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Cui N, Zhang W, Su F, Zhang Z, Li B, Peng D, Sun Y, Zeng Y, Yang B, Kuang H, Wang Q. Metabolomic and lipidomic studies on the intervention of taurochenodeoxycholic acid in mice with hyperlipidemia. Front Pharmacol 2023; 14:1255931. [PMID: 38034994 PMCID: PMC10684951 DOI: 10.3389/fphar.2023.1255931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
Bile acids are the main component of animal bile and are directly involved in the metabolic process of lipids in vivo. Taurochenodeoxycholic acid (TCDCA) is the primary biologically active substance in bile acids and has biological functions such as antioxidant, antipyretic, anti-inflammatory, and analgesic activities and improves immunity. In the present study, we assessed the impact of TCDCA on hyperlipidemia development in mouse models. Mice were fed a high-fat diet (HFD) to induce hyperlipidemia and orally administered different doses of TCDCA orally for 30 days. Then, indicators such as triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in mice were detected. Using HE and ORO staining techniques, the morphology of the mice's liver tissue was detected. Based on metabolomic and lipidomic analyses, we determined the mechanism of TCDCA in treating hyperlipidemia. The results showed that TCDCA had a significant ameliorating effect on dietary hyperlipidemia. In addition, it exerted therapeutic effects through glycerophospholipid metabolism.
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Affiliation(s)
- Na Cui
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Wensen Zhang
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fazhi Su
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zhihong Zhang
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Biao Li
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Donghui Peng
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yanping Sun
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yuanning Zeng
- School of Chinese Materia Medica, Guangdong Engineering Technology Research Center for Standardized Processing of Chinese Materia Medica Guangdong Pharmaceutical University, Guangdong, China
| | - Bingyou Yang
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Haixue Kuang
- Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Qiuhong Wang
- School of Chinese Materia Medica, Guangdong Engineering Technology Research Center for Standardized Processing of Chinese Materia Medica Guangdong Pharmaceutical University, Guangdong, China
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Anushiravani A, Jafari Khamirani H, Mohamadkhani A, Mani A, Dianatpour M, Malekzadeh R. A Form of Metabolic-Associated Fatty Liver Disease Associated with a Novel LIPA Variant. ARCHIVES OF IRANIAN MEDICINE 2023; 26:86-91. [PMID: 37543928 PMCID: PMC10685898 DOI: 10.34172/aim.2023.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 08/08/2023]
Abstract
BACKGROUND The LIPA gene on chromosome 10q23.31 contains 10 exons and encodes lipase A, the lysosomal acid lipase (LAL) containing 399 amino acids. Pathogenic variants in the LIPA result in autosomal recessive Wolman disease and cholesteryl ester storage disease (CESD). Here, we report a novel missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA in an Iranian family with fatty liver disease identified by whole-exome sequencing and confirmed by Sanger sequencing. METHODS A 28-year-old woman referred with lean NASH cirrhosis and extremely high cholesterol levels. Fatty liver disease was found in six of her family members using vibration-controlled transient elastography (VCTE). Baseline routine laboratory tests were performed and whole-exome sequencing and confirmation by Sanger sequencing were done. RESULTS The index case had severe dyslipidemia and cirrhosis despite a body mass index of 21.09 kg/m2 . Six other family members had dyslipidemia and fatty liver or cirrhosis. A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA which caused LAL-D was found to be associated with fatty liver disease and/or cirrhosis. CONCLUSION A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of the LIPA gene which caused LAL-D was found to be associated with dyslipidemia, fatty liver disease and/or cirrhosis in six members of an Iranian family. These results should be confirmed by functional studies and extending the study to at least three families.
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Affiliation(s)
- Amir Anushiravani
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ashraf Mohamadkhani
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Arya Mani
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Mehdi Dianatpour
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Malekzadeh
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol 2022; 14:1844-1861. [PMID: 36340750 PMCID: PMC9627439 DOI: 10.4254/wjh.v14.i10.1844] [Citation(s) in RCA: 6] [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: 12/27/2021] [Revised: 04/21/2022] [Accepted: 09/21/2022] [Indexed: 02/06/2023] Open
Abstract
Lysosomal storage disorders (LSD) are a rare group of genetic disorders. The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage [Gaucher disease (GD) and Niemann-Pick disease] and lysosomal acid lipase deficiency [cholesteryl ester storage disease and Wolman disease (WD)]. These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension. Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders. Dyslipidemia causes micronodular cirrhosis in lipid storage disorders. These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults. GD, Niemann-Pick type C, and WD also cause neonatal cholestasis and infantile liver failure. Genotype and liver phenotype correlation is variable in these conditions. Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease. The diagnosis of all LSD is based on enzymatic activity, tissue histology, and genetic testing. Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome. Those that progress invariably require liver transplantation with variable outcomes. The prognosis of Niemann-Pick type C and WD is universally poor. Enzyme replacement therapy has a promising role in cholesteryl ester storage disease. This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.
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Affiliation(s)
- Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Parijat Ram Tripathi
- Department of Pediatric Gastroenterology, Ankura Hospital for Women and Children, Hyderabad 500072, India
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Giraldo P, López de Frutos L, Cebolla JJ. Recommendations for overcoming challenges in the diagnosis of lysosomal acid lipase deficiency. Expert Opin Orphan Drugs 2022. [DOI: 10.1080/21678707.2022.2131393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Pilar Giraldo
- Hematology. Hospital Quironsalud. Zaragoza. SPAIN
- Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y otras lisosomales (FEETEG). Zaragoza. SPAIN
- Grupo de Investigación en Enfermedades Metabólicas y Hematológicas Raras (GIIS-012). Instituto de Investigación Sanitaria Aragón (ISS Aragón). SPAIN
| | - Laura López de Frutos
- Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y otras lisosomales (FEETEG). Zaragoza. SPAIN
- Grupo de Investigación en Enfermedades Metabólicas y Hematológicas Raras (GIIS-012). Instituto de Investigación Sanitaria Aragón (ISS Aragón). SPAIN
| | - Jorge J Cebolla
- Grupo de Investigación en Enfermedades Metabólicas y Hematológicas Raras (GIIS-012). Instituto de Investigación Sanitaria Aragón (ISS Aragón). SPAIN
- Departamento de Bioquímica, Biología Molecular y Celular. Universidad de Zaragoza. SPAIN
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Pshenichnikova II, Zakharova IN, Skorobogatova EV, Bocharova TI, Koba YV. Lysosomal acid lipase deficiency – an underestimated cause of hypercholesterolemia in children. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2022:250-255. [DOI: 10.21518/2079-701x-2022-16-1-250-255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Lysosomal acid lipase deficiency (LAL-D) is a rare, progressive, autosomal recessive disease, which develops due to impaired degradation and subsequent intra-lysosomal accumulation of triglycerides and cholesterol esters causing dyslipidemia. The clinical manifestations of the disease presumably depend on the residual activity of the enzyme, lysosomal acid lipase. A profound deficiency of the enzyme known as Wolman’s disease has an onset in the first 6 months of life. The disease reveals itself by dyspeptic disorders in the form of vomiting and diarrhea, lack of weight gain, hepatosplenomegaly, and adrenal calcification. If the Wolman’s disease is not treated, children die within the first 6 months as a result of exhaustion caused by malabsorption syndrome combined with progressive deterioration of liver and adrenal glands. Partial deficiency of lysosomal acid lipase manifests itself at a later age and is called cholesterol ester storage disease. Its clinical presentations include hepatosplenomegaly, elevated transaminases, hypercholesterolemia, and, in some cases, hypertriglyceridemia. Liver failure is the main cause of death in the natural course of cholesterol ester storage disease. Delayed diagnosis of the disease leads to its progression causing irreversible liver damage. The implementation of mass screening programs with the determination of cholesterol levels in childhood is critical to identifying asymptomatic patients.The article presents a clinical case of a patient aged 3 years. The molecular genetic testing showed a mutation in exon 8 of the LIPA gene: NM_000235.3:c.894G>A synonymous variant in the homozygous state. It was also found that both parents of the girl had this type of mutation in the heterozygous state. The patient was prescribed sebelipase alfa in a dose of 1 mg/kg once every 14 days. The treatment was well tolerated. Due to the early verification of the diagnosis and timely pathogenetic therapy, the prognosis of the course of LAL-D, the duration and quality of life of the child were considered to be favourable.Raising the awareness of doctors along with the introduction of effective screening programs for the timely detection of dyslipidemia in children contributes to timely diagnosis and early initiation of pathogenetic therapy, which can increase the life expectancy of patients with lysosomal acid lipase deficiency and improve their quality of life.
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Affiliation(s)
| | - I. N. Zakharova
- Russian Medical Academy of Continuing Professional Education
| | | | | | - Yu. V. Koba
- Russian Medical Academy of Continuing Professional Education
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The Emerging Battle: Lysosomal Acid Lipase Deficiency vs Familial Hypercholesterolemia in Children. ACG Case Rep J 2021; 8:e00516. [PMID: 33457437 PMCID: PMC7808463 DOI: 10.14309/crj.0000000000000516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 09/04/2020] [Indexed: 11/25/2022] Open
Abstract
Lysosomal acid lipase is an under-recognized enzyme involved in the modulation and expression of genes that part-take in the synthesis and uptake of cholesterol. We describe the unusual course of a 2-year-old patient who presented with hypercholesterolemia and elevated liver enzymes, initially misdiagnosed with familial hypercholesterolemia. The absence of a suggestive family history triggered further testing that revealed complete lysosomal acid lipase deficiency that typically presents in infancy as Wolman disease with failure to thrive, malabsorption, and liver failure. Interestingly, the patient's clinical picture suggested cholesteryl ester storage disease instead, a milder phenotype in older patients.
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Rashu EB, Junker AE, Danielsen KV, Dahl E, Hamberg O, Borgwardt L, Christensen VB, Wewer Albrechtsen NJ, Gluud LL. Cholesteryl ester storage disease of clinical and genetic characterisation: A case report and review of literature. World J Clin Cases 2020; 8:1642-1650. [PMID: 32432142 PMCID: PMC7211528 DOI: 10.12998/wjcc.v8.i9.1642] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/26/2020] [Accepted: 04/16/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cholesteryl ester storage disease (CESD) is a rare genetic disease. Its symptoms and severity are highly variable. CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver, as well as gastrointestinal and cardiovascular disease. The majority of patients require liver transplantation due to decompensated cirrhosis. Enzyme replacement therapy has been approved based on a randomized trial. Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation, as well as their first-degree family members.
CASE SUMMARY The siblings were compound heterozygous for the missense variant in LIPA exon 8, c.894G>A, (p.Gln298Gln) and a single base pair deletion, c.482del (p.Asn161Ilefs*19). Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients. Clinically, both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD. Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value. One of these carriers, a seven-year-old boy, was found to have severe dyslipidemia and was subsequently treated with statins.
CONCLUSION Our study underlines that CESD is a multi-organ disease, the progression of which may occur post-liver transplantation. Our findings underline the need for monitoring of complications and assessment of possible further treatment.
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Affiliation(s)
- Elias Badal Rashu
- Gastrounit, Copenhagen University Hospital Hvidovre, Hvidovre 2650, Denmark
| | | | | | - Emilie Dahl
- Department of Hepatology, Rigshospitalet, Copenhagen University, Copenhagen 2100, Denmark
| | - Ole Hamberg
- Department of Hepatology, Rigshospitalet, Copenhagen University, Copenhagen 2100, Denmark
| | - Line Borgwardt
- Centre of Genomic Medicine, Rigshospitalet, Copenhagen University, Copenhagen 2100, Denmark
| | - Vibeke Brix Christensen
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University, Copenhagen 2100, Denmark
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
- Department for Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen 2200, Denmark
| | - Lise L Gluud
- Gastrounit, Copenhagen University Hospital Hvidovre, Hvidovre 2650, Denmark
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Haemmerle G, Lass A. Genetically modified mouse models to study hepatic neutral lipid mobilization. Biochim Biophys Acta Mol Basis Dis 2019; 1865:879-894. [PMID: 29883718 PMCID: PMC6887554 DOI: 10.1016/j.bbadis.2018.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/25/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023]
Abstract
Excessive accumulation of triacylglycerol is the common denominator of a wide range of clinical pathologies of liver diseases, termed non-alcoholic fatty liver disease. Such excessive triacylglycerol deposition in the liver is also referred to as hepatic steatosis. Although liver steatosis often resolves over time, it eventually progresses to steatohepatitis, liver fibrosis and cirrhosis, with associated complications, including liver failure, hepatocellular carcinoma and ultimately death of affected individuals. From the disease etiology it is obvious that a tight regulation between lipid uptake, triacylglycerol synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent triacylglycerol deposition in the liver. In addition to triacylglycerol, also a tight control of other neutral lipid ester classes, i.e. cholesteryl esters and retinyl esters, is crucial for the maintenance of a healthy liver. Excessive cholesteryl ester accumulation is a hallmark of cholesteryl ester storage disease or Wolman disease, which is associated with premature death. The loss of hepatic vitamin A stores (retinyl ester stores of hepatic stellate cells) is incidental to the onset of liver fibrosis. Importantly, this more advanced stage of liver disease usually does not resolve but progresses to life threatening stages, i.e. liver cirrhosis and cancer. Therefore, understanding the enzymes and pathways that mobilize hepatic neutral lipid esters is crucial for the development of strategies and therapies to ameliorate pathophysiological conditions associated with derangements of hepatic neutral lipid ester stores, including liver steatosis, steatohepatitis, and fibrosis. This review highlights the physiological roles of enzymes governing the mobilization of neutral lipid esters at different sites in liver cells, including cytosolic lipid droplets, endoplasmic reticulum, and lysosomes. This article is part of a Special Issue entitled Molecular Basis of Disease: Animal models in liver disease.
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Affiliation(s)
- Guenter Haemmerle
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, 8010 Graz, Austria.
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, 8010 Graz, Austria; BioTechMed-Graz, Austria.
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Botero V, Garcia VH, Gomez-Duarte C, Aristizabal AM, Arrunategui AM, Echeverri GJ, Pachajoa H. Lysosomal Acid Lipase Deficiency, a Rare Pathology: The First Pediatric Patient Reported in Colombia. AMERICAN JOURNAL OF CASE REPORTS 2018; 19:669-672. [PMID: 29884776 PMCID: PMC6024709 DOI: 10.12659/ajcr.908808] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 03/07/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Lysosomal acid lipase deficiency is a rare genetic metabolic lipid storage disease, with a high morbidity, and mortality, in children and adults. It is characterized by a mutation in the LIPA gene that causes an alteration of lipid metabolism, resulting in deposits of cholesterol esters and triglycerides in organs such as the liver, blood vessels, and gastrointestinal tract. Lysosomal acid lipase deficiency is predominantly caused by the mutation c.894G>A, seen in approximately 50-70% of patients. Our objective is to report the first pediatric case of lysosomal acid lipase deficiency in a pediatric patient in Colombia. CASE REPORT The patient is a 14-year-old boy with isolated hepatomegaly since 6 years of age without a family history of dyslipidemia. In the pediatric control, laboratory exams revealed dyslipidemia, and a hepatic biopsy was performed, revealing severe fibrosis with septation and grade 3 microvesicular steatosis (>75%). He was referred to our center and was suspected to have lysosomal acid lipase deficiency. Enzymatic activity was measured, showing absent activity. Confirmatory diagnosis with genetic sequencing showed a pathological homozygous mutation of c.894G>A. CONCLUSIONS Lysosomal acid lipase deficiency can manifest as early- or late-onset, with variable and severe signs and symptoms. The late-onset form has a broad spectrum of manifestations with mild symptoms, leading to under-diagnosis, which increases the actual disease burden. Early diagnosis is essential to initiate enzyme replacement therapy, since the natural disease course can be changed. More studies should be conducted in Latin America to evaluate the prevalence of the disease.
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Affiliation(s)
- Verónica Botero
- Department of Pediatric Gastroenterology and Hepatology, Valle del Lili Foundation, Cali, Valle del Cauca, Colombia
| | - Victor H. Garcia
- Center for Research on Advanced Surgery and Transplants (CICAT), Icesi University, Cali, Valle del Cauca, Colombia
| | - Catalina Gomez-Duarte
- Center for Research on Advanced Surgery and Transplants (CICAT), Icesi University, Cali, Valle del Cauca, Colombia
| | - Ana M. Aristizabal
- Center for Research on Advanced Surgery and Transplants (CICAT), Icesi University, Cali, Valle del Cauca, Colombia
| | - Ana M. Arrunategui
- Department of Pathology, Valle del Lili Foundation, Cali, Valle del Cauca, Colombia
| | - Gabriel J. Echeverri
- Department of Transplant Surgery, Colombiana de Trasplantes, Barranquilla, Atlantico, Colombia
| | - Harry Pachajoa
- Department of Genetics, Valle del Lili Foundation, Cali, Valle del Cauca, Colombia
- Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Icesi University, Cali, Valle del Cauca, Colombia
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