Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficiency of amylo-1,6-glucosidase, 4-alpha-glucanotransferase enzyme (AGL or glycogen debrancher enzyme) is responsible for glycogen storage disease type III, a rare autosomal recessive disorder of glycogen metabolism. The AGL gene is located on chromosome 1p21, and contains 35 exons translated in a monomeric protein product. The disease has recognized clinical and biochemical heterogeneity, reflecting the genotype-phenotype heterogeneity among different subjects. The clinical manifestations of GSD III are represented by hepatomegaly, hypoglycemia, hyperlipidemia, short stature and, in a number of subjects, cardiomyopathy and myopathy. In this article, we discuss the genotypic-phenotypic heterogeneity of GSD III by the molecular characterization of mutations responsible for the disease on a collection of 18 independent alleles from the Mediterranean area. We identified by heteroduplex band shift, DNA direct sequencing, and restriction analysis, seven novel mutations (four nonsense point-mutations: R34X, S530X, R1218X, W1398X; two microinsertions: 1072insT and 4724insAA; and one bp deletion: 676DeltaG), together with two new cases carrying a IVS21 + 1 G --> A splicing site mutation previously described in Italian patients. Altogether, 15 alleles were characterized. The correlation between type of mutation and clinical severity was studied in six patients in whom both mutated alleles were detected. Our data confirm the extreme genetic heterogeneity of this disease, thus precluding a strategy of mutation finding based on screening of recurrent common mutations.
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PMID:Clinical and genetic variability of glycogen storage disease type IIIa: seven novel AGL gene mutations in the Mediterranean area. 1197 76

Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes glycogen storage disease type Ia (GSD-Ia), an autosomal recessive disorder characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. G6Pase is an endoplasmic reticulum-associated transmembrane protein expressed primarily in the liver and the kidney. Therefore, enzyme replacement therapy is not feasible using current strategies, but somatic gene therapy, targeting G6Pase to the liver and the kidney, is an attractive possibility. Previously, we reported the development of a mouse model of G6Pase deficiency that closely mimics human GSD-Ia. Using neonatal GSD-Ia mice, we now demonstrate that a combined adeno virus and adeno-associated virus vector-mediated gene transfer leads to sustained G6Pase expression in both the liver and the kidney and corrects the murine GSD-Ia disease for at least 12 months. Our results suggest that human GSD-Ia would be treatable by gene therapy.
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PMID:Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice. 1218 68

Insulin resistant metabolic syndrome is a major clinical disorder including hyperlipidaemia, hypertension, impaired glucose tolerance and/or type 2 diabetes and central obesity, which are well established cardiovascular risk factors. We report the case of a 61-year-old woman who developed severe hypercholesterolaemia and hypertriglyceridaemia after liver transplantation. In her forties she had hypertension, mixed hyperlipidaemia, mild hyperglycaemia and moderate abdominal obesity, suggesting the presence of the metabolic syndrome. She had liver enzyme elevation and severe steatosis and hepatomegaly at ultrasonography. At age 52, cryptogenic liver cirrhosis was diagnosed and rapidly progressing liver failure developed. In 1992 she underwent liver transplantation. Seven years after transplant the patient had abdominal obesity, high blood pressure, marked hypercholesterolaemia, hypertriglyceridaemia and moderate elevation of alanine aminotransferase. She also had impaired glucose tolerance and markedly increased basal and post-glucose load plasma insulin levels. Steatohepatitis was demonstrated by serial liver biopsies. This is the first case that reports the recurrence of the metabolic syndrome following liver transplantation. We postulate that metabolic syndrome may have promoted fatty liver and subsequent progression to end stage liver disease. We also stress the need for careful management of the metabolic syndrome in order to decrease the long-term risk for cardiovascular disease.
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PMID:Recurrence of insulin resistant metabolic syndrome following liver transplantation. 1254 3

OBJECTIVE: To o present up-to-date knowledge about Glycogen storage disease type I (GSD-type I) - a disease caused by the deposit of glycogen resulting from the deficiency of the enzyme glucose-6- phosphatase - and to provide the pediatricians with the necessary information for a precocious diagnosis and an adequate conduct for those cases where this metabolic disturbance is present. METHODS: Through Medline, the most significant articles published during the last 20 years were selected from national and international journals of medicine, with special attention to dietary treatment of glycogen storage disease type I. RESULTS: The metabolism of glycogen and the metabolic consequences of glycogen storage disease type I were discussed, especially hypoglycemia, the principal metabolic disturbance of the disease. The clinical and laboratory findings are described together with the histopathology. The use of uncooked cornstarch and enteral carbohydrate infusion are the means used for the maintenance of normoglycemia. The control of hyperuricemia, hyperlipidemia and platelet disorders are other aspects of the treatment as well as the prevention of infections and the use of G-CSF for glycogen storage type Ib. Hepatic transplant and its principal indications are commented on. Hepatic adenomae, which always have the potential of malignant transformation, are the results of incomplete treatment. CONCLUSIONS: Although it occurs rarely, glycogen storage type I is an important cause of volumous hepatomegaly which is associated with hypoglycemia among the infants. The dietary treatment of this illness has significantly altered the clinical course and has improved the prognosis. Therefore it is indispensable that the general pediatrician should be familiar with the diagnosis of this clinical state so as to act rigorously in favor of the dietary control.
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PMID:[Glycogenosis type I] 1468 23

We retrospectively studied the records of 6 Malaysian children who were diagnosed with Alagille Syndrome (AGS) according to this criteria from January 1999 to January 2001, at the Institute of Paediatrics, Kuala Lumpur Hospital. Four patients (66%) had a positive family history. Thirteen individuals (6 patients and 7 relatives) were diagnosed with AGS in these 5 families. Only 6/13 (46%) of them presented with liver involvement. All 6 patients presented with typical facies and cholestasis (100%). Three (50%) presented with portal hypertension (PHT) with synthetic liver dysfunction (1 died), 1/6 (17%) have PHT and normal synthetic liver function. Two have cleared their jaundice but have biochemical evidence of hepatitis and hepatomegaly, four have congenital heart disease 5/6 posterior embryotoxon, 2/6 butterfly vertebrae, 4/6 hyperlipidaemia and 4/6 failure to thrive. One patient has a Jagged-1 gene disruption at the translocation breakpoint locus 20p12.3 2n = 46,XX,t(12.20) (q22, p12.3). 5/6 (83%) are still alive. Two-thirds of our patients developed chronic liver disease by 3 years of age. Two-thirds of the index patients have a family history. Only 46% of individuals in these families have clinical evidence of liver involvement. Mortality depends on cardiac/renal disease, end-stage liver failure and intercurrent infection.
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PMID:Morbidity in Alagille syndrome in 6 Malaysian children. 1519 Jun 47

Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein predominantly expressed in adipose tissue and liver. Several recent studies demonstrated that ANGPTL4 is the target gene of peroxisome proliferation activators, the agonists of which are widely used as the antidiabetic and lipid-lowering drugs. Here we provide evidence that ANGPTL4 is a blood-borne hormone directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. Adenovirus-mediated expression of ANGPTL4 potently decreased blood glucose and improved glucose tolerance, whereas it induced hyperlipidemia, fatty liver, and hepatomegaly in C57 mice. In db/db diabetic mice, ANGPTL4 treatment reduced hyperglycemia to a normal level, and markedly alleviated glucose intolerance and hyperinsulinemia. Ex vivo studies on primary rat hepatocytes revealed that ANGPTL4 significantly decreased hepatic glucose production and enhanced insulin-mediated inhibition of gluconeogenesis. Serum levels of ANGPTL4 in human subjects inversely correlated with plasma glucose concentrations and HOMA IR, the homeostasis model assessment of insulin resistance. In patients with type 2 diabetes, serum levels of ANGPTL4 were significantly lower than those in healthy subjects, suggesting that the decreased ANGPTL4 could be a causative factor of this disease. These results collectively indicate that ANGPTL4 exerts distinct effects on glucose and lipid metabolism, and that its beneficial effect on glucose homeostasis might be useful for the treatment of diabetes.
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PMID:Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. 1583 23

Non-alcoholic steatohepatitis (NASH) represents only a part of a wide spectrum of non-alcoholic fatty liver disease (NAFLD) and its prevalence is only 2 - 3% in the general population. Obesity, diabetes, hyperlipidemia and female sex are important risk factors for NASH. Two hit theory describes very well the pathogenesis of NASH wherein hepatic steatosis, the first hit is followed up by the second hit, one of which may be reactive oxygen species. Mitochondria is the main source of reactive oxygen species which may trigger steatohepatitis by lipid peroxidation, cytokine induction or induction of fas-ligand. Insulin resistance syndrome is the only metabolic syndrome that has been consistently associated with NASH. The diagnosis rests on the hallmark histological features and rigorous exclusion of significant alcohol consumption. Most patients are asymptomatic, have mild-to-moderate elevations of serum aminotransferase levels, clinical hepatomegaly and features of fatty liver on imaging. Liver biopsy is essential for positive diagnosis and prognostication of NASH. Histologically, fat deposition is typically macrovesicular and inflammation of steatohepatitis is predominantly lobular. Neutrophilic cells in lobular inflammatory infilterate are a distinguishing feature of steatohepatitis and differentiate it from other chronic hepatitis. The pattern of collagen deposition is perivenular & peri-sinusoidal spaces in zone 3. NASH is a progressive disease in more than one in four and has spontaneous regression in less than one in six. Therapy options include weight reduction in obese, good control in diabetics and exercise. Ursodeoxycholic acid has membrane stabilizing, cytoprotective and immunological effect and normalizes raised transaminases. Liver transplantation has been done in NASH but transplanted liver shows re-development in more than two thirds. Many more therapies are in the pipeline and show promise for the future.
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PMID:Non-alcoholic steatohepatitis. 1592 3

A 45-year-old patient with von Gierke disease was scheduled for emergency operation due to acute appenditis. He had a significant hepatomegaly and was on oral medication for hyperlipemia and hyperlithuria. General anesthesia was induced with thiopental and suxamethonium, and maintained with nitrous oxide, oxygen, sevoflurane and vecuronium. The perioperative course was uneventful, although the patient revealed mild metabolic acidosis.
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PMID:[Anesthetic management for an emergency operation in a patient with von Gierke disease]. 1610 54

Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin resistance, which can be seen in patients of NASH are lipomatosis, lipoatrophy/lipodystrophy and panniculitis. Most other rare conditions known to cause NASH like peroxisomal diseases, mitochondialpathies, Weber-Christian disease, Mauriac syndrome, Madelung's lipomatosis and abetaliopprotenemia also have insulin resistance. This is believed that primary defect underlying insulin resistance is impairment in postreceptor pathways (through tyrosine kinase activity) of insulin action. Primary defect in insulin receptors appear uncommon. This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. As a result, monocyte glucose uptake by GLUT4 increases glucose disposal from blood and reduced need for insulin. PKC-0 is a likely candidate as serine kinase in muscle regulated by fatty acids that can impair the activation of IRS-1. Insulin resistance is usually evaluated by fasting insulin levels, Quantitative Insulin Check Index (QUICKI) and Homeostasis Model Assessment of Insulin Resistance (HOMA), C-peptid/insulin ratio oral glucose tolerance test and hyper insulinemic euglycemic clamp. The clamp technique is considered the gold standard.
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PMID:Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH). 1619 20

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue since birth and insulin resistance. The diagnosis is made on the basis of lack of body fat, muscular hypertrophy, acanthosis nigricans, hirsutism, hepatomegaly with fatty liver, hyperlipidemia and hyperglycemia with insulin resistance. We describe a 4-year-old Chinese girl with the clinical features of CGL.
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PMID:Congenital generalized lipodystrophy in a 4 year old Chinese girl. 1626 43


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