A Form of Metabolic-Associated Fatty Liver Disease Associated with a Novel LIPA Variant.

BACKGROUND: The LIPA gene on chromosome 10q23.31 contains 10 exons and encodes lipase A, the lysosomal acid lipase (LAL) containing 399 amino acids. Pathogenic variants in the LIPA result in autosomal recessive Wolman disease and cholesteryl ester storage disease (CESD). Here, we report a novel missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA in an Iranian family with fatty liver disease identified by whole-exome sequencing and confirmed by Sanger sequencing. METHODS: A 28-year-old woman referred with lean NASH cirrhosis and extremely high cholesterol levels. Fatty liver disease was found in six of her family members using vibration-controlled transient elastography (VCTE). Baseline routine laboratory tests were performed and whole-exome sequencing and confirmation by Sanger sequencing were done. RESULTS: The index case had severe dyslipidemia and cirrhosis despite a body mass index of 21.09 kg/m2 . Six other family members had dyslipidemia and fatty liver or cirrhosis. A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA which caused LAL-D was found to be associated with fatty liver disease and/or cirrhosis. CONCLUSION: A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of the LIPA gene which caused LAL-D was found to be associated with dyslipidemia, fatty liver disease and/or cirrhosis in six members of an Iranian family. These results should be confirmed by functional studies and extending the study to at least three families.

Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase.

Lysosomal acid lipase (LAL) is the sole lysosomal enzyme responsible for the degradation of cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency (LAL-D), a severe and fatal disease characterized by ectopic lysosomal lipid accumulation. Reduced LAL activity also contributes to the development and progression of non-alcoholic fatty liver disease (NAFLD). To advance our understanding of LAL-related liver pathologies, we performed comprehensive proteomic profiling of livers from mice with systemic genetic loss of LAL (Lal-/-) and from mice with hepatocyte-specific LAL-D (hepLal-/-). Lal-/- mice exhibited drastic proteome alterations, including dysregulation of multiple proteins related to metabolism, inflammation, liver fibrosis, and cancer. Global loss of LAL activity impaired both acidic and neutral lipase activities and resulted in hepatic lipid accumulation, indicating a complete metabolic shift in Lal-/- livers. Hepatic inflammation and immune cell infiltration were evident, with numerous upregulated inflammation-related gene ontology biological process terms. In contrast, both young and mature hepLal-/- mice displayed only minor changes in the liver proteome, suggesting that loss of LAL solely in hepatocytes does not phenocopy metabolic alterations observed in mice globally lacking LAL. These findings provide valuable insights into the mechanisms underlying liver dysfunction in LAL-D and may help in understanding why decreased LAL activity contributes to NAFLD. Our study highlights the importance of LAL in maintaining liver homeostasis and demonstrates the drastic consequences of its global deficiency on the liver proteome and liver function.

Lysosomal Acid Lipase Deficiency: Genetics, Screening, and Preclinical Study.

Lysosomal acid lipase (LAL) is a lysosomal enzyme essential for the degradation of cholesteryl esters through the endocytic pathway. Deficiency of the LAL enzyme encoded by the LIPA gene leads to LAL deficiency (LAL-D) (OMIM 278000), one of the lysosomal storage disorders involving 50-60 genes. Among the two disease subtypes, the severe disease subtype of LAL-D is known as Wolman disease, with typical manifestations involving hepatomegaly, splenomegaly, vomiting, diarrhea, and hematopoietic abnormalities, such as anemia. In contrast, the mild disease subtype of this disorder is known as cholesteryl ester storage disease, with hypercholesterolemia, hypertriglyceridemia, and high-density lipoprotein disappearance. The prevalence of LAL-D is rare, but several treatment options, including enzyme replacement therapy, are available. Accordingly, a number of screening methodologies have been developed for this disorder. This review summarizes the current discussion on LAL-D, covering genetics, screening, and the tertiary structure of human LAL enzyme and preclinical study for the future development of a novel therapy.

Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases.

OBJECTIVES: Lysosomal acid lipase (LAL) is the key enzyme, which degrades neutral lipids at an acidic pH in lysosomes. The role of LAL in various cellular processes has mostly been studied in LAL-knockout mice, which share phenotypical characteristics with humans suffering from LAL deficiency. In vitro, the cell-specific functions of LAL have been commonly investigated by using the LAL inhibitors Lalistat-1 and Lalistat-2. METHODS: We performed lipid hydrolase activity assays and serine hydrolase-specific activity-based labeling combined with quantitative proteomics to investigate potential off-target effects of Lalistat-1 and -2. RESULTS: Pharmacological LAL inhibition but not genetic loss of LAL impairs isoproterenol-stimulated lipolysis as well as neutral triglyceride and cholesteryl ester hydrolase activities. Apart from LAL, Lalistat-1 and -2 also inhibit major cytosolic lipid hydrolases responsible for lipid degradation in primary cells at neutral pH through off-target effects. Their binding to the active center of the enzymes leads to a decrease in neutral lipid hydrolase activities in cells overexpressing the respective enzymes. CONCLUSIONS: Our findings are critically important since they demonstrate that commonly used concentrations of these inhibitors are not suitable to investigate the role of LAL-specific lipolysis in lysosomal function, signaling pathways, and autophagy. The interpretation of their effects on lipid metabolism should be taken with caution and the applied inhibitor concentrations in cell culture studies should not exceed 1 µM.

Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth.

Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency.

Effect of a common missense variant in LIPA gene on fatty liver disease and lipid phenotype: New perspectives from a single-center observational study.

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disease characterized by hypoalphalipoproteinemia, mixed hyperlipemia, and fatty liver (FL) due to mutations in LIPAse A, lysosomal acid type (LIPA) gene. The rs1051338 single-nucleotide polymorphism (SNP) in LIPA gene, in vitro, could adversely affect the LAL activity (LAL-A). Nonalcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome, and the diagnosis requires the exclusion of excess of alcohol intake and other causes of hepatic disease. The aim of the study was to evaluate the impact of rs1051338 rare allele on lipid phenotype, severity of FL, and LAL-A in patients suffering from dyslipidemia associated with NAFLD. We selected 74 subjects with hypoalphalipoproteinemia or mixed hyperlipemia and evaluated transaminases, liver assessment with controlled attenuation parameter (CAP), LAL-A, rs1051338 SNP genotype. The presence of rare allele caused higher levels of triglycerides and hepatic transaminase and lower levels of high-density lipoprotein cholesterol (HDL-C). Multivariate analysis highlighted independent association between rare allele and FL severity in subjects with NAFLD. The rs1051338 SNP may modulate FL severity and atherogenic dyslipidemia in patients suffering from NAFLD.

Evaluation of two approaches to lysosomal acid lipase deficiency patient identification: An observational retrospective study.

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency (LALD) leads to the accumulation of cholesteryl esters and/or triglycerides (TG) in lysosomes due to the lack of the enzyme codified by the LIPA gene. The most common symptoms are dyslipidaemia and hypertransaminasemia, together with manifestations common to other lysosomal storage disorders (LSDs), including visceromegalies and elevated plasma biomarkers. Alteration of the lipid-liver profile (LLP) has been widely applied as a criterion for LALD screening, but the usefulness of biomarkers has not yet been explored. Our purpose was to explore the utility of plasma chitotriosidase activity (ChT) and CCL18/PARC concentration in addition to LLP to identify LALD patients in an observational retrospective study of two different sample collections. METHODS: Biological samples refining: Collection 1 (primary hypercholesterolemia suspected) included unrelated individuals with hyperlipidaemia and without LDLR, APOB and PCSK9 gene mutations (Set 1), and Collection 2 (LSD suspected) included individuals without definitive LSD diagnosis (Set 2). We assessed plasma LLP (total cholesterol and its fractions, TG concentration and transaminases activities), as well as plasma ChT and CCL18/PARC. All subjects with anomalous LLP and/or biomarker levels were LIPA sequenced. RESULTS: Twenty-four subjects showed altered LLP and/or biomarkers. We identified two LALD patients (one homozygous and one compound heterozygous) and one carrier of a novel LIPA variant. CONCLUSIONS: The measurement of plasma ChT and CCL18/PARC combined with LLP will be a useful approach to identifying LALD patients in retrospective LALD patient studies.

Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target.

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for metabolic purposes in the cell. The process also occurs in immune cells that adapt their metabolic machinery to cope with the different energetic requirements associated with cell activation, proliferation, and polarization. LAL deficiency (LALD) causes severe lipid accumulation and affects the immunometabolic signature in animal models. In humans, LAL deficiency is associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis. These observations suggest that LAL might play an important role in cellular immunometabolic modulation, and availability of an effective enzyme replacement strategy makes LAL an attractive target to rewire the metabolic machinery of immune cells beyond its role in controlling cellular lipid metabolism.

Screening for lysosomal acid lipase deficiency: A retrospective data mining study and evaluation of screening criteria.

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency (LAL-D) is a lysosomal storage disorder. In severe cases, it can cause life-threatening organ failure due to lipid substrates accumulation. However, mild phenotypes of this disorder are increasingly recognized. The aim of this study is to determine the number of missed LAL-D patients in a large pediatric hospital population. METHODS: In a retrospective data mining study, the medical files of children, who visited the outpatient clinic at a university hospital between 2000 and 2016, with high plasma low density lipoprotein cholesterol (LDL-C) levels, were evaluated. Previously developed LAL-D screening criteria, with lipid and alanine aminotransferase (ALT) values adjusted for children, were used to analyze which children are suspect for LAL-D. For suspicion of LAL-D, at least 3 out of 5 screening criteria had to be met. Subsequently data on presentation and follow-up were collected to determine if the clinical picture was compatible with LAL-D. RESULTS: We identified 2037 children with high LDL-C levels. Of those, 36 children complied with ≥3 screening criteria. Thirty-one of those had an underlying disorder other than LAL-D that explained the abnormalities and, in the 5 remaining children, ALT and lipid levels normalized spontaneously, thus excluding LAL-D. CONCLUSIONS: This study shows that retrospective data mining is unlikely to yield a significant number of LAL-D cases in children. The screening algorithm adjusted for children seems useful and accurate in the selection of children for further testing, suggesting it can be applied prospectively, although further validation is warranted.

Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies.

PURPOSE OF REVIEW: Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride delivered to the lysosome. This review highlights the novel pathophysiological role of LAL, the functional genomic discoveries of LIPA as a risk locus for coronary heart diseases (CHD), and the clinical advance in therapies for LAL deficiency. RECENT FINDINGS: The essential role of LAL in lipid metabolism has been confirmed in human and mice with LAL deficiency. In humans, loss-of-function mutations of LIPA cause rare lysosomal disorders, Wolman disease, and cholesteryl ester storage disease, in which LAL enzyme replacement therapy has shown significant benefits in a phase 3 clinical trial. Recent studies have revealed the role of LAL-mediated lysosomal lipolysis in regulating macrophage M2 polarization, lipid mediator production, VLDL secretion, lysosomal function and autophagy, extracellular degradation of aggregated-LDL, and adipose tissue lipolysis. Genome-wide association studies and functional genomic studies have identified LIPA as a risk locus for CHD, but the causal variants and mechanisms remain to be determined. SUMMARY: Despite years of research, our understanding of LAL is incomplete. Future studies will continue to focus on the key pathophysiological functions of LAL in health and diseases including CHD.

Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis.

Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester storage disease, atherosclerosis and Alzheimer's disease, Niemann-Pick type C and Tangier disease is described.

Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics.

BACKGROUND: Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. RESULTS: We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. CONCLUSION: The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development.

Childhood/adult-onset lysosomal acid lipase deficiency: A serious metabolic and vascular phenotype beyond liver disease-four new pediatric cases.

BACKGROUND: The childhood/adult-onset lysosomal acid lipase deficiency (LALD; late-onset LALD) is a rare genetic disease. Children present severe fatty liver disease with early cirrhosis. Before enzyme replacement therapy, statins were the standard treatment to improve the severe dyslipidemia. However, late-onset LALD should be considered as a systemic metabolic disease: chronic hyper-low-density lipoprotein and hypo-high-density lipoprotein cholesterolemia induces early atherosclerosis in addition to the liver morbidity. OBJECTIVE: To assess 4 new pediatric cases of late-onset LALD with an evaluation of hepatic, metabolic, and vascular evolution under statin. METHODS: Four patients were retrospectively described. Anthropometric data (weight, height, and body mass index) and laboratory data (LIPA mutations, acid lipase residual activity, liver and lipid profile, and homeostatic model assessment index) were collected. Liver histology was assessed by the noninvasive tests FibroScan and FibroTest and confirmed by liver biopsy. Vascular impact was followed up by carotid intima-media thickness (cIMT) assessment. RESULTS: The 4 cases of late-onset LALD came from 2 families, each with a boy (aged 8.6 and 11 years at diagnosis) and a girl (aged 10.6 and 13 years at diagnosis). Treatment with statins was performed for 8 and 5 years, respectively, from diagnosis. Statins decreased the low-density lipoprotein cholesterol mean value of 40%. All children showed significant liver fibrosis (F3 [n = 3]; F2 [n = 1]). cIMT showed the following for all children: abnormal measures without improvement and atherosclerotic plaques. One child developed a deleterious metabolic phenotype with obesity and insulin resistance (homeostatic model assessment = 3.08) associated with higher mean hepatic transaminases (149 vs 98, 88, and 61 IU/L) and increased mean cIMT values (raising from 0.47 to 0.5 mm vs 0.43 and 0.43 mm). CONCLUSION: Late-onset LALD is a rare metabolic disease with a larger impact than liver disease. Our work shows the importance of having a global metabolic view and to evaluate the cardiovascular impact of the new enzymatic treatment.

Managing Cardiovascular Risk in Lysosomal Acid Lipase Deficiency.

Lysosomal acid lipase deficiency (LAL-D) is a rare, life-threatening, autosomal recessive, lysosomal storage disease caused by mutations in the LIPA gene, which encodes for lysosomal acid lipase (LAL). This enzyme is necessary for the hydrolysis of cholesteryl ester and triglyceride in lysosomes. Deficient LAL activity causes accumulation of these lipids in lysosomes and a marked decrease in the cytoplasmic free cholesterol concentration, leading to dysfunctional cholesterol homeostasis. The accumulation of neutral lipid occurs predominantly in liver, spleen, and macrophages throughout the body, and the aberrant cholesterol homeostasis causes a marked dyslipidemia. LAL-D is characterized by accelerated atherosclerotic cardiovascular disease (ASCVD) and hepatic microvesicular or mixed steatosis, leading to inflammation, fibrosis, cirrhosis and liver failure. LAL-D presents as a clinical continuum with two phenotypes: the infantile-onset phenotype, formally referred to as Wolman disease, and the later-onset phenotype, formerly referred to as cholesteryl ester storage disease. Infants with LAL-D present within the first few weeks of life with vomiting, diarrhea, hepatosplenomegaly, failure to thrive and rapid progression to liver failure and death by 6-12 months of age. Children and young adults with LAL-D generally present with marked dyslipidemia, hepatic enzyme elevation, hepatomegaly and mixed steatosis by liver biopsy. The average age of the initial signs and symptoms of the later-onset phenotype is about 5 years old. The typical dyslipidemia is a significantly elevated low-density lipoprotein cholesterol (LDL-C) concentration and a low high-density lipoprotein cholesterol (HDL-C) concentration, placing these individuals at heightened risk for premature ASCVD. Diagnosis of the later-onset phenotype of LAL-D requires a heightened awareness of the disease because the dyslipidemia and hepatic transaminase elevation combination are common and overlap with other metabolic disorders. LAL-D should be considered in the differential diagnosis of healthy weight children and young adults with unexplained hepatic transaminase elevation accompanied by an elevated LDL-C level (>160 mg/dL) and low HDL-C level (<35 mg/dL) that is not caused by monogenic and polygenic lipid disorders or secondary factors. Treatment of LAL-D with sebelipase alfa (LAL replacement enzyme) should be considered as the standard of treatment in all individuals diagnosed with LAL-D. Other ASCVD risk factors that may be present (hypertension, tobacco use, diabetes mellitus, etc.) should be managed appropriately, consistent with secondary prevention goals.

Lysosomal acid lipase deficiency: Expanding differential diagnosis.

The differential diagnoses for metabolic liver diseases may be challenging in clinical settings, which represents a critical issue for disorders such as lysosomal acid lipase deficiency (LAL-D). LAL-D is caused by deficient activity of the LAL enzyme, resulting in the accumulation of cholesteryl esters and triglycerides throughout the body, predominately in the liver, spleen, gastrointestinal tract, and blood vessel walls. LAL-D is a progressive, multi-organ disease with early mortality and significant morbidity characterized by a combination of hepatic dysfunction and dyslipidemia. Evidence suggests LAL-D may be substantially underdiagnosed or misdiagnosed, which is critical given that disease progression can be unpredictable, with liver failure and/or accelerated atherosclerosis potentially contributing to early mortality. However, given the development of a simple diagnostic test and recently approved treatment, LAL-D should be incorporated into the differential diagnosis in relevant clinical settings. LAL-D can be diagnosed using an LAL enzyme-based biochemical test, thereby allowing for active monitoring of patients to detect potential disease complications and consider treatment options including diet, lipid-lowering medication, and treatment with sebelipase alfa, a recombinant enzyme replacement therapy shown to provide clinical benefit and improve disease-relevant markers in clinical trials. To illustrate the complexity of diagnosing LAL-D, this manuscript will describe the path to diagnosing LAL-D in a series of patient cases in which LAL-D was diagnosed as well as in patients where other diseases, such as Gaucher disease and Niemann-Pick disease, were initially suspected.

Identification and metabolic profiling of patients with lysosomal acid lipase deficiency.

BACKGROUND: Lysosomal acid lipase (LAL), encoded by the LIPA gene, catalyzes the intracellular hydrolysis of cholesteryl esters and triglycerides in hepatocytes and macrophages. LIPA defects cause accumulation of these lipids in lysosomes. LAL deficiency (LAL D) presents and progresses as a continuum with dyslipidemia, hepatomegaly, and liver fibrosis. OBJECTIVE: To improve the understanding of the genetic basis of LAL D, an underappreciated cause of dyslipidemia and cirrhosis, we studied DNA samples from patients with various phenotypes of dyslipidemia. METHODS: Participants (N = 1357) were identified by lipid profiles and screened for the common disease causing LIPA exon 8 skipping splice-site mutation (c.894G>A; p.Ser275_Gln298del; rs116928232). RESULTS: Six patients were heterozygous for this variant. Complete LIPA sequencing revealed a patient, subsequently confirmed to have LAL D, with a heterozygous frameshift mutation involving deletion of exon 4 (p.Gly77Valfs*17 c.230-106_c.428+541del). A family study revealed a sister with the same genotype and phenotype. Genetic, clinical, and lipoprotein profiles of these sisters plus 6 additional family members are reported. Profiles of 2 other LAL D patients monitored for 2 decades are presented. Cholesterol homeostasis was studied to investigate rates of cholesterol synthesis and absorption in 4 LAL D patients. High-density lipoprotein (HDL) subspecies were also analyzed. CONCLUSIONS: We used this LIPA sequencing strategy (detection of the relatively common exon 8 variant followed by complete gene sequencing to identify additional mutations) as a means to further elucidate the genetic basis of LAL D among individuals with a suggestive clinical phenotype.

Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation.

UNLABELLED: The lysosomal acid lipase (LAL) is the enzyme responsible of the hydrolysis of cholesteryl esters and triglycerides within endo-lysosomes. Loss of enzyme activity leads to accumulation of cholesteryl esters and triglycerides in the lysosome of most tissues. The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition which may be genetically determined or secondary to infections, malignancies, immune deficiencies, and rheumatologic disorders. So far, some inborn errors of metabolism have been associated with HLH (e.g., lysinuric protein intolerance, Gaucher's disease), and it has been anecdotally described in three WD patients, without any specific pathogenetic hypothesis. Here, we report on a WD patient, showing clear clinical, biochemical, and histological features indicative of HLH. We discuss the pathophysiological role of cholesteryl ester-induced inflammasome activation in macrophages, leading to a secondary HLH. CONCLUSION: This case indicates that WD can cause secondary HLH and suggests that a careful metabolic workup should be performed when facing to a pediatric patient with HLH.

Lysosomal acid lipase deficiency: wolman disease and cholesteryl ester storage disease.

Cholesteryl ester storage disease (CESD, OMIM #278000) and Wolman disease (OMIM #278000) are autosomal recessive lysosomal storage disorders caused by a deficient activity of lysosomal acid lipase (cholesteryl ester hydrolase, LAL). Human lysosomal acid lipase is essential for the metabolism of cholesteryl esters and triglycerides. In Wolman disease, LAL activity is usually absent, whereas CESD usually presents some residual LAL activity. In infants, poor weight gain, massive hepatosplenomegaly, calcified adrenal glands (present about 2/3 of the time), vomiting, diarrhea and failure to thrive are indicative of Wolman disease. The clinical picture is more variable in CESD. Hepatomegaly and/or elevation of liver transaminases are almost always present. Hepatic steatosis often leads to fibrosis and cirrhosis. Other signs often include splenomegaly, high total cholesterol and LDL-cholesterol, elevated triglycerides, and low HDL-cholesterol. The diagnosis of LAL deficiency requires clinical experience and specialized laboratory tests. The diagnosis is based on finding deficient activity of acid lipase and/or molecular tests. Pilot screening projects using dried blood spot testing in 1) children with atypical fatty liver disease in the absence of overweight, 2) patients with dyslipidaemia and presence of hepatomegaly and/or elevated transaminases, 3) newborns/neonates with hepatomegaly and abdominal distension/failure to thrive/elevated transaminases are currently underway. Early diagnosis is particularly important for the enzyme replacement therapy. Human trials with recombinant LAL are currently ongoing, raising the prospect for specific correction of LAL deficiency in this progressive and often debilitating disorder.