WordNet

an impairment of health or a condition of abnormal functioning
(computer science) the process of storing information in a computer memory or on a magnetic tape or disk
the act of storing something
the commercial enterprise of storing goods and materials
caused by or altered by or manifesting disease or pathology; "diseased tonsils"; "a morbid growth"; "pathologic tissue"; "pathological bodily processes" (同)morbid, pathologic, pathological
an animal sterol that is normally synthesized by the liver; the most abundant steroid in animal tissues (同)cholesterin
formed by reaction between an acid and an alcohol with elimination of water

PrepTutorEJDIC

(体の)『病気』,疾患 / (精神・道徳などの)病気,病弊
女性の話術芸人 =diseur
(倉庫などに)貯蔵すること,保管 / 貯蔵所,倉庫 / 保管料
病気にかかった / 病的な,不健全な(morbid)
コレステロール(胆汁・血液・神経組織などの脂肪性成分)
エステル(酸とアルコールから水を分離してできる化合物の総称)

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/01/29 18:45:53」(JST)

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Cholesteryl Ester Storage Disease (CESD) is the late onset phenotype for Lysosomal Acid Lipase (LAL) Deficiency, a Lysosomal storage disease, which also has an early onset phenotype known as Wolman disease that primarily affects infants. CESD can present in childhood but often goes unrecognized until adulthood when the underlying pathology is advanced. Many of the signs and symptoms are common to patients with other liver conditions.

CESD is an autosomal recessive genetic condition and is characterized by hepatomegaly, persistently abnormal LFTs and type II hyperlipidemia. Splenomegaly and evidence of mild hypersplenism may affect some patients. Untreated, CESD may lead to fibrosis, cirrhosis, liver failure and death.
Disease Risk In Families:
• 25 per million incidence
• Autosomal recessive disorder, LAL deficiency is carried on chromosome 10
• Parents with an affected son or daughter have a 1 in 4 chance of having another affected child

Diagnosis and Testing

Patients with Cholesteryl Ester Storage Disease typically have elevated cholesterol and triglyceride levels (type II hyperlipidemia) and may present at an early age with the following liver abnormalities:
• Unexplained hepatomegaly
• Elevated transaminases
• Unexplained fatty liver
• Progressive and/or unexplained chronic liver disease

Type II hyperlipidemia in association with unexplained fatty liver or elevated transaminases in more than one sibling in a family would warrant consideration of a diagnosis of CESD.

Patients with CESD are typically investigated for infectious, metabolic and autoimmune liver disease. Imaging may suggest hepatic steatosis and liver biopsies when performed show accumulation of fat in hepatocytes and Kupffer cells. Periportal fibrosis and cirrhosis is not uncommon. Descriptive terms including sea blue Histiocytosis may be applied to the liver abnormalities.

Useful Diagnostic Clues

• Low normal High-density lipoprotein (HDL)(<10th percentile or <35 mg/dL for men and women), especially very low HDL (<5-10 mg/dL)
• Excessive hepatomegaly and/or transaminase increase for a given BMI
• Unusual coexisting lymphadenopathy or enlarged lymph nodes
• Onset of liver abnormalities in childhood
• Clinical suspicion of visceral Niemann Pick not confirmed by enzyme analysis
• An enlarged spleen that is disproportionate in size to the degree of liver involvement/disease

Other Manifestations
• Short stature
• Premature cardiac disease
• Premature stroke
• Malabsorption

Challenges in Diagnosis
Cholesteryl Ester Storage Disease (CESD) is rare and can be difficult to diagnose. Recent studies using genetic analysis suggest that heterozygote carriers of a common disease causing mutation for CESD are more common than previously thought with a carrier frequency for this mutation of about 1 in 200 or 5000 per million. Based on these carrier frequencies and the mutation spectrum of published CESD cases this translates to an estimate of approximately 25 cases of CESD per million births.

Delayed diagnosis may be the result of disease under-recognition and/or symptoms being mistaken for those of other disorders, such as:

• Non-alcoholic fatty liver disease (NAFLD)
• Non-alcoholic steatohepatitis (NASH)
• Alcoholic liver disease
• Cryptogenic Cirrhosis

Clinical diagnosis is based upon presentation of signs, symptoms and laboratory abnormalities (lipids, liver transaminases) and may be confirmed by enzyme assay (blood test) detecting low or absent levels of lysosomal acid lipase or in relatives of affected patients by mutation linkage analysis (blood test).

Treatment

There is no disease modifying treatment for Cholesteryl Ester Storage Disease (CESD). Combining drugs that reduce blood cholesterol with a low cholesterol diet has been effective at reducing some of the symptoms associated with this genetic disorder.

Synageva BioPharma Corp. of Lexington, Massachusetts, is recruiting patients to participate in a clinical trial that evaluates an enzyme replacement therapy of Lysosomal Acid Lipase (LAL) Deficiency. For more information, refer to the Synageva.com.

External links

Synageva BioPharma Corp.
Clinical Trials.gov
Hide and Seek Foundation For Lysosomal Disease Research
Lipid Storage Diseases Fact Sheet at ninds.nih.gov
LAL Solace (Support Organization for LAL Deficiency - Advocacy, Care and Expertise)

References

^[1]

^[2]

^ Sandro Muntoni, Heiko Wiebusch, Marianne Jansen-Rust, Stephan Rust, Udo Seedorf, et al; "Prevalence of Cholesteryl Ester Storage Disease." Journal of the American Heart Association, Arterioscler. Thromb. Vasc. Biol., 2007; 27; 1866-1868
^ Peter J. Meikle; John J. Hopwood; Alan E. Clague; et al. "Prevalence of Lysosomal Storage Disorders." JAMA, 1999; 281(3): 249-254

UpToDate Contents

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1. 小児における原発性副腎不全の原因および臨床症状 causes and clinical manifestations of primary adrenal insufficiency in children
2. アルコール性脂肪性肝炎およびアルコール性肝硬変の臨床症状および診断 clinical manifestations and diagnosis of alcoholic fatty liver disease and alcoholic cirrhosis
3. Causes of cholestasis in neonates and young infants
4. 副腎ステロイド生合成 adrenal steroid biosynthesis
5. 成人における非アルコール性脂肪性肝疾患（NAFLD）の疫学、臨床的特徴、および診断 epidemiology clinical features and diagnosis of nonalcoholic fatty liver disease in adults

English Journal

Ezetimibe markedly attenuates hepatic cholesterol accumulation and improves liver function in the lysosomal acid lipase-deficient mouse, a model for cholesteryl ester storage disease.

Chuang JC1, Lopez AM2, Posey KS3, Turley SD4.Author information 1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, United States. Electronic address: jen-chieh.chuang@utsouthwestern.edu.2Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, United States. Electronic address: adam.lopez@utsouthwestern.edu.3Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, United States. Electronic address: kenneth.posey@utsouthwestern.edu.4Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, United States. Electronic address: stephen.turley@utsouthwestern.edu.AbstractLysosomal acid lipase (LAL) plays a critical role in the intracellular handling of lipids by hydrolyzing cholesteryl esters (CE) and triacylglycerols (TAG) contained in newly internalized lipoproteins. In humans, mutations in the LAL gene result in cholesteryl ester storage disease (CESD), or in Wolman disease (WD) when the mutations cause complete loss of LAL activity. A rat model for WD and a mouse model for CESD have been described. In these studies we used LAL-deficient mice to investigate how modulating the amount of intestinally-derived cholesterol reaching the liver might impact its mass, cholesterol content, and function in this model. The main experiment tested if ezetimibe, a potent cholesterol absorption inhibitor, had any effect on CE accumulation in mice lacking LAL. In male Lal(-/-) mice given ezetimibe in their diet (20 mg/day/kg bw) for 4 weeks starting at 21 days of age, both liver mass and hepatic cholesterol concentration (mg/g) were reduced to the extent that whole-liver cholesterol content (mg/organ) in the treated mice (74.3±3.4) was only 56% of that in those not given ezetimibe (133.5±6.7). There was also a marked improvement in plasma alanine aminotransferase (ALT) activity. Thus, minimizing cholesterol absorption has a favorable impact on the liver in CESD.
Biochemical and biophysical research communications.Biochem Biophys Res Commun.2014 Jan 17;443(3):1073-7. doi: 10.1016/j.bbrc.2013.12.096. Epub 2013 Dec 25.
Lysosomal acid lipase (LAL) plays a critical role in the intracellular handling of lipids by hydrolyzing cholesteryl esters (CE) and triacylglycerols (TAG) contained in newly internalized lipoproteins. In humans, mutations in the LAL gene result in cholesteryl ester storage disease (CESD), or in Wol
PMID 24370824

Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia.

Stitziel NO1, Fouchier SW, Sjouke B, Peloso GM, Moscoso AM, Auer PL, Goel A, Gigante B, Barnes TA, Melander O, Orho-Melander M, Duga S, Sivapalaratnam S, Nikpay M, Martinelli N, Girelli D, Jackson RD, Kooperberg C, Lange LA, Ardissino D, McPherson R, Farrall M, Watkins H, Reilly MP, Rader DJ, de Faire U, Schunkert H, Erdmann J, Samani NJ, Charnas L, Altshuler D, Gabriel S, Kastelein JJ, Defesche JC, Nederveen AJ, Kathiresan S, Hovingh GK; National Heart, Lung, and Blood Institute GO Exome Sequencing Project.Author information 1From the Cardiovascular Division, Department of Medicine (N.O.S.) and Division of Statistical Genomics (N.O.S.), Washington University School of Medicine, Saint Louis, MO; Department of Vascular Medicine (B.S., S.S., J.J.P.K., G.K.H.) Department of Experimental Vascular Medicine (S.W.F., J.C.D), and Radiology (A.J.N.), Academic Medical Center, Amsterdam, The Netherlands; Center for Human Genetic Research, Boston, MA (G.M.P., A.M.M., D.A., S.K.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.M.P., A.M.M., D.A., S.K.); Fred Hutchinson Cancer Research Center, Seattle, WA (P.L.A., C.K.); Wellcome Trust Centre for Human Genetics (A.G., M.F., H.W.) and Cardiovascular Medicine, Radcliffe Department of Medicine (A.G., M.F., H.W.), University of Oxford, Oxford, United Kingdom; Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (B.G., U.d.F.); Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom (T.A.B., N.J.S.); Department of Clinical Sciences, Hypertension and Cardiovascular Diseases (O.M.) and Diabetes and Cardiovascular Disease Genetic Epidemiology (M.O.-M.), Skania University Hospital, Lund University, Malmö, Sweden; Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy (S.D.); Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.N.); Department of Medicine, University of Verona, Verona, Italy (N.M., D.G.); Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus (R.D.J.); Departments of Epidemiology, Genetics and Biostatistics, Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill (L.A.L.); Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy (D.A.); The John & JennifAbstractOBJECTIVE: Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family.
Arteriosclerosis, thrombosis, and vascular biology.Arterioscler Thromb Vasc Biol.2013 Dec;33(12):2909-14. doi: 10.1161/ATVBAHA.113.302426. Epub 2013 Sep 26.
OBJECTIVE: Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not ex
PMID 24072694

Senescent case of cholesterol ester storage disease that progressed to liver cirrhosis with a novel mutation (N250H) of lysosomal acid lipase gene.

Kojima S1, Watanabe N, Takashimizu S, Kagawa T, Shiraishi K, Koizumi J, Hirabayashi K, Ohkubo T, Kamiguchi H, Tsuda M, Mine T.Author information 1Department of Gastroenterology, Tokai University Hachioji Hospital, Tokyo.AbstractThe patient, a 69-year-old man, had a chief complaint of hepatomegaly. The liver was palpated four fingerbreadths below the costal margin, and the spleen was three fingerbreadths below the costal margin. There were no other abnormal findings. Laparoscopy showed that the liver resembled an orange-yellow crayon in appearance and was nodular. The pathological findings of the liver biopsy tissue were consistent with liver cirrhosis. Inside the fibrous septum was an apparent aggregation of enlarged macrophages that phagocytosed lipid components, as well as enlarged Kupffer cells that phagocytosed lipid droplets. Electron microscopy showed the lipid droplets to have a moth-eaten appearance. Using monocytes extracted from the peripheral blood, acid lipase activity was measured by fluorescence spectrometry using 4-methylumbelliferone palmitate as a substrate. This patient's human lysosomal acid lipase activity was 0.020 nM/min per 10(6) cells, corresponding to 5.9% of that in healthy subjects (0.332 ± 0.066 nM/min per 10(6) cells). Cholesterol ester storage disease was therefore diagnosed. The acid lipase A base sequence obtained from leukocytes by direct sequencing was compared with a library. This patient had a point mutation of N250H/N250H in exon 7, a novel gene abnormality that has not previously been reported.
Hepatology research : the official journal of the Japan Society of Hepatology.Hepatol Res.2013 Dec;43(12):1361-7. doi: 10.1111/hepr.12087. Epub 2013 May 15.
The patient, a 69-year-old man, had a chief complaint of hepatomegaly. The liver was palpated four fingerbreadths below the costal margin, and the spleen was three fingerbreadths below the costal margin. There were no other abnormal findings. Laparoscopy showed that the liver resembled an orange-yel
PMID 23675960

Japanese Journal

Molecular defects underlying Wolman disease appear to be more heterogenous than those resulting in cholesterol ester storage disease

LOHSE P.
J. Lipid Res. 40, 221-228, 1999
NAID 80010962741

Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease

ANDERSON R. A.
Mol. Gen. Metab. 68, 333-345, 1999
NAID 30018902351

Cholesterol Ester Storage Diseaseと思われる一症例

川口元也 [他],日高覚,池尻直幹,前山豊明,江口尚久,佐藤晋昭,安倍弘彦,谷川久一,中山和道
肝臓 18(10), 786-794, 1977
… A case of cholesterol-ester storage disease, the first reported case in Japan, was described. … Liver function tests were fairly normal and serum cholesterol and low density lipoprotein were slightly elevated. … Cholesterol ester content in the liver tissue was more than 20 times the normal. …
NAID 130000873422