Brief report
Pediatric patients with lysosomal acid lipase deficiency
Pacientes pediátricos con deficiencia de lipasa ácida lisosomal
David A. Suarez-Zamoraa, Maria M. Rojas-Rojasb, Felipe Ordoñez-Guerreroc, Jacqueline Mugnier-Quijanod, Rocio Lopez-Panquevaa,e,
Corresponding author
a Department of Pathology and Laboratories, Fundación Santa Fe de Bogotá, Bogotá, DC, Colombia
b Department of Diagnostic Imaging, Fundación Santa Fe de Bogotá, Bogotá, DC, Colombia
c Section of Pediatric Gastrohepatology, Fundación Cardioinfantil, Bogotá, DC, Colombia
d Section of Pathology, Fundación Cardioinfantil, Bogotá, DC, Colombia
e School of Medicine, Universidad de los Andes, Bogotá, DC, Colombia
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(confidencial, enviado).</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">AC: adenocarcinoma; ALK: <span class="elsevierStyleItalic">anaplastic lymphoma kinase</span>; BRAF: <span class="elsevierStyleItalic">B-Raf proto-oncogene</span>; CPNCP: carcinoma de pulmón de células no pequeñas; CPNCP-NE: CPNCP subtipo no especificado; EGFR: <span class="elsevierStyleItalic">epidermal growth factor receptor</span>; FISH: hibridación fluorescente <span class="elsevierStyleItalic">in situ</span>; H&E: <span class="elsevierStyleItalic">haematoxylin and eosin</span>; IHQ: inmunohistoquímica; KRAS: <span class="elsevierStyleItalic">kirsten rat sarcoma virus</span>; MET: <span class="elsevierStyleItalic">mesenchymal epithelial transition factor</span>; NGS: <span class="elsevierStyleItalic">next-generation sequencing</span>; NTRK: <span class="elsevierStyleItalic">neurotrophic tyrosine receptor kinase</span>; PCR: <span class="elsevierStyleItalic">polymerase chain reaction</span>; PD-L1: <span class="elsevierStyleItalic">programmed death ligand-1;</span> RET: <span class="elsevierStyleItalic">rearranged during transfection</span>; ROS1: <span class="elsevierStyleItalic">c-ros oncogene 1</span>.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Dolores Isla, María D. 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The parents reported no other abnormalities. Physical examination revealed a weight of 13.2<span class="elsevierStyleHsp" style=""></span>kg (between the 3rd and 15th percentile) and a height of 95.7<span class="elsevierStyleHsp" style=""></span>cm (at the 3rd percentile for her age), mild right upper abdominal pain with deep palpation, and hepatomegaly without splenomegaly. Laboratory workup revealed high total cholesterol: 329.2<span class="elsevierStyleHsp" style=""></span>mg/dL (optimal: less than 170<span class="elsevierStyleHsp" style=""></span>mg/dL), high low-density lipoprotein (LDL) cholesterol: 274<span class="elsevierStyleHsp" style=""></span>mg/dL (optimal: less than 110<span class="elsevierStyleHsp" style=""></span>mg/dL), low high-density lipoprotein (HDL) cholesterol: 17.9<span class="elsevierStyleHsp" style=""></span>mg/dL (optimal: greater than 35<span class="elsevierStyleHsp" style=""></span>mg/dL) and high triglyceride levels: 186<span class="elsevierStyleHsp" style=""></span>mg/dL (reference value: 32-116<span class="elsevierStyleHsp" style=""></span>mg/dL), together with high aspartate aminotransferase (AST): 54<span class="elsevierStyleHsp" style=""></span>U/L (reference value: 13–35<span class="elsevierStyleHsp" style=""></span>U/L) and alanine aminotransferase (ALT) levels: 46<span class="elsevierStyleHsp" style=""></span>U/L (reference value: 10–25<span class="elsevierStyleHsp" style=""></span>U/L).<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">7</span></a> Serum bilirubin levels were within the normal range. Imaging studies revealed a generalized increase of liver size (longitudinal diameter of the right lobe was 13.8<span class="elsevierStyleHsp" style=""></span>cm), without focal lesions or evidence of portal hypertension.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The patient underwent percutaneous liver biopsy without any complications (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Two soft fragments of yellow hepatic tissue were obtained which displayed 28 portal tracts with mild chronic inflammatory infiltrate and without interface hepatitis, together with prominent microvesicular steatosis in hepatocytes. Masson's trichrome and reticulum stains showed fibrous portal expansion with fine portal-portal bridging and pericentral fibrosis (an Ishak score of 3). Immunohistochemistry for lysosomal markers showed strong, diffuse reactivity for cathepsin D and LAMP1 around the lipid vacuoles. Based on these clinical and histopathological findings, a diagnosis of LAL deficiency was suggested. A dried blood spot sample was collected which confirmed a complete absence of LAL activity by fluorometric analysis (reference range: 55–850<span class="elsevierStyleHsp" style=""></span>pmol/h/spot). Genetic analysis also corroborated the [c.894G>A];[c.386A>G] pathogenic variant in the LIPA gene. Subsequently, the patient started intravenous enzymatic replacement therapy in February 2018 (13<span class="elsevierStyleHsp" style=""></span>mg of sebelipase alfa once every two weeks) and 11 days after the second dose (March 2018), laboratory workup demonstrated a slight improvement in liver transaminase levels (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), but without significant changes in the lipid profile parameters. The dose was increased to 14<span class="elsevierStyleHsp" style=""></span>mg once every two weeks, and four days after the fifth dose (April 2018), laboratory testing displayed a slight rise in the HDL cholesterol level from 23 to 28.5<span class="elsevierStyleHsp" style=""></span>mg/dL. Unfortunately, the treatment was suspended after the sixth dose (May 2018) due to administrative issues, leading to a significant increase in AST level from 46.2 to 218<span class="elsevierStyleHsp" style=""></span>U/L and ALT level from 51.9 to 210<span class="elsevierStyleHsp" style=""></span>U/L.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Case 2 description</span><p id="par0020" class="elsevierStylePara elsevierViewall">A 6-year-old boy with a previous medical history of atopic dermatitis and laryngotracheobronchitis, was referred to the Genetics Service due to the finding of LAL deficiency in his 4-year-old sister (Case 1). The parents had noticed no symptoms, such as jaundice, choluria, or acholia. Physical examination revealed a healthy weight of 19.2<span class="elsevierStyleHsp" style=""></span>kg and a height of 111<span class="elsevierStyleHsp" style=""></span>cm, with a BMI of 15.6<span class="elsevierStyleHsp" style=""></span>at the 56th percentile for his age and hepatomegaly without splenomegaly. Laboratory workup demonstrated high total cholesterol: 340<span class="elsevierStyleHsp" style=""></span>mg/dL (optimal: less than 170<span class="elsevierStyleHsp" style=""></span>mg/dL), high LDL cholesterol: 283<span class="elsevierStyleHsp" style=""></span>mg/dL (optimal: less than 110<span class="elsevierStyleHsp" style=""></span>mg/dL), normal HDL cholesterol: 37.4<span class="elsevierStyleHsp" style=""></span>mg/dL (optimal: greater than 35<span class="elsevierStyleHsp" style=""></span>mg/dL), and normal triglyceride levels: 102.5<span class="elsevierStyleHsp" style=""></span>mg/dL (reference value: 32–116<span class="elsevierStyleHsp" style=""></span>mg/dL), along with high AST: 98.4<span class="elsevierStyleHsp" style=""></span>U/L (reference value: 15–40<span class="elsevierStyleHsp" style=""></span>U/L) and high ALT levels: 130.7<span class="elsevierStyleHsp" style=""></span>U/L (reference value: 10–25<span class="elsevierStyleHsp" style=""></span>U/L).<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">7</span></a> An absent LAL activity was measured in a dried blood spot sample, confirming the diagnosis of LAL deficiency. His genetic analysis was the same as his sister's, corroborating the [c.894G>A];[c.386A>G] pathogenic variant in the LIPA gene. The patient underwent percutaneous liver biopsy (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Three soft fragments of hepatic tissue were obtained which displayed a total of 20 portal tracts with moderate chronic portal inflammatory infiltrate and mild interface hepatitis, prominent and diffuse microvesicular steatosis in hepatocytes and hypertrophic Kupffer cells and portal macrophages with foamy cytoplasm that stained strongly with PAS. Birefringent cholesteryl ester crystals were not observed under polarized light. Masson's trichrome and reticulum stains displayed fibrous portal expansion with fine portal-portal and portal-central bridging (an Ishak score of 4). Immunohistochemistry also showed reactivity for cathepsin D and LAMP1 around the lipid vacuoles. The patient was subsequentially treated with intravenous sebelipase alfa (19<span class="elsevierStyleHsp" style=""></span>mg once every two weeks) starting in February 2018. 11 days after the second dose (March 2018), laboratory testing demonstrated a decline in AST (from 123 to 70.9<span class="elsevierStyleHsp" style=""></span>U/L) and ALT (from 120 to 68.9<span class="elsevierStyleHsp" style=""></span>U/L) levels (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>), in addition to a reduction in total (from 291 to 229<span class="elsevierStyleHsp" style=""></span>mg/dL) and LDL cholesterol (from 237 to 178<span class="elsevierStyleHsp" style=""></span>mg/dL) levels.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">Raising awareness among clinicians and pathologists is an essential step in detecting LAL deficiency in pediatric patients.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5,8</span></a> In 2013, Bernstein and colleagues<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">4</span></a> reviewed the literature identifying all papers describing LAL deficiency patients in Pubmed since the original description. After excluding cases with Wolman disease who died in the first year of life, 135 individuals were included in the analysis, of which 56 (45.2%) were males and 68 (54.8%) were females, with a median age at presentation of five years. They found that about 99.3% of patients presented hepatomegaly and 74% also had splenomegaly. Patients also reported abdominal and epigastric pain, vomiting, persistent diarrhea, malabsorption, steatorrhea, and failure to thrive, among others.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1,4</span></a> Although data regarding cardiovascular involvement in children with LAL deficiency is limited, patients can experience premature atherosclerosis, as well as dyslipidemia characterized by elevated levels of total and LDL cholesterol, elevated levels of triglycerides and normal to reduced levels of HDL cholesterol.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">3,8,9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The defective LAL activity produces reduced hydrolysis of cholesteryl esters and triglycerides and their massive accumulation in multiple cells throughout the body, although the lysosomes of Kupffer cells and hepatocytes are the most affected.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">4,5</span></a> As in the present cases, liver biopsy can provide relevant information for the diagnosis of LAL deficiency. Macroscopically, liver specimens tend to display a striking orange-yellowish color.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1,4</span></a> On light microscopy, microvesicular steatosis involving hepatocytes, Kupffer cells and macrophages, with uniform distribution in the hepatic lobule, is considered the characteristic finding, but it is not unique to the disease.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">2–4,10</span></a> Although microvesicular steatosis is uncommon in other metabolic causes of liver disease, rare conditions such as Reye's syndrome, congenital defects of urea cycle enzymes and fatty acid beta-oxidation and toxicity from certain medications like valproic acid can also demonstrate microvesicular or mixed steatosis with microvesicular predominance.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">2,4</span></a> As the diagnosis is challenging, many adult patients with deficient LAL activity maybe either undiagnosed or misdiagnosed as having non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or cryptogenic liver disease.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1,4</span></a> NAFLD, which includes NASH, is characterized by macrovesicular steatosis (its presence is less supportive of a diagnosis of LAL deficiency), hepatocellular ballooning, lobular and perisinusoidal inflammation and Mallory bodies.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> Unfortunately, steatosis can advance to fibrosis, micronodular cirrhosis and, ultimately, liver failure.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">2,9</span></a> Only the older sibling had evidence of advanced liver fibrosis with an Ishak score of 4 (on a scale from 0 to 6, with higher scores representing a greater degree of fibrosis). Other liver biopsy findings include foamy macrophages within the sinusoids and portal tracts of young patients, containing lipid and ceroid accumulation, and crystals of cholesteryl esters within hepatocytes and/or Kupffer cells, exhibiting Maltese cross-type birefringence in unfixed frozen liver samples.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1,4,9,10</span></a> Hůlková and Elleder<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> demonstrated that the presence of luminal (cathepsin D) or membrane (LAMP1, LAMP2, and LIMP2) lysosomal markers around the lipid vacuoles in patients with microvesicular steatosis can facilitate the diagnosis of LAL deficiency in paraffin-embedded material. Immunohistochemistry in our liver biopsies showed strong, diffuse reactivity for cathepsin D and LAMP1 around the lipid vacuoles, reflecting their lysosomal nature.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The diagnosis of LAL deficiency can be confirmed by measurement of LAL enzyme activity in a dried blood spot sample.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5,8</span></a> In 2012, Hamilton and colleges<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">11</span></a> described a new method for the measurement of LAL activity in a dried blood spot test, calculating the difference between the total lipase activity with and without the addition of Lalistat 2, a specific LAL inhibitor. They demonstrated that this technique differentiated clearly between healthy individuals, carriers and LAL deficient patients. However, the specimen should be transported promptly at lower temperatures to ensure sample stability and sufficient diagnostic accuracy.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5,11</span></a> Genetic analysis of the LIPA gene for the identification of the underlying mutation is highly recommended in the case of a positive LAL dried blood spot test and not as a screening method in a suspicious case.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">5,8</span></a> To date, over 120 LIPA mutations causing LAL deficiency have been described<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">5</span></a>; the most frequent defect is a splice-junction mutation in the exon 8 [E8SJM; c.894G>A], which is found in about half of all patients with deficient LAL activity.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1,8</span></a> In our cases, dried blood sport testing showed absent LAL activity and genetic sequencing corroborated the [c.894G>A];[c.386A>G] pathogenic variant in the LIPA gene.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Liver failure is considered the leading cause of death in patients with LAL deficiency with around 50% of the deaths occurring at a young age, before the age of 21.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">4,5</span></a> Despite liver transplantation, approximately 61% of LAL deficiency patients develop multi-systemic progression of the disease.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">3,5</span></a> Initially, the management of patients with deficient LAL activity was focused on the control of dyslipidemia through dietary modifications and the use of lipid-lowering drugs including statins, cholestyramine, and ezetimibe, but recently a new enzyme replacement therapy has become the mainstay of treatment for patients with LAL deficiency.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">3,8</span></a> In 2013, Balwani and colleges<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">12</span></a> reported for the first time the clinical use of sebelipase alfa (Kanuma®, Alexion Pharmaceuticals, Inc., New Haven, CT, United States), a recombinant human LAL enzyme, in the treatment of people with liver abnormalities due to LAL deficiency. According to the literature, this medication safely reduces transaminase elevation and hepatic fat content, decreases LDL cholesterol and triglycerides and increases the levels of HDL cholesterol.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">12–14</span></a> Unfortunately, the treatment in our cases was suspended after the sixth dose due to administrative issues, leading to a significant increase in AST and ALT levels.</p><p id="par0045" class="elsevierStylePara elsevierViewall">In conclusion, a detailed medical history including the specific symptoms and signs frequently found in LAL deficiency should be obtained. The biological siblings of a patient with a confirmed diagnosis of LAL deficiency have a 25% chance of being affected, thus genetic counseling is recommended. Plasma lipids should be evaluated in all patients suspected of having LAL deficiency. Patients can present with elevated levels of total and LDL cholesterol, and normal to reduced levels of HDL cholesterol. Indicators of liver injury, such as serum levels of ALT and AST, are frequently elevated in LAL deficiency. Hepatomegaly frequently leads to a liver biopsy, which can provide important information. The presence of microvesicular steatosis, diffuse reactivity for lysosomal markers (such as cathepsin D, LAMP1, LAMP2, and LIMP2) around the lipid vacuoles and the measurement of LAL activity in a dried blood spot sample support the diagnosis of LAL deficiency in pediatric patients. Enzyme replacement therapy with sebelipase alfa reduces serum aminotransferase levels, hepatic fat content and disease-related lipid abnormalities.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Statement of prior presentation</span><p id="par0050" class="elsevierStylePara elsevierViewall">Presented in abstract form at the 2019 College of American Pathologists Annual Meeting (CAP19), Kissimmee, FL, United States [<a href="https://doi.org/10.5858/arpa.2019-0901-AB">https://doi.org/10.5858/arpa.2019-0901-AB</a>].</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Funding</span><p id="par0055" class="elsevierStylePara elsevierViewall">This short article received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Research ethics and patient consent</span><p id="par0060" class="elsevierStylePara elsevierViewall">The ethics committee of our institution approved the study protocol to identify patients with lysosomal acid lipase deficiency (approval #CCEI-9878-2018). Informed consent was not necessary.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1894619" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1639389" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1894620" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1639390" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case 1 description" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Case 2 description" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Statement of prior presentation" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Research ethics and patient consent" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-11-23" "fechaAceptado" => "2021-03-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1639389" "palabras" => array:6 [ 0 => "Lysosomal acid lipase" 1 => "Lysosomal acid lipase deficiency" 2 => "Cholesteryl ester" 3 => "Cholesteryl ester storage disease" 4 => "Liver biopsy" 5 => "Microvesicular steatosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1639390" "palabras" => array:6 [ 0 => "Lipasa ácida lisosomal" 1 => "Deficiencia de lipasa ácida lisosomal" 2 => "Ésteres de colesterol" 3 => "Enfermedad por almacenamiento de ésteres de colesterol" 4 => "Biopsia hepática" 5 => "Esteatosis microvesicular" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Lysosomal acid lipase (LAL) deficiency is a rare, autosomal recessive disease caused by mutations in the LIPA gene, which produces cholesteryl ester and triglyceride accumulation predominantly in hepatocytes, adrenal glands, and gastrointestinal tract. We describe two new cases occurring in siblings, aged 5 and 7 years, who presented with hepatomegaly, dyslipidemia, and abnormal liver function. Percutaneous liver biopsy revealed portal inflammation, hypertrophic Kupffer cells with a foamy appearance and microvesicular steatosis with fibrosis. Immunostaining for lysosomal markers, cathepsin D and LAMP1 reflected the lysosomal nature of the lipid vacuoles. After enzymatic confirmation, enzyme replacement therapy was initiated for both siblings. Follow-up transaminase levels and lipid profiles showed a notable decrease in AST and ALT and a slight increase in HDL cholesterol. It is crucial to increase awareness of this rare condition among clinicians and pathologists. The expression of lysosomal markers around the lipid vacuoles might help diagnose LAL deficiency in pediatric patients.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La deficiencia de lipasa ácida lisosomal (LAL) es una enfermedad autosómica recesiva inusual, causada por mutaciones en el gen <span class="elsevierStyleItalic">LIPA</span>, que genera acumulación de éster de colesterol y triglicéridos predominantemente en hepatocitos, glándulas suprarrenales y tracto gastrointestinal. Describimos 2 casos adicionales que ocurrieron en 2 hermanos, de 5 y 7 años, que presentaron hepatomegalia, dislipidemia y función hepática anormal. La biopsia hepática percutánea reveló inflamación portal leve, células de Kupffer hipertróficas, con un aspecto espumoso y esteatosis microvesicular difusa con fibrosis. La inmunotinción de marcadores lisosomales, catepsina D y LAMP1, reflejó la naturaleza lisosomal de las vacuolas lipídicas. Después de la confirmación enzimática, ambos hermanos iniciaron terapia de reemplazo enzimático. Los niveles de transaminasas y los perfiles lipídicos de seguimiento mostraron una disminución notoria en AST y ALT y un ligero aumento en el colesterol HDL. Es crucial aumentar la conciencia de esta inusual condición entre médicos y patólogos. La expresión de marcadores lisosomales alrededor de las vacuolas lipídicas podría ayudar a diagnosticar la deficiencia de LAL en pacientes pediátricos.</p></span>" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1091 "Ancho" => 1505 "Tamanyo" => 585014 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Percutaneous liver biopsy showing prominent microvesicular steatosis (a-200× and b-1000×). Reticulum stain displaying fibrous portal expansion with fine portal-portal bridging and pericentral fibrosis (c-100×). LAMP1 stain reflecting the lysosomal nature of lipid vacuoles (d-400×).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1928 "Ancho" => 2175 "Tamanyo" => 212137 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Case 1, liver transaminase levels.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1091 "Ancho" => 1505 "Tamanyo" => 398395 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Percutaneous liver biopsy showing moderate chronic portal inflammation (a-100×), diffuse microvesicular steatosis (b-200×), and hypertrophic Kupffer cells with foamy appearance (c-1000×). Masson's trichrome stain displaying fibrous portal expansion with fine portal-portal and portal-central bridging (d-100×).</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1751 "Ancho" => 2175 "Tamanyo" => 216256 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Case 2, liver transaminase levels.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:14 [ 0 => array:3 [ "identificador" => "bib0075" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lysosomal acid lipase deficiency: an under-recognized cause of dyslipidaemia and liver dysfunction" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Ž. 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| Year/Month | Html | Total | |
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