Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease
TL;DR: All 112 liver biopsied patients had the characteristic pathology, which is progressive, and includes microvesicular steatosis, which leads to fibrosis, micronodular cirrhosis, and ultimately to liver failure.
About: This article is published in Journal of Hepatology.The article was published on 2013-06-01 and is currently open access. It has received 284 citations till now. The article focuses on the topics: Cholesterol ester storage disease & Lysosomal acid lipase deficiency.
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Washington University in St. Louis1, The Chinese University of Hong Kong2, Boston Children's Hospital3, Newcastle University4, National Scientific and Technical Research Council5, University of California, San Francisco6, University of Turin7, University of California, San Diego8, Saint Louis University9, Northwestern University10
TL;DR: No effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery, however, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.
546 citations
TL;DR: This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid'lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases.
Abstract: Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.
312 citations
National Operating Committee on Standards for Athletic Equipment1, University of Modena and Reggio Emilia2, University of Verona3, University of Bologna4, University of Pittsburgh5, University of Turin6, University of Florence7, Sapienza University of Rome8, University of Naples Federico II9, University of Palermo10, University of Milan11
TL;DR: The results of ongoing studies are eagerly expected to lead to introduce into the clinical arena new diagnostic and prognostic biomarkers, prevention and surveillance strategies as well as to new drugs for a tailored approach to the management of NAFLD in the individual patient.
243 citations
TL;DR: Practical guidance is provided to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease and a diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase.
236 citations
Cites background or result from "Cholesteryl ester storage disease: ..."
...Progressive liver disease is another characteristic feature of LAL-D, and patients typically present with hepatomegaly, elevated transaminase levels and/or microvesicular steatosis [1]....
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...Liver dysfunction is common, with hepatomegaly being an almost universal finding at diagnosis [1,18]....
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...This estimate conflicts with the small number of cases of LAL-D reported in the literature, indicating that the disease may be substantially underdiagnosed, especially in patients of European ancestry [1]....
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...LAL-D is a heterogeneous disease that presents along a clinical continuum, with signs and symptoms and rate of progression varying between affected individuals [1]....
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...Firstly it is unlikely that statins would reduce the liver damage associated with accumulation of cholesterol esters in the liver and there is evidence of persistence of elevation of serum transaminases and continued progression of liver fibrosis to cirrhosis in affected patients on statins [1,33]....
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Icahn School of Medicine at Mount Sinai1, University of Zagreb2, Cincinnati Children's Hospital Medical Center3, Autonomous University of Madrid4, Ege University5, Cambridge University Hospitals NHS Foundation Trust6, Istituto Giannina Gaslini7, Stanford University8, Women & Children's Hospital of Buffalo9, Gazi University10, University of Pennsylvania11, Alfred I. duPont Hospital for Children12, University of California, San Francisco13, University of Arizona14, University of Mainz15, Harvard University16, University of Newcastle17, Royal Children's Hospital18, University of Padua19, University of Freiburg20, Royal Brisbane and Women's Hospital21, Inova Fairfax Hospital22, Pfizer23
TL;DR: Sbelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency and observed improvements in lipid levels and reduction in hepatic fat content.
Abstract: BackgroundLysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. MethodsIn this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. ResultsSubstantial disease burden at baseline included a very high level of low-densit...
207 citations
Cites background from "Cholesteryl ester storage disease: ..."
...Event leading to paused dosing 1 (3)† 0...
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...Serious adverse event related to study drug 1 (3) † 0...
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TL;DR: In this paper, the authors present a list of disorders of MITOCHONDRIAL FUNCTION, including the following: DISORDERS OF MIOCHONDRIC FERTILITY XIX, XVI, XIX.
Abstract: I. INTRODUCTION II. PERSPECTIVES III. GENERAL THEMES IV. CANCER V. CHROMOSOMES VI. DIAGNOSTIC APPROACHES VII. CARBOHYDRATES VIII. AMINO ACIDS IX. ORGANIC ACIDS X. DISORDERS OF MITOCHONDRIAL FUNCTION XI. PURINES AND PYRIMIDINES XII. LIPIDS XIII. PORPHYRINS XIV. METALS XV. PEROXISOMES XVI. LYSOSOMAL DISORDERS XVII. VITAMINS XVIII. HORMONES XIX. BLOOD XX. IMMUNE AND DEFENSE SYSTEMS XXI. MEMBRANE TRANSPORT DISORDERS XXII. CONNECTIVE TISSUE XXIII. CARDIOVASCULAR SYSTEM XXIV. KIDNEY XXV. MUSCLE XXVI. LUNG XXVII. SKIN XXVIII. NEUROGENETICS XXIX. EYE XXX. MULTISYSTEM INBORN ERRORS OF DEVELOPMENT
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"Cholesteryl ester storage disease: ..." refers background in this paper
...38 E8 SJ M -1 G >A /L 35 7P E8 SJ M -1 G >A /L 33 6P F <1 4 19 SM N B IIb [1 2]...
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...delS275_Q298; IVS8 ; hereafter designated E8SJM ; rs 116928232) has been identified in patients of European ancestry [2,37,38] (Fig....
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...In contrast, CESD is an often unrecognized, later-onset subtype thatmaypresent in infancy, childhood, or adulthood, dependingon the residual in vitro LAL activity, which typically ranges from 1% to 12% of normal [2,3,12,13]....
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...Feeding difficulties and malabsorption lead to malnutrition, growth retardation, cachexia, which together with the severe liver disease, contribute to demise in the first three to 12 months of life [2,3,10,11]....
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TL;DR: The metabolic basis of inherited disease, the metabolic basis for inherited disease as mentioned in this paper, The metabolic basis in inherited disease and inherited diseases, and inherited disease diagnosis and management, in the context of inherited diseases
Abstract: The metabolic basis of inherited disease , The metabolic basis of inherited disease , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی
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TL;DR: Although originally established for the scientific study of mutational mechanisms in human genes, HGMD has since acquired a much broader utility for researchers, physicians, clinicians and genetic counselors as well as for companies specializing in biopharmaceuticals, bioinformatics and personalized genomics.
Abstract: The Human Gene Mutation Database (HGMD®) is a comprehensive core collection of germline mutations in nuclear genes that underlie or are associated with human inherited disease. Here, we summarize the history of the database and its current resources. By December 2008, the database contained over 85,000 different lesions detected in 3,253 different genes, with new entries currently accumulating at a rate exceeding 9,000 per annum. Although originally established for the scientific study of mutational mechanisms in human genes, HGMD has since acquired a much broader utility for researchers, physicians, clinicians and genetic counselors as well as for companies specializing in biopharmaceuticals, bioinformatics and personalized genomics. HGMD was first made publicly available in April 1996, and a collaboration was initiated in 2006 between HGMD and BIOBASE GmbH. This cooperative agreement covers the exclusive worldwide marketing of the most up-to-date (subscription) version of HGMD, HGMD Professional, to academic, clinical and commercial users.
853 citations
"Cholesteryl ester storage disease: ..." refers background in this paper
...In contrast, missense mutations which encoded residual enzyme activity (1–5%) in vitro were found in CESD patients [36,110]....
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...To date, over 40 LIPA mutations causing CESD and WD have been identified [36] (Fig....
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...The most common mutation, E8SJM , has been found only in CESD patients and the two exon 8 splice-junction variants, E8SJM and E8SJM, occurred only in WD patients [3,36]....
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TL;DR: In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis), which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis.
448 citations