Liver disease and dyslipidemia as a manifestation of lysosomal acid lipase deficiency (LAL-D). Clinical and  diagnostic aspects, and a new treatment. An update

Bay, Luisa; Velasco, Cristina Canero; Ciocca, Mirta; Cotti, Andrea; Cuarterolo, Miriam; Fainboim, Alejandro; Fassio, E; Galoppo, Marcela; Piñero, Federico; Rozenfeld, Paula

doi:10.5546/aap.2017.eng.287

Cited by 10 publications

(13 citation statements)

References 38 publications

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“…Compared to mild or absent features in CESD, WD has marked hepatomegaly, splenomegaly, malabsorption, growth failure and dyslipidemia. And 50% of WD have adrenal calcification which is rarely found in CESD[ 66 ]. The two entities are described separately.…”

Section: Lal-dmentioning

confidence: 99%

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Natural history and management of liver dysfunction in lysosomal storage disorders

Sarma¹,

Tripathi²

2022

World J Hepatol

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Lysosomal storage disorders (LSD) are a rare group of genetic disorders. The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage [Gaucher disease (GD) and Niemann-Pick disease] and lysosomal acid lipase deficiency [cholesteryl ester storage disease and Wolman disease (WD)]. These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension. Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders. Dyslipidemia causes micronodular cirrhosis in lipid storage disorders. These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults. GD, Niemann-Pick type C, and WD also cause neonatal cholestasis and infantile liver failure. Genotype and liver phenotype correlation is variable in these conditions. Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease. The diagnosis of all LSD is based on enzymatic activity, tissue histology, and genetic testing. Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome. Those that progress invariably require liver transplantation with variable outcomes. The prognosis of Niemann-Pick type C and WD is universally poor. Enzyme replacement therapy has a promising role in cholesteryl ester storage disease. This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.

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Section: Lal-dmentioning

confidence: 99%

“…CESD should be suspected in non-obese patients with hepatomegaly and unexplained hypertransaminasemia with abnormal lipid profile (low HDL and high LDL)[ 65 , 66 ].…”

Section: Cesdmentioning

confidence: 99%

Natural history and management of liver dysfunction in lysosomal storage disorders

Sarma¹,

Tripathi²

2022

World J Hepatol

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“…Недавние исследования установили, что умеренный ненаследственный дефицит ЛКЛ может играть значимую роль в развитии неалкогольной жировой болезни печени (НАЖБП) и криптогенного цирроза печени у детей и взрослых [18][19][20][21][22][23][24].…”

Section: трудный диагнозunclassified

“…БНЭХ необходимо включать в дифференциально-диагностический алгоритм при наличии у ребенка любого возраста гепатоспленомегалии и повышения печеночных трансаминаз в сочетании с гиперхолестеринемией и гипертриглицеридемией. ДЛКЛ может быть заподозрен у больных с неалкогольной жировой болезнью печени и криптогенным циррозом печени [24]. Дислипидемия, развиваю щаяся у больных с ДЛКЛ, может быть ошибочно расценена как проявление семейной гиперхолестеринемии.…”

Section: трудный диагнозunclassified

Lysosomal acid lipase deficiency – an underestimated cause of hypercholesterolemia in children

et al. 2022

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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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“…Fasting plasma dyslipidemia is characterized by increased TAG and LDL-cholesterol content, and accompanied by increased apolipoprotein-B levels, while HDL-cholesterol content is decreased, indicative for increased VLDL secretion [59,151]. In Wolman disease, secondary abnormalities due to chronic diarrhea and malabsorption may lead to a decline of fat in subcutaneous tissue [152,153].…”

Section: Targeting Lalmentioning

confidence: 99%

Genetically modified mouse models to study hepatic neutral lipid mobilization

Haemmerle¹,

Lass²

2019

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Excessive accumulation of triacylglycerol is the common denominator of a wide range of clinical pathologies of liver diseases, termed non-alcoholic fatty liver disease. Such excessive triacylglycerol deposition in the liver is also referred to as hepatic steatosis. Although liver steatosis often resolves over time, it eventually progresses to steatohepatitis, liver fibrosis and cirrhosis, with associated complications, including liver failure, hepatocellular carcinoma and ultimately death of affected individuals. From the disease etiology it is obvious that a tight regulation between lipid uptake, triacylglycerol synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent triacylglycerol deposition in the liver. In addition to triacylglycerol, also a tight control of other neutral lipid ester classes, i.e. cholesteryl esters and retinyl esters, is crucial for the maintenance of a healthy liver. Excessive cholesteryl ester accumulation is a hallmark of cholesteryl ester storage disease or Wolman disease, which is associated with premature death. The loss of hepatic vitamin A stores (retinyl ester stores of hepatic stellate cells) is incidental to the onset of liver fibrosis. Importantly, this more advanced stage of liver disease usually does not resolve but progresses to life threatening stages, i.e. liver cirrhosis and cancer. Therefore, understanding the enzymes and pathways that mobilize hepatic neutral lipid esters is crucial for the development of strategies and therapies to ameliorate pathophysiological conditions associated with derangements of hepatic neutral lipid ester stores, including liver steatosis, steatohepatitis, and fibrosis. This review highlights the physiological roles of enzymes governing the mobilization of neutral lipid esters at different sites in liver cells, including cytosolic lipid droplets, endoplasmic reticulum, and lysosomes. This article is part of a Special Issue entitled Molecular Basis of Disease: Animal models in liver disease.

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Liver disease and dyslipidemia as a manifestation of lysosomal acid lipase deficiency (LAL-D). Clinical and diagnostic aspects, and a new treatment. An update

Cited by 10 publications

References 38 publications

Natural history and management of liver dysfunction in lysosomal storage disorders

Natural history and management of liver dysfunction in lysosomal storage disorders

Lysosomal acid lipase deficiency – an underestimated cause of hypercholesterolemia in children

Genetically modified mouse models to study hepatic neutral lipid mobilization

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