/2023] Open
Abstract
Background: Several non-invasive markers have been reported as being effective for the assessment of fibrosis in adults with chronic viral hepatitis. The infantile liver is more susceptible to cholestasis, and it is important to promptly evaluate liver fibrosis to guide the clinical treatment. However, the clinical value of these markers in infants with cholestasis remains unknown. Aim: To investigate the correlation between serum laminin (LN), hyaluronic acid (HA), procollagen III N-terminal peptide (PIIINP) level, and liver fibrosis stage in infants with cholestasis. Methods: One hundred and thirty-seven term infants with cholestasis were included. Laparoscopic exploration and cholangiography were performed to diagnose or rule out biliary atresia. Serum LN, HA, and PIIINP were measured prior to laparoscopic exploration. Liver biopsy was performed for all patients. Liver fibrosis was staged on a five-point scale (F0-F4) according to the METAVIR scoring system. The correlation between serum markers and liver fibrosis stage was assessed. A receiver operator characteristic analysis was performed to determine the accuracy of serum markers for predicting the liver fibrosis stage. Results: Serum PIIINP and HA were positively correlated with liver fibrosis stage (r = 0.622, P < 0.001, and r = 0.41, P < 0.001, respectively). There was no significant correlation between serum LN and liver fibrosis stage (P > 0.05). Serum aspartate aminotransferase, total bilirubin, direct bilirubin, and PIIINP were independently correlated with the fibrosis stage on multivariate ordinal regression analysis. Receiver operating curve (ROC) analysis showed that serum PIIINP was the most effective for the diagnosis of fibrosis grade. The area under the ROC curves (AUROCs) for serum PIIINP for diagnosing fibrosis stages ≥F1, ≥F2, ≥F3, and F4 (cirrhosis) were 0.843, 0.789, 0.82, and 0.891, respectively. The cut-off serum PIIINP value for predicting fibrosis stage ≥F1 was 242.3 ng/mL, with 73.8% sensitivity and 90% specificity. The cut-off value for predicting cirrhosis was 698.7 ng/mL, with 75% sensitivity and 96% specificity. Conclusion: Serum PIIINP is a promising biomarker for predicting liver fibrosis stage, especially cirrhosis. Its assessment is a simple and non-invasive diagnostic method for liver fibrosis in infants with cholestasis.
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Affiliation(s)
- Yingcan Wang
- Department of Neonatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weihua Pan
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongying Zhao
- Department of Neonatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Chen
- Department of Neonatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuting Chen
- Department of Neonatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongping Xia
- Department of Neonatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Mosca A, Comparcola D, Romito I, Mantovani A, Nobili V, Byrne CD, Alisi A, Targher G. Plasma N-terminal propeptide of type III procollagen accurately predicts liver fibrosis severity in children with non-alcoholic fatty liver disease. Liver Int 2019; 39:2317-2329. [PMID: 31436362 DOI: 10.1111/liv.14225] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS We examined the diagnostic performance of plasma N-terminal propeptide of type III procollagen (PIIINP) levels, aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for predicting non-alcoholic steatohepatitis (NASH) and liver fibrosis stage in children/adolescents with non-alcoholic fatty liver disease (NAFLD). METHODS We enrolled 204 children/adolescents with biopsy-proven NAFLD at the "Bambino Gesù" Children's Hospital. We measured plasma PIIINP levels using a commercially available enzyme-linked immunosorbent assay kit and calculated APRI and FIB-4 scores using standard methods. RESULTS Children with NASH had higher plasma PIIINP levels, APRI and FIB-4 scores compared with those without NASH (all P < .001). However, PIIINP levels had much better diagnostic performance and accuracy than APRI and FIB-4 scores for predicting liver fibrosis stage. PIIINP levels correlated with the total NAFLD activity score (NAS) and its constituent components (P < .0001). The risk of either NASH or F ≥ 2 fibrosis progressively increased with increasing PIIINP levels (P < .0001), independent of age, gender, adiposity measures, insulin resistance, NAS score and the patatin-like phospholipase domain-containing protein-3 rs738409 polymorphism. For every 3.6 ng/mL increase in PIIINP levels, the likelihood of having F ≥ 2 fibrosis increased by ~14-fold (adjusted-odds ratio 14.1, 95% CI 5.50-35.8, P < .0001) after adjustment for the aforementioned risk factors. The area under the receiver operating characteristics curve was 0.921 (95% CI 0.87-0.97) for F ≥ 2 fibrosis, and 0.993 (95% CI 0.98-1.0) for F3 fibrosis respectively. CONCLUSIONS Unlike APRI and FIB-4 scores, plasma PIIINP levels are a promising, non-invasive biomarker for diagnosing liver fibrosis stage in children/adolescents with biopsy-proven NAFLD.
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Affiliation(s)
- Antonella Mosca
- Hepatology Gastroenterology and Nutrition, Bambino Gesù Children's Hospital, Rome, Italy
| | - Donatella Comparcola
- Hepato-Metabolic Disease Unit, IRCCS, Bambino Gesù Children's Hospital, Rome, Italy
| | - Ilaria Romito
- Research Unit of Molecular Genetics of Complex Phenotypes, IRCCS, Bambino Gesù Children's Hospital, Rome, Italy
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Valerio Nobili
- Hepatology Gastroenterology and Nutrition, Bambino Gesù Children's Hospital, Rome, Italy.,Department of Pediatrics, University La Sapienza, Rome, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, Southampton General Hospital, University Hospital Southampton, Southampton, UK.,Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, IRCCS, Bambino Gesù Children's Hospital, Rome, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Alkhouri N, Kohli R, Feldstein AE. Designing Clinical Trials in Pediatric Nonalcoholic Steatohepatitis: Tips for Patient Selection and Appropriate Endpoints. Hepatol Commun 2019; 3:1563-1570. [PMID: 31832567 PMCID: PMC6887671 DOI: 10.1002/hep4.1449] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/20/2019] [Indexed: 12/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is common in children and may progress to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and even cirrhosis in childhood or early adulthood, indicating the need for pharmacologic treatment in this age group. Multiple trials are evaluating different therapeutic targets for NASH with fibrosis in adults, and the U.S. Food and Drug Administration has recently provided clear guidance to the pharmaceutical industry on developing drugs for the treatment of noncirrhotic NASH with liver fibrosis. Pediatric NAFLD has several unique aspects that distinguish it from the adult disease in terms of histology, our understanding of the natural history, and the utility of noninvasive tests. These differences have the potential to impact the design of clinical trials to test different drugs in the pediatric population. The aim of this article is to provide a review of common misconceptions regarding pediatric NAFLD and key differences from adult NAFLD. We have provided our recommendations on the design of early proof-of-concept and late phase 2 trials based on lessons learned from previous clinical trials. We believe that clinical drug development for children with NAFLD should happen in parallel with ongoing adult trials.
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Affiliation(s)
- Naim Alkhouri
- Metabolic Health Center Texas Liver Institute University of Texas Health San Antonio San Antonio TX
| | - Rohit Kohli
- Division of Gastroenterology, Hepatology and Nutrition Children's Hospital Los Angeles Keck School of Medicine of University of Southern California Los Angeles CA
| | - Ariel E Feldstein
- Department of Pediatric Gastroenterology University of California San Diego La Jolla CA
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44
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Ko JS. New Perspectives in Pediatric Nonalcoholic Fatty Liver Disease: Epidemiology, Genetics, Diagnosis, and Natural History. Pediatr Gastroenterol Hepatol Nutr 2019; 22:501-510. [PMID: 31777715 PMCID: PMC6856496 DOI: 10.5223/pghn.2019.22.6.501] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 10/29/2019] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. The global prevalence of pediatric NAFLD from general populations is 7.6%. In obese children, the prevalence is higher in Asia. NAFLD has a strong heritable component based on ethnic difference in the prevalence and clustering within families. Genetic polymorphisms of patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2, and glucokinase regulatory protein (GCKR) are associated with the risk of NAFLD in children. Variants of PNPLA3 and GCKR are more common in Asians. Alterations of the gut microbiome might contribute to the pathogenesis of NAFLD. High fructose intake increases the risk of NAFLD. Liver fibrosis is a poor prognostic factor for disease progression to cirrhosis. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction are more accurate for steatosis quantification than ultrasound. Noninvasive imaging methods to assess liver fibrosis, such as transient elastography, shear-wave elastography, and magnetic resonance elastography are useful in predicting advanced fibrosis, but they need further validation. Longitudinal follow-up studies into adulthood are needed to better understand the natural history of pediatric NAFLD.
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Affiliation(s)
- Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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45
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Draijer L, Benninga M, Koot B. Pediatric NAFLD: an overview and recent developments in diagnostics and treatment. Expert Rev Gastroenterol Hepatol 2019; 13:447-461. [PMID: 30875479 DOI: 10.1080/17474124.2019.1595589] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adults in industrialized countries. Besides liver-related morbidity, NAFLD is also associated with an increased risk of cardiovascular disease, type 2 diabetes and mortality at adult age. However, despite the high prevalence and serious complications, diagnosing and staging of disease remains complicated due to a lack of accurate screening tools and non-invasive methods to detect fibrosis. Areas covered: Recent insights in epidemiology, pathogenesis, diagnostic evaluation and treatment options in pediatric NAFLD are being reviewed, with a particular focus on new developments in diagnostic tools. Expert opinion: Due to their long life span, children with NAFLD are particularly at risk of complications in their lifetime. Therefore, an effective screening strategy for children to identify those with NAFLD at risk of complications is urgently needed. This is further underscored by new pharmacological therapies that are expected to become available in the next 5 years. Momentarily no accurate non-invasive method for diagnosing pediatric NAFLD is available. New promising biomarkers and imaging tools could hopefully provide better screening tools and could contribute to the development of a successful management plan to identify children with NAFLD.
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Affiliation(s)
- Laura Draijer
- a Department of Pediatric Gastroenterology and Nutrition , Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children's Hospital , Amsterdam , The Netherlands
| | - Marc Benninga
- a Department of Pediatric Gastroenterology and Nutrition , Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children's Hospital , Amsterdam , The Netherlands
| | - Bart Koot
- a Department of Pediatric Gastroenterology and Nutrition , Amsterdam University Medical Centers, Location Academic Medical Center/Emma Children's Hospital , Amsterdam , The Netherlands
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NAFLD and Liver Transplantation in Children—Working Group Report From the ILTS Single Topic Conference on NAFLD. Transplantation 2019; 103:68-70. [DOI: 10.1097/tp.0000000000002490] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Mann JP, Vreugdenhil A, Socha P, Jańczyk W, Baumann U, Rajwal S, Casswall T, Marcus C, van Mourik I, O'Rahilly S, Savage DB, Noble-Jamieson G, Lacaille F, Dabbas M, Dubern B, Kelly DA, Nobili V, Anstee QM. European paediatric non-alcoholic fatty liver disease registry (EU-PNAFLD): Design and rationale. Contemp Clin Trials 2018; 75:67-71. [DOI: 10.1016/j.cct.2018.11.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 10/17/2018] [Accepted: 11/04/2018] [Indexed: 02/07/2023]
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Predictive Value of a Noninvasive Serological Hepatic Fibrosis Scoring System in Cirrhosis Combined with Oesophageal Varices. Can J Gastroenterol Hepatol 2018; 2018:7671508. [PMID: 30186822 PMCID: PMC6112226 DOI: 10.1155/2018/7671508] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/25/2018] [Indexed: 01/26/2023] Open
Abstract
OBJECTIVE In recent years, the noninvasive serological scoring system has become a research hotspot in predicting hepatic fibrosis and has achieved good results. However, it has rarely been applied to the prediction of oesophageal varices. The aim of the study was to evaluate the predictive value of the four following scoring systems in cirrhosis combined with oesophageal varices: aspartate and platelet ratio index (APRI), aspartate aminotransferase-alanine aminotransferase ratio (AAR), FIB-4, and S index. METHODS A total of 153 patients with cirrhosis were categorized into groups with or without oesophageal varices. In addition, cirrhosis patients with oesophageal varices were further divided into mild, moderate, and severe grades. The rank sum test was used to compare the significant differences of APRI, AAR, FIB-4, and S index between the two groups of cirrhosis patients with or without oesophageal varices. A ROC curve was generated to compare the area under the curve of the three groups and to obtain the corresponding optimal prediction value. Moreover, multivariate logistic regression analysis was employed to assess the predictive factors for cirrhosis combined with oesophageal varices. RESULTS 44 patients had no oesophageal varices and 108 patients had oesophageal varices. Of the 108 patients with oesophageal varices, 43 were mild, 32 were moderate, and 33 were severe. The rank sum test indicated that the APRI, FIB-4, and S index were statistically significant between two groups (P < 0.05), while no significant difference was detected in terms of AAR between the two groups (P > 0.05). In addition, all four scoring systems were statistically significant between nonoesophageal varices group and severe oesophageal varices group (P < 0.05). In the ROC curve of oesophageal varices, the AUC values of APRI, FIB-4, and S index for predicting oesophageal varices were 0.681, 0642, and 0.673, respectively. However, in the ROC curve of severe oesophageal varices, the AUC values of APRI, AAR, FIB-4, and S index were 0.729, 0.648, 0.673, and 0.695, respectively. Multivariate logistic regression analysis indicated that APRI and FIB-4 were predictors of disease progression (P < 0.05). CONCLUSION AAR harboured a poor predictive value for oesophageal varices, APRI can be used as a reference index for the prediction of severe oesophageal varices, and the S index harboured potential value in predicting the degree of progression of cirrhosis.
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Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased substantially in the past two decades and NAFLD has now become the most common cause of chronic liver disease in children and adolescents. NAFLD is a broad clinicopathologic spectrum ranging from simple steatosis to varying degrees of necroinflammation called nonalcoholic steatohepatitis (NASH), leading to fibrosis and subsequently to cirrhosis. Despite the increasing prevalence and progressive nature of NAFLD even among children, therapy for NAFLD in both adults and children are limited. Weight loss remains the only consistently effective therapy for NAFLD. Pharmacologic options are even more limited in children than in adults with NAFLD. Vitamin E has been shown to be effective in improving histology in children with NASH. Few pharmacologic options such as metformin, probiotics, omega-3 fatty acids, and cysteamine bitartrate have been studied in children, with limited beneficial effects. However, these studies are limited by small sample size and heterogeneity of outcome assessment after treatment. Recent studies show promising results with bariatric surgery with regards to weight loss and improvement in liver histology in adolescents with NAFLD. In this review article, we discuss epidemiology, pathophysiology, and extrahepatic comorbidities of pediatric NAFLD and review existing therapeutic options for children with NAFLD. We also review novel therapeutic strategies studied in adults that could potentially be studied in children in the future.
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Mandelia C, Kabbany MN, Conjeevaram Selvakumar PK, Alkhouri N. The search for noninvasive methods to identify liver fibrosis in children with nonalcoholic fatty liver disease. Biomark Med 2018. [PMID: 29517271 DOI: 10.2217/bmm-2017-0038] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the obesity epidemic. Recent studies have clearly shown that the stage of fibrosis in adults with NAFLD is the most important histological feature in long-term outcomes and the development of liver-related complications. Despite the paucity of data regarding the natural history of pediatric NAFLD, its progression to cirrhosis and end-stage liver disease requiring liver transplantation is well documented. Given the high prevalence of NAFLD in children and adults, there is an urgent need to find safe and cost-effective alternatives to biopsy to determine the stage of liver fibrosis. In this review, we provide a concise overview of different noninvasive methods for diagnosing and staging liver fibrosis in children with NAFLD.
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Affiliation(s)
- Chetan Mandelia
- Department of Pediatric Gastroenterology & Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Mohammad Nasser Kabbany
- Department of Pediatric Gastroenterology & Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA
| | | | - Naim Alkhouri
- Texas Liver Institute, UT Health San Antonio, San Antonio, TX 78215, USA
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