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Musso G, Saba F, Cassader M, Gambino R. Lipidomics in pathogenesis, progression and treatment of nonalcoholic steatohepatitis (NASH): Recent advances. Prog Lipid Res 2023; 91:101238. [PMID: 37244504 DOI: 10.1016/j.plipres.2023.101238] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/20/2023] [Accepted: 05/21/2023] [Indexed: 05/29/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting up to 30% of the general adult population. NAFLD encompasses a histological spectrum ranging from pure steatosis to non-alcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and is becoming the most common indication for liver transplantation, as a result of increasing disease prevalence and of the absence of approved treatments. Lipidomic readouts of liver blood and urine samples from experimental models and from NASH patients disclosed an abnormal lipid composition and metabolism. Collectively, these changes impair organelle function and promote cell damage, necro-inflammation and fibrosis, a condition termed lipotoxicity. We will discuss the lipid species and metabolic pathways leading to NASH development and progression to cirrhosis, as well as and those species that can contribute to inflammation resolution and fibrosis regression. We will also focus on emerging lipid-based therapeutic opportunities, including specialized proresolving lipid molecules and macrovesicles contributing to cell-to-cell communication and NASH pathophysiology.
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Affiliation(s)
- Giovanni Musso
- Dept of Emergency Medicine, San Luigi Gonzaga University Hospital, Orbassano, Turin, Italy.
| | - Francesca Saba
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - Maurizio Cassader
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - Roberto Gambino
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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Korbelius M, Kuentzel KB, Bradić I, Vujić N, Kratky D. Recent insights into lysosomal acid lipase deficiency. Trends Mol Med 2023; 29:425-438. [PMID: 37028992 DOI: 10.1016/j.molmed.2023.03.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/14/2023] [Accepted: 03/14/2023] [Indexed: 04/09/2023]
Abstract
Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid storage disorders with complete or partial absence of LAL activity. This review discusses the consequences of defective LAL-mediated lipid hydrolysis on cellular lipid homeostasis, epidemiology, and clinical presentation. Early detection of LAL deficiency (LAL-D) is essential for disease management and survival. LAL-D must be considered in patients with dyslipidemia and elevated aminotransferase concentrations of unknown etiology. Enzyme replacement therapy, sometimes in combination with hematopoietic stem cell transplantation (HSCT), is currently the only therapy for LAL-D. New technologies based on mRNA and viral vector gene transfer are recent efforts to provide other effective therapeutic strategies.
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Affiliation(s)
- Melanie Korbelius
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Katharina B Kuentzel
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Ivan Bradić
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Nemanja Vujić
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Dagmar Kratky
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
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Bashir A, Duseja A, Verma A, De A, Tiwari P. Lysosomal Acid Lipase Activity in Non-alcoholic Fatty Liver Disease as a Novel Diagnostic and Therapeutic Target: A Systematic Literature Review of Current Evidence and Future Directions. J Clin Exp Hepatol 2022; 12:1535-1546. [PMID: 36340307 PMCID: PMC9630019 DOI: 10.1016/j.jceh.2022.04.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 04/10/2022] [Indexed: 12/12/2022] Open
Abstract
Background and aim Non-alcoholic fatty liver disease (NAFLD) presents with the accumulation of excessive intra-hepatic fat without significant alcohol intake. Multifactorial pathogenesis is reported to be involved. Reduced lysosomal acid lipase (LAL) activity is suggested as one of the novel-involved pathogenic mechanisms. This review summarizes the available evidence on the role of LAL activity in NAFLD pathogenesis. Methods Four databases namely, PubMed/Medline, Science direct, Cochrane Library, and Google scholar were searched to identify relevant observational records evaluating the role of LAL activity in the pathogenesis of NAFLD. All studies were assessed for their quality by using Newcastle-Ottawa Scale or The Joanna Briggs Institute Critical Appraisal tools for cohort and cross-sectional studies, respectively. The estimates of LAL activity and other clinical outcomes were expressed as mean (SD) and number (%) as presented in the primary studies. Results A total of nine good quality studies with 1711 patients with NAFLD and 877 controls from different groups (healthy volunteers, alcoholics, cryptogenic cirrhosis, and HCV-positive) were included. From the NAFLD group, 59.55% were males and the overall mean age ranged between the studies from 12.6 ± 8.5 months in pediatrics to 58.90 ± 13.82 years in adults. In the NAFLD group, the LAL activity varied from 0.53 ± 0.08 to 1.3 ± 0.70 (nmol/spot/hr) between the studies which was less than all control groups except cryptogenic cirrhosis patients (0.5 ± 0.15 nmol/spot/hr). Of the other outcomes of interest, ALT, AST, total cholesterol, triglyceride, and LDL cholesterol were found elevated in NAFLD patients than in controls. Conclusion The current evidence suggests a potential correlation of reduced LAL activity with NAFLD pathogenesis according to its severity. Large-scale studies are recommended, more importantly in patients with NAFLD having no metabolic or genetic involvement. Further LAL can act as a new non-invasive diagnostic biomarker to identify that specific NAFLD subgroup.
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Key Words
- ALT, Alanine aminotransferase
- AST, Aspartate aminotransferase
- CESD, Cholesterol ester storage disease
- HCC, Hepatocellular carcinoma
- JBI, Joanna Briggs Institute
- LAL
- LAL, Lysosomal acid lipase
- MAFLD, Metabolic (dysfunction)-associated fatty liver disease
- NAFLD
- NAFLD, Non-alcoholic fatty liver disease
- NASH
- NASH, Non-alcoholic steatohepatitis
- NOS, Newcastle–Ottawa Scale
- PNPLA3, Patatin-like phospholipase domain containing 3 protein
- WD, Wolman disease
- pathogenesis
- systematic review
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Affiliation(s)
- Aamir Bashir
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar Mohali, Punjab, 160062, India
| | - Ajay Duseja
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Ashish Verma
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar Mohali, Punjab, 160062, India
| | - Arka De
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Pramil Tiwari
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar Mohali, Punjab, 160062, India
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Besler KJ, Blanchard V, Francis GA. Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease. Front Genet 2022; 13:1013266. [PMID: 36204319 PMCID: PMC9530988 DOI: 10.3389/fgene.2022.1013266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 09/06/2022] [Indexed: 11/13/2022] Open
Abstract
Lysosomal acid lipase (LAL), encoded by the gene LIPA, is the sole neutral lipid hydrolase in lysosomes, responsible for cleavage of cholesteryl esters and triglycerides into their component parts. Inherited forms of complete (Wolman Disease, WD) or partial LAL deficiency (cholesteryl ester storage disease, CESD) are fortunately rare. Recently, LAL has been identified as a cardiovascular risk gene in genome-wide association studies, though the directionality of risk conferred remains controversial. It has also been proposed that the low expression and activity of LAL in arterial smooth muscle cells (SMCs) that occurs inherently in nature is a likely determinant of the propensity of SMCs to form the majority of foam cells in atherosclerotic plaque. LAL also likely plays a potential role in fatty liver disease. This review highlights the nature of LAL gene mutations in WD and CESD, the association of LAL with prediction of cardiovascular risk from genome-wide association studies, the importance of relative LAL deficiency in SMC foam cells, and the need to further interrogate the pathophysiological impact and cell type-specific role of enhancing LAL activity as a novel treatment strategy to reduce the development and induce the regression of ischemic cardiovascular disease and fatty liver.
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KÖSE E, ÇAĞATAY E, YARAŞ T, TEKE KISA P, GÜLER S, ARSLAN GÜLTEN Z, AKARSU M, OKTAY Y, AYAR KAYALI H, ARSLAN N. Could lysosomal acid lipase enzyme activity be used for clinical follow-up in cryptogenic cirrhosis? Turk J Med Sci 2022; 52:1075-1084. [PMID: 36326406 PMCID: PMC10387917 DOI: 10.55730/1300-0144.5410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 08/10/2022] [Accepted: 03/27/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cholesterol ester storage disease (CESD) is one of the rare causes that should be kept in mind in the etiology of cirrhosis. Recent studies detected that significantly reduced lysosomal acid lipase deficiency enzyme (LAL) in patients with cryptogenic cirrhosis (CC). Moreover, studies have evaluated that LAL activity is as effective as scoring systems in assessing the severity of cirrhosis. In this study, we aimed to investigate the CESD with LAL level and mutation analysis of LIPA gene in patients diagnosed with CC and to compare LAL activities between patients with CC and healthy volunteers. METHODS Laboratory parameters and cirrhosis stage (CHILD and MELD) were recorded for the patient group included in the study. In addition, blood samples were taken from each case included in the study for LAL activity determination and LIPA gene analysis. RESULTS A statistically significant decrease in LAL activity was found in patients diagnosed with CC compared to the healthy group. LIPA gene analysis did not detect CESD in any patient group. Correlation analysis showed a positive correlation between LAL activity and white blood cell and platelet counts in both healthy volunteers and CC patient groups. In the univariate and multivariate logistic regression analysis of the parameters associated with the MELD of ≥10 in patients with CC, significant relationship was found between the MELD of ≥10 and the LAL activity. DISCUSSION In our study, LAL activity was significantly lower in CC patients than in the normal population. LAL activity level appears to be a parameter that can be used to assess the severity of cirrhosis.
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Affiliation(s)
- Engin KÖSE
- Department of Pediatric Metabolism, Faculty of Medicine, Ankara University, Ankara,
Turkey
| | - Elçin ÇAĞATAY
- Department of Molecular Biology and Genetics, International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir,
Turkey
| | - Tutku YARAŞ
- Department of Basic and Translational Research, International Biomedicine and Genome Center, İzmir,
Turkey
| | - Pelin TEKE KISA
- Department of Pediatric Metabolism, Faculty of Medicine, Dokuz Eylül University, İzmir,
Turkey
| | - Seminay GÜLER
- Department of Gastroenterology, Faculty of Medicine, Dokuz Eylül University, İzmir,
Turkey
| | - Zümrüt ARSLAN GÜLTEN
- Department of Pediatric Metabolism, Faculty of Medicine, Dokuz Eylül University, İzmir,
Turkey
| | - Mesut AKARSU
- Department of Gastroenterology, Faculty of Medicine, Dokuz Eylül University, İzmir,
Turkey
| | - Yavuz OKTAY
- Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, İzmir,
Turkey
| | - Hülya AYAR KAYALI
- Department of Science Chemistry, Dokuz Eylül University, İzmir,
Turkey
| | - Nur ARSLAN
- Department of Pediatric Metabolism, Faculty of Medicine, Dokuz Eylül University, İzmir,
Turkey
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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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Carotti S, Lettieri-Barbato D, Piemonte F, Ruggiero S, Rosina M, Zalfa F, Zingariello M, Arciprete F, Valentini F, Francesconi M, D'Amico J, De Vincentis A, Baiocchini A, Perrone G, Antonelli-Incalzi R, Morini S, Picardi A, Aquilano K, Vespasiani-Gentilucci U. Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver. Cell Death Dis 2021; 12:1092. [PMID: 34795230 PMCID: PMC8602623 DOI: 10.1038/s41419-021-04382-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 10/26/2021] [Accepted: 11/03/2021] [Indexed: 01/05/2023]
Abstract
Recent studies demonstrated reduced blood lysosomal acid lipase (LAL) activity in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to verify hepatic LAL protein content and activity in in vitro and in vivo models of fat overload and in NAFLD patients. LAL protein content and activity were firstly evaluated in Huh7 cells exposed to high-glucose/high-lipid (HGHL) medium and in the liver of C57BL/6 mice fed with high-fat diet (HFD) for 4 and 8 months. LAL protein was also evaluated by immunohistochemistry in liver biopsies from 87 NAFLD patients and 10 controls, and correlated with hepatic histology. Huh7 cells treated with HGHL medium showed a significant reduction of LAL activity, which was consistent with reduced LAL protein levels by western blotting using an antibody towards the N-term of the enzyme. Conversely, antibodies towards the C-term of the enzyme evidenced LAL accumulation, suggesting a post-translational modification that masks the LAL N-term epitope and affects enzymatic activity. Indeed, we found a high rate of ubiquitination and extra-lysosomal localization of LAL protein in cells treated with HGHL medium. Consistent with these findings, inhibition of proteasome triggered dysfunctional LAL accumulation and affected LAL activity. Accumulation of ubiquitinated/dysfunctional LAL was also found in the liver of HFD fed mice. In NAFLD patients, hepatic levels of non-ubiquitinated/functional LAL were lower than in controls and inversely correlated with disease activity and some of the hallmarks of reduced LAL. Fat overload leads to LAL ubiquitination and impairs its function, possibly reducing hepatic fat disposal and promoting NAFLD activity.
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Affiliation(s)
- Simone Carotti
- Unit of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, Rome, Italy.
| | | | - Fiorella Piemonte
- Unit of Neuromuscular and Neurodegenerative Diseases, Children's Hospital and Research Institute "Bambino Gesù", Rome, Italy
| | - Sergio Ruggiero
- Internal Medicine, Geriatrics and Hepatology Unit, University Campus Bio-Medico, Rome, Italy
| | - Marco Rosina
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Zalfa
- Unit of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, Rome, Italy
| | - Maria Zingariello
- Unit of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, Rome, Italy
| | - Francesca Arciprete
- Unit of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, Rome, Italy
| | - Francesco Valentini
- Paediatric Unit Sant'Andrea Hospital, Faculty of Medicine and Psychology, "Sapienza" University, Rome, Italy
| | - Maria Francesconi
- Unit of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, Rome, Italy
| | - Jessica D'Amico
- Unit of Neuromuscular and Neurodegenerative Diseases, Children's Hospital and Research Institute "Bambino Gesù", Rome, Italy
| | - Antonio De Vincentis
- Internal Medicine, Geriatrics and Hepatology Unit, University Campus Bio-Medico, Rome, Italy
| | - Andrea Baiocchini
- Laboratory of Pathology of the National Institute for Infectious Diseases, Lazzaro Spallanzani, Rome, Italy
| | - Giuseppe Perrone
- Unit of Anatomical Pathology, University Campus Bio-Medico, Rome, Italy
| | | | - Sergio Morini
- Unit of Microscopic and Ultrastructural Anatomy, CIR, University Campus Bio-Medico, Rome, Italy
| | - Antonio Picardi
- Internal Medicine, Geriatrics and Hepatology Unit, University Campus Bio-Medico, Rome, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
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Thoen RU, Longo L, Neto SC, Álvares-da-Silva MR. Low levels of Lysosomal Acid Lipase (LAL) activity increases necroinflammation in adult patients with biopsy-proven metabolic associated fatty liver disease. Clin Res Hepatol Gastroenterol 2021; 45:101638. [PMID: 33662773 DOI: 10.1016/j.clinre.2021.101638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/29/2020] [Accepted: 01/16/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVE Metabolic associated fatty liver disease (MAFLD), characterized by intra-hepatic fat accumulation, will soon be the leading cause of end-stage liver disease. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. We investigated its activity in patients with biopsy-proven MAFLD. METHODS Prospective cross-sectional study in patients with biopsy-proven MAFLD. Blood LAL-activity (pmol/punch/h) was measured with dried blood spot extracts using Lalistat 2. Demographic, clinical, and laboratory data were collected. RESULTS 101 adult patients were recruited. Among them, 11.9% had a diagnosis of MAFLD without steatohepatitis and 88.1% had MAFLD with steatohepatitis. The median of LAL-activity in patients with MAFLD was 76.8 pmol/punch/h. MAFLD patients with steatohepatitis showed an increase in gamma-glutamyl transferase (p = 0.042), insulin (p = 0.001), homeostatic model assessment for insulin resistance (HOMA-IR, p = 0.001) and advanced liver fibrosis (p < 0.001), compared to cases of MAFLD without steatohepatitis. There was no statistical difference in LAL-activity between the cases (p = 0.296). When considering LAL-activity above and below 77 pmol/punch/h as a cut-off value, patients with reduced LAL-activity had a significant increase in necroinflammatory activity according to the METAVIR score (p = 0.040), and NAFLD activity score (NAS, p = 0.031) compared to cases with higher LAL-activity. CONCLUSION Our findings suggest that reduced LAL-activity is associated with increased necroinflammatory activity and severity of the NAS. A better knowledge of the role of LAL may provide new insights into the pathogenesis and progression of MAFLD.
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Affiliation(s)
- Rutiane Ullmann Thoen
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Experimental Laboratory of Hepatology and Gastroenterology, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Larisse Longo
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Experimental Laboratory of Hepatology and Gastroenterology, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
| | - Santiago Cassales Neto
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Mário Reis Álvares-da-Silva
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Experimental Laboratory of Hepatology and Gastroenterology, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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Mann JP, Carter P, Armstrong MJ, Abdelaziz HK, Uppal H, Patel B, Chandran S, More R, Newsome PN, Potluri R. Hospital admission with non-alcoholic fatty liver disease is associated with increased all-cause mortality independent of cardiovascular risk factors. PLoS One 2020; 15:e0241357. [PMID: 33108366 PMCID: PMC7591046 DOI: 10.1371/journal.pone.0241357] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 10/13/2020] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is common and strongly associated with the metabolic syndrome. Though NAFLD may progress to end-stage liver disease, the top cause of mortality in NAFLD is cardiovascular disease (CVD). Most of the data on liver-related mortality in NAFLD derives from specialist liver centres. It is not clear if the higher reported mortality rates in individuals with non-cirrhotic NAFLD are entirely accounted for by complications of atherosclerosis and diabetes. Therefore, we aimed to describe the CVD burden and mortality in NAFLD when adjusting for metabolic risk factors using a ‘real world’ cohort. We performed a retrospective study of patients followed-up after an admission to non-specialist hospitals with a NAFLD-spectrum diagnosis. Non-cirrhotic NAFLD and NAFLD-cirrhosis patients were defined by ICD-10 codes. Cases were age-/sex-matched with non-NAFLD hospitalised patients. All-cause mortality over 14-years follow-up after discharge was compared between groups using Cox proportional hazard models adjusted for demographics, CVD, and metabolic syndrome components. We identified 1,802 patients with NAFLD-diagnoses: 1,091 with non-cirrhotic NAFLD and 711 with NAFLD-cirrhosis, matched to 24,737 controls. There was an increasing burden of CVD with progression of NAFLD: for congestive heart failure 3.5% control, 4.2% non-cirrhotic NAFLD, 6.6% NAFLD-cirrhosis; and for atrial fibrillation 4.7% control, 5.9% non-cirrhotic NAFLD, 12.1% NAFLD-cirrhosis. Over 14-years follow-up, crude mortality rates were 14.7% control, 13.7% non-cirrhotic NAFLD, and 40.5% NAFLD-cirrhosis. However, after adjusting for demographics, non-cirrhotic NAFLD (HR 1.3 (95% CI 1.1–1.5)) as well as NAFLD-cirrhosis (HR 3.7 (95% CI 3.0–4.5)) patients had higher mortality compared to controls. These differences remained after adjusting for CVD and metabolic syndrome components: non-cirrhotic NAFLD (HR 1.2 (95% CI 1.0–1.4)) and NAFLD-cirrhosis (HR 3.4 (95% CI 2.8–4.2)). In conclusion, from a large non-specialist registry of hospitalised patients, those with non-cirrhotic NAFLD had increased overall mortality compared to controls even after adjusting for CVD.
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Affiliation(s)
- Jake P. Mann
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
- Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom
- ACALM Study Unit in collaboration with Aston Medical School, Aston University, Birmingham, United Kingdom
- * E-mail:
| | - Paul Carter
- ACALM Study Unit in collaboration with Aston Medical School, Aston University, Birmingham, United Kingdom
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Matthew J. Armstrong
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Hesham K. Abdelaziz
- Lancashire Cardiac Centre, Blackpool Victoria Hospital, Blackpool, United Kingdom
- Department of Cardiovascular Medicine, Ain Shams University Hospital, Cairo, Egypt
| | - Hardeep Uppal
- ACALM Study Unit in collaboration with Aston Medical School, Aston University, Birmingham, United Kingdom
| | - Billal Patel
- Lancashire Cardiac Centre, Blackpool Victoria Hospital, Blackpool, United Kingdom
| | - Suresh Chandran
- Department of Medicine, Pennine Acute Hospitals NHS Trust, Manchester, United Kingdom
| | - Ranjit More
- Lancashire Cardiac Centre, Blackpool Victoria Hospital, Blackpool, United Kingdom
| | - Philip N. Newsome
- National Institute for Health Research Liver Biomedical Research Unit at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, United Kingdom
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Rahul Potluri
- ACALM Study Unit in collaboration with Aston Medical School, Aston University, Birmingham, United Kingdom
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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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11
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Nascimbeni F, Dionisi Vici C, Vespasiani Gentilucci U, Angelico F, Nobili V, Petta S, Valenti L. AISF update on the diagnosis and management of adult-onset lysosomal storage diseases with hepatic involvement. Dig Liver Dis 2020; 52:359-367. [PMID: 31902560 DOI: 10.1016/j.dld.2019.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 12/07/2019] [Accepted: 12/10/2019] [Indexed: 12/11/2022]
Abstract
Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited disorders caused by loss-of-function mutations in genes encoding for lysosomal enzymes/proteins. The consequence is a progressive accumulation of substrates in these intracellular organelles, resulting in cellular and tissue damage. The overall incidence is about 1/8000 live births, but is likely underestimated. LSDs are chronic progressive multi-systemic disorders, generally presenting with visceromegaly, and involvement of the central nervous system, eyes, the skeleton, and the respiratory and cardiovascular systems. The age at onset and phenotypic expression are highly variable, according to the specific enzymatic defect and tissues involved, the residual activity, and the disease-causing genotype. Enzyme-replacement therapies and substrate-reduction therapies have recently become available, leading to the improvement in symptoms, disease progression and quality of life of affected individuals. Liver involvement and hepatosplenomegaly are frequent features of LSDs and a hallmark of adult-onset forms, frequently leading to medical attention. LSDs should therefore be considered in the differential diagnosis of liver disease with organomegaly. The present document will provide a short overview of adult-onset LSDs with hepatic involvement, highlighting the specificities and systemic manifestations of the ones most frequently encountered in clinical practice, which may hint at the correct diagnosis and the appropriate treatment.
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Affiliation(s)
- Fabio Nascimbeni
- Regional Referral Centre for Lysosomal Storage Diseases, Division of Internal Medicine and Metabolism, Civil Hospital, AOU of Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Dionisi Vici
- Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | | | - Francesco Angelico
- Department of Public Health and Infective Diseases, Università Sapienza, Roma, Italy
| | - Valerio Nobili
- Division of Hepatology and Gastroenterology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Salvatore Petta
- Gastroenterology and Hepatology, PROMISE, Palermo University, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
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12
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Ferri F, Mischitelli M, Tozzi G, Messina E, Mignini I, Mazzuca S, Pellone M, Parisse S, Marrapodi R, Visentini M, Baratta F, Del Ben M, Pastori D, Perciballi R, Attilia ML, Carbone M, De Santis A, Violi F, Angelico F, Ginanni Corradini S. Correction to: Reduced Lysosomal Acid Lipase Activity in Blood and Platelets Is Associated With Nonalcoholic Fatty Liver Disease. Clin Transl Gastroenterol 2020; 11:e00171. [PMID: 32251015 PMCID: PMC7145031 DOI: 10.14309/ctg.0000000000000116] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 11/11/2019] [Indexed: 02/06/2023] Open
Abstract
To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD.
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Affiliation(s)
- Flaminia Ferri
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Monica Mischitelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Giulia Tozzi
- Hepatology, Gastroenterology and Nutrition Unit, IRCCS “Bambino Gesù” Children's Hospital, Rome, Italy
| | - Emanuele Messina
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Irene Mignini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Sergio Mazzuca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Monica Pellone
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Simona Parisse
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Ramona Marrapodi
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Marcella Visentini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesco Baratta
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Maria Del Ben
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Daniele Pastori
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Roberta Perciballi
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Maria Luisa Attilia
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Martina Carbone
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Adriano De Santis
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesco Violi
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
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Baratta F, Pastori D, Tozzi G, D'Erasmo L, Di Costanzo A, Arca M, Ettorre E, Ginanni Corradini S, Violi F, Angelico F, Del Ben M. Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non-alcoholic fatty liver disease. Liver Int 2019; 39:2301-2308. [PMID: 31392821 DOI: 10.1111/liv.14206] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 07/15/2019] [Accepted: 07/26/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Recent evidence showed a reduced activity of the lysosomal acid lipase (LAL) in patients with non-alcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC). However, the relationship between LAL activity and liver fibrosis has never been investigated. METHODS Cross-sectional study including 575 outpatients referred for the management of cardio-metabolic and liver disease. The absence of liver fibrosis was defined by a FIB-4 < 1.30 and NAFLD fibrosis score (NFS) <-1.455. LAL activity was measured with dried blood spot technique. RESULTS Overall, 515 patients had a diagnosis of NAFLD (454 NAFL and 61 biopsy-proven NASH) and 60 of CC. The value of LAL activity progressively decreased from healthy subjects to NAFL/NASH patients to CC (P < .001). LAL activity was reduced by 10% in patients with NAFL, by 20% in NASH and by 50% in CC. The prevalence of CC decreased across the tertiles of LAL activity: 22.2% in the lowest, 4.6% in the intermediate and 0.5% in the highest tertile. In NAFLD patients, 69.9% had a FIB4 < 1.30, and 43.1% a NFS <-1.455. Multivariate logistic regression analysis showed that Log (LAL activity) was associated with FIB-4 < 1.30 (Odds ratio [OR] 2.19 95% confidence interval [CI] 1.33-3.62, P = .002) and NFS < -1.455 (OR 2.43, 95% CI 1.51-3.91, P < .001) after adjustment for confounding factors. CONCLUSIONS We found a progressive reduction of LAL activity according to liver disease severity. LAL activity was inversely associated with markers of liver fibrosis in patients with NAFLD.
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Affiliation(s)
- Francesco Baratta
- I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
- Department of Anatomical Sciences, Histological, Legal Medical and Locomotor, Sapienza University of Rome, Rome, Italy
| | - Daniele Pastori
- I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Giulia Tozzi
- Hepatology, Gastroenterology and Nutrition Unit, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
| | - Laura D'Erasmo
- I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Alessia Di Costanzo
- I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Marcello Arca
- I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Evaristo Ettorre
- Division of Gerontology, Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza University, Rome, Italy
| | | | - Francesco Violi
- I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Maria Del Ben
- I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
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14
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Gomaraschi M, Fracanzani AL, Dongiovanni P, Pavanello C, Giorgio E, Da Dalt L, Norata GD, Calabresi L, Consonni D, Lombardi R, Branchi A, Fargion S. Lipid accumulation impairs lysosomal acid lipase activity in hepatocytes: Evidence in NAFLD patients and cell cultures. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:158523. [PMID: 31505261 DOI: 10.1016/j.bbalip.2019.158523] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 08/27/2019] [Accepted: 09/05/2019] [Indexed: 12/23/2022]
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Baratta F, Pastori D, Ferro D, Carluccio G, Tozzi G, Angelico F, Violi F, Del Ben M. Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease? World J Gastroenterol 2019; 25:4172-4180. [PMID: 31435171 PMCID: PMC6700703 DOI: 10.3748/wjg.v25.i30.4172] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/20/2019] [Accepted: 07/02/2019] [Indexed: 02/06/2023] Open
Abstract
Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.
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Affiliation(s)
- Francesco Baratta
- Department of Internal Medicine and Medical Specialties, Sapienza - University of Rome, Rome 00155, Italy
| | - Daniele Pastori
- Department of Internal Medicine and Medical Specialties, Sapienza - University of Rome, Rome 00155, Italy
| | - Domenico Ferro
- Department of Internal Medicine and Medical Specialties, Sapienza - University of Rome, Rome 00155, Italy
| | - Giovanna Carluccio
- Department of Internal Medicine and Medical Specialties, Sapienza - University of Rome, Rome 00155, Italy
| | - Giulia Tozzi
- Hepatogastroenterology and Nutrition Unit - Pediatric Department, Bambino Gesù Children’s Hospital, Rome 00156, Italy
| | - Francesco Angelico
- Department of Public Health and Infectious Disease, Sapienza - University of Rome, Rome 00161, Italy
| | - Francesco Violi
- Department of Internal Medicine and Medical Specialties, Sapienza - University of Rome, Rome 00155, Italy
| | - Maria Del Ben
- Department of Internal Medicine and Medical Specialties, Sapienza - University of Rome, Rome 00155, Italy
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16
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Gravito-Soares M, Gravito-Soares E, Gomes D, Tome L. Lysosomal Acid Lipase: Can it be a New Non-Invasive Serum Biomarker of Cryptogenic Liver Fibrosis and Cirrhosis? Ann Hepatol 2019; 18:78-88. [PMID: 31113613 DOI: 10.5604/01.3001.0012.7865] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Accepted: 01/10/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM The association between lysosomal acid lipase (LAL) activity and liver steatosis or fibrosis is poorly studied. The aim of our study was to determine the predictive power of LAL for cryptogenic liver steatosis and cryptogenic significant fibrosis/cirrhosis. MATERIAL AND METHODS Cross-sectional observational study of 101 adult patients with unexplained elevated liver enzymes/hepatomegaly with or without dyslipidemia submitted to the determination of LAL activity and LIPA gene (E8SJM-C.894G^A) mutation. Seventy-one patients underwent liver biopsy or FibroScan®. Patients with an identifiable liver dysfunction cause and well-stablished NAFLD/NASH risk factors were excluded. Predictors for liver steatosis, significant fibrosis (> F2) or cirrhosis (F4) were evaluated. RESULTS Liver steatosis and fibrosis were mainly assessed by liver biopsy (74.6%; n = 53). Steatosis was present in 62.0% (n = 44), significant fibrosis in 47.9% (n = 34) and cirrhosis in 39.4% (n = 28). The median LAL was 0.36 (0.21-0.46)nmol/spot/h (vs. 0.29 (0.20-0.47); p = 0.558) for liver steatosis, 0.22 (0.11-0.29) nmol/spot/h (vs. 0.40 (0.34-0.51); p <0.001) for significant fibrosis and 0.21 (0.11-0.27) nmol/spot/h (vs. 0.40 (0.32-0.52); p < 0.001) for cirrhosis. No LIPA gene mutations were found. LAL activity was the strongest predictor of significant fibrosis (AUROC: 0.833; p < 0.001) with a cut-off of 0.265 (sensitivity: 85.9%; specificity: 75.0%) and cirrhosis (AUROC: 0.859; p < 0.001) with a cut-off of 0.235 (sensitivity: 86.2%; specificity: 75.0%), being higher than FIB4, GUCI or APRI. However, LAL activity was not associated with liver steatosis (AUROC: 0.536; p =0.558). CONCLUSION LAL activity can be considered a non-invasive new marker of cryptogenic liver fibrosis with higher accuracy than other known biomarkers. LAL activity < 0.265 nmol/spot/h was strongly associated with cryptogenic significant fibrosis and <0.235 nmol/spot/h with cryptogenic cirrhosis. LAL activity was not associated with cryptogenic liver steatosis.
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Affiliation(s)
- Marta Gravito-Soares
- Department of Gastroenterology, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Authors contributed equally to this work.
| | - Elisa Gravito-Soares
- Department of Gastroenterology, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Authors contributed equally to this work
| | - Dario Gomes
- Department of Gastroenterology, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Luis Tome
- Department of Gastroenterology, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Reynolds TM, Mewies C, Hamilton J, Wierzbicki AS. Identification of rare diseases by screening a population selected on the basis of routine pathology results-the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy. J Clin Pathol 2018; 71:608-613. [PMID: 29358478 DOI: 10.1136/jclinpath-2017-204727] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 11/27/2017] [Accepted: 12/13/2017] [Indexed: 01/04/2023]
Abstract
AIMS Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder of cholesterol ester storage associated with hepatic disease, cirrhosis and accelerated atherosclerosis. Its prevalence in the general population, patients with dyslipidaemia and raised transaminases is unclear. This study attempted to identify the prevalence of LALD from patients with abnormal results in laboratory databases. METHODS Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of low high-density lipoprotein-cholesterol (≤0.85 mmol/L; 33 mg/dL) and with elevated alanine or aspartate transaminases (≥60 IU/L) on one occasion or more over a 3-year time interval. Patients were recalled, and a dried blood spot sample was collected for lysosomal acid lipase determination by a fluorimetric enzyme assay. Histopathology databases of liver biopsies were interrogated for patients with features of 'microvesicular cirrhosis' or 'cryptogenic cirrhosis' in the report. Histological blocks were sampled, and samples were analysed by next-generation sequencing for the presence of mutations in the LAL gene. RESULTS Samples were obtained from 1825 patients with dyslipidaemia and elevated transaminases. No cases of LALD were identified. Liver biopsies were obtained from six patients. DNA extraction was successful from four patients. Two patients were homozygous for the LAL c.46A>C;p.Thr16Pro unclassified variant in exon 2. CONCLUSIONS Pathology databases hold routine information that can be used to identify patients with specific patterns of results or those who had biopsies to allow targeted testing for possible causes of disease. Biochemical screening suggests that the gene frequency of LAL deficiency in adults is less than 1 in 100.
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Affiliation(s)
- Timothy M Reynolds
- Department of Chemical Pathology, Queen's Hospital, Burton, UK
- Division of Health Sciences, Wolverhampton University, Wolverhampton, UK
| | - Clare Mewies
- Department of Chemical Pathology, Queen's Hospital, Burton, UK
| | - John Hamilton
- Biochemistry Department, Queen Elizabeth University Hospital Laboratory, Glasgow, UK
| | - Anthony S Wierzbicki
- Department of Metabolic Medicine/Chemical Pathology, Guy's & St Thomas' Hospitals, London, UK
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18
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Polimeni L, Pastori D, Baratta F, Tozzi G, Novo M, Vicinanza R, Troisi G, Pannitteri G, Ceci F, Scardella L, Violi F, Angelico F, Del Ben M. Spleen dimensions are inversely associated with lysosomal acid lipase activity in patients with non-alcoholic fatty liver disease. Intern Emerg Med 2017; 12:1159-1165. [PMID: 28900817 DOI: 10.1007/s11739-017-1746-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 09/04/2017] [Indexed: 12/28/2022]
Abstract
Fatty liver and splenomegaly are typical features of genetic lysosomal acid lipase (LAL) deficiency. No data in adult patients with non-genetic reduction of LAL activity are available. We investigate the association between spleen dimensions and LAL activity in non-alcoholic fatty liver disease (NAFLD) patients, in whom a reduced LAL activity has been reported. We include 425 consecutive patients who underwent abdominal ultrasound to evaluate hepatic steatosis and spleen dimensions. LAL activity was measured with dried blood spot method (Lalistat2). NAFLD was present in 74.1% of screened patients. Higher median spleen longitudinal diameter (10.6 vs. 9.9 cm; p < 0.001) and spleen area (SA) (32.7 vs. 27.7 cm2; p < 0.001), together with a higher and proportion of splenomegaly (17.8 vs. 5.5%, p = 0.001), are present in patients with NAFLD compared to those without. In NAFLD patients, median LAL activity is 0.9 nmol/spot/h. LAL activity is lower in 56 patients with splenomegaly, as compared to those without (p = 0.009). At multivariable logistic regression analysis, age (above median, OR 0.344; p = 0.003), LAL activity (below median, OR 2.206, p = 0.028), and platelets (OR 0.101, p = 0.002) are significantly associated with splenomegaly. NAFLD patients disclose a relatively high prevalence of spleen enlargement and splenomegaly, which are significantly associated with a reduced LAL activity, suggesting that LAL may contribute to spleen enlargement in this setting.
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Affiliation(s)
- Licia Polimeni
- Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy
| | - Daniele Pastori
- Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy.
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, Rome, Italy.
| | - Francesco Baratta
- Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, Rome, Italy
| | - Giulia Tozzi
- Unit for Neuromuscular and Neurodegenerative Diseases, Children's Hospital and Research Institute "Bambino Gesù", Rome, Italy
| | - Marta Novo
- Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy
| | - Roberto Vicinanza
- Department of Cardiovascular, Respiratory Nephrologic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | - Giovanni Troisi
- Department of Cardiovascular, Respiratory Nephrologic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | - Gaetano Pannitteri
- Department of Cardiovascular, Respiratory Nephrologic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | - Fabrizio Ceci
- Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I Hospital, "La Sapienza" University, Rome, Italy
| | - Laura Scardella
- Department of Surgical Sciences, Sapienza University, Rome, Italy
| | - Francesco Violi
- Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University, Rome, Italy
| | - Maria Del Ben
- Department of Internal Medicine and Medical Specialties, Sapienza University, Rome, Italy
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19
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Block RC, Razani B. Linking lysosomal acid lipase insufficiency to the development of cryptogenic cirrhosis. Atherosclerosis 2017; 262:140-142. [PMID: 28502381 DOI: 10.1016/j.atherosclerosis.2017.04.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 04/21/2017] [Indexed: 01/21/2023]
Affiliation(s)
- Robert C Block
- Department of Public Health Sciences, Cardiology Division, University of Rochester School of Medicine and Dentistry, Rochester, NY 14618, USA; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14618, USA.
| | - Babak Razani
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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