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      Clinical Features of Lysosomal Acid Lipase Deficiency

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          Abstract

          Objective:

          The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.

          Methods:

          Investigators reviewed medical records of LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset.

          Results:

          A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0–42); mean age at diagnosis was 15.2 years (range 1–46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ∼1.15 multiples of normal (MN) and median spleen volume was ∼2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9–43.5 years).

          Conclusion:

          This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.

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          Most cited references17

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          Liver fibrosis.

          Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
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            Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.

            Nonalcoholic steatohepatitis (NASH) may present with increased hepatic fibrosis progressing to end-stage liver disease. No factors that determine increasing fibrosis and histologically advanced disease have been recognized, thus, liver biopsy is recommended in all patients for diagnosis and prognosis. Our aim was to identify independent predictors of severe hepatic fibrosis in patients with NASH. One hundred and forty-four patients were studied. All patients underwent liver biopsy. Clinical and biochemical variables were examined with univariate and multivariate analysis. Thirty-seven (26%) patients had no abnormal fibrosis, 53 (37%) had mild fibrosis, 15 (10%) had moderate fibrosis, 14 (10%) had bridging fibrosis, and 25 (17%) had cirrhosis. In multivariate analysis, older age (P =. 001), obesity (P =.002), diabetes mellitus (P =.009), and aspartate transaminase/alanine transaminase (AST/ALT) ratio greater than 1 (P =.03) were significant predictors of severe liver fibrosis (bridging/cirrhosis). Body mass index (P =.003) was the only independent predictor of the degree of fat infiltration. Increased transferrin saturation correlated positively with the severity of fibrosis (P =.02) in univariate analysis, and there was a trend for more female patients among those with more advanced fibrosis (P =. 09). However, iron studies or gender were not significant when controlled for age, obesity, diabetes, and AST/ALT ratio. In conclusion, older age, obesity, and presence of diabetes mellitus help identify those NASH patients who might have severe liver fibrosis. This is the subgroup of patients with NASH who would be expected to derive the most benefit from having a liver biopsy and considering investigational therapies.
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              PCSK9: a convertase that coordinates LDL catabolism.

              The identification and characterization of proprotein convertase subtilisin-like/kexin type 9 (PCSK9) have provided new insights into LDL metabolism and the causal role of LDL in coronary heart disease (CHD). PCSK9 is a secreted protease that mediates degradation of the LDL receptor by interacting with the extracellular domain and targeting the receptor for degradation. Individuals with loss-of-function mutations in PCSK9 have reduced plasma levels of LDL cholesterol and are protected from CHD; these observations have validated PCSK9 as a therapeutic target and suggested new approaches for the treatment and prevention of CHD.
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                Author and article information

                Journal
                J Pediatr Gastroenterol Nutr
                J. Pediatr. Gastroenterol. Nutr
                JPGA
                Journal of Pediatric Gastroenterology and Nutrition
                Lippincott Williams & Wilkins
                0277-2116
                1536-4801
                December 2015
                24 November 2015
                : 61
                : 6
                : 619-625
                Affiliations
                []Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
                []Department of Medicine, Addenbrooke's Hospital NHS Trust, Cambridge, UK
                []Medical Genetics Division, Stanford University, Stanford, CA
                [§ ]Department of Pediatrics, Regina Margherita Hospital, Turin, Italy
                [|| ]Seattle Children's Hospital, Seattle, WA
                []Department of Vascular Medicine-Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
                [# ]New York-Presbyterian/Columbia University Medical Center, New York, NY
                [∗∗ ]Department of Pediatrics, First Faculty of Medicine, Charles University, Prague, Czech Republic
                [†† ]Departement de l’Enfant et de l’Adolescent, Hopitaux Universitaires de Geneve, Geneva, Switzerland
                [‡‡ ]Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
                [§§ ]Department of Pediatrics, Unit of Rare Diseases, Gaslini Institute Genoa, Genova, Italy
                [|||| ]Department of Inherited Metabolic Disorders, Birmingham Children's Hospital, Birmingham, UK
                [¶¶ ]Department of Adult Inherited Metabolic Diseases, Salford Royal NHS Foundation, Salford, UK
                [## ]Screening Department, Institute of Mother and Child, Warsaw, Poland
                [∗∗∗ ]University of Minnesota, Minneapolis, MN
                [††† ]Synageva BioPharma Corp, Lexington, MA
                [‡‡‡ ]Hopital Necker-Enfants Malades, Paris, France.
                Author notes
                Address correspondence and reprint requests to Barbara K. Burton, MD, Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 East Chicago Ave, No. 59, Chicago, IL 60611-2605 (e-mail: bburton@ 123456luriechildrens.org).
                Article
                00005
                10.1097/MPG.0000000000000935
                4645959
                26252914
                49f912ab-e687-4585-89e9-e13c91a14410
                Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                : 19 January 2015
                : 31 July 2015
                Categories
                Original Articles: Gastroenterology
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                cholesteryl ester storage disease,lipa deficiency,wolman disease

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