Lysosomal Acid Lipase Deficiency Leading to Liver Cirrhosis: a Case Report of a Rare Variant Mutation

Cunha‐Silva, Marlone; Mazo, Daniel Ferraz de Campos; Corrêa, Bárbara; Lopes, Tirzah M.; Arrelaro, Raquel C.; Ferreira, Gabriel L.; Rabello, Marcello Imbrizi; Sevá‐Pereira, Tiago; Escanhoela, C.A.F.; Almeida, José R.

doi:10.5604/01.3001.0012.7930

Cited by 3 publications

(7 citation statements)

References 25 publications

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“…Details the case and all steps for diagnosing LAL-D have already been published. [1] His LAL activity was undetectable using the blood spot test (at Seattle Children´s Hospital) and a variant mutation in the gene LIPA was observed (allele c.386A > G homozygous p.H129R). [1] He has been on atorvastatin, vitamin D3, hydrochlorothiazide, and carvedilol and has not started the enzyme replacement for economic reasons, as this therapy is not available in the Brazilian public health system.…”

Section: Case Presentationmentioning

confidence: 99%

“…Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive genetic disorder associated with mutations in the gene LIPA, that encodes the enzyme lysosomal acid lipase (LAL). [ 1 ] Its clinical spectrum ranges from an earlier-onset presentation (Wolman´s disease), with high mortality in the first 2 years of life, to a later-onset form, known as cholesteryl esters storage disease (CESD), which is characterized by a systemic accumulation of cholesteryl esters and triglycerides, including in hepatocytes and Kupffer cells. Patients with CESD may have serum lipid abnormalities, hepatosplenomegaly, elevated liver enzymes and progress to atherosclerosis, chronic liver disease and complications.…”

Section: Introductionmentioning

confidence: 99%

“…Patients with CESD may have serum lipid abnormalities, hepatosplenomegaly, elevated liver enzymes and progress to atherosclerosis, chronic liver disease and complications. [ 1 , 2 ] Intestinal polyps leading to chronic diarrhea [ 3 ] or bowel obstruction [ 4 ] as initial manifestation have been reported. LAL-D is underrecognized and some patients present with cirrhosis and signs of portal hypertension at diagnosis.…”

Section: Introductionmentioning

confidence: 99%

“…LAL-D is underrecognized and some patients present with cirrhosis and signs of portal hypertension at diagnosis. [ 1 , 2 ]…”

Section: Introductionmentioning

confidence: 99%

“…LAL-D is underrecognized and some patients present with cirrhosis and signs of portal hypertension at diagnosis. [1,2] In affected adults, it is necessary to prevent and treat hepatic and cardiovascular complications, perform hepatocellular carcinoma (HCC) screening, and assess the need for liver transplantation. The specific approach consists of enzyme replacement (sebelipase alfa), which may improve the disease parameters such as transaminases, hepatomegaly, and dyslipidemia, reducing the progression of liver damage, [5][6][7] but this therapy is not widely available.…”

Section: Introductionmentioning

confidence: 99%

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15-Year progression to liver cancer in the lack of treatment for lysosomal acid lipase deficiency: A case report

et al. 2022

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Rationale: Lysosomal acid lipase deficiency (LAL-D) is a poorly diagnosed genetic disorder characterized by the accumulation of cholesteryl esters and triglycerides in many tissues, leading to dyslipidemia and cardiovascular complications. In the liver, deposits are found within hepatocytes and Kupffer cells, generating microvesicular steatosis, progressive fibrosis, and cirrhosis. Sebelipase alfa is the target therapy which can improve laboratory changes and reduce the progression of liver damage, but this is not yet widely available.Patient Concerns: We are reporting a 15-year follow-up of a Brazilian man who was diagnosed with cirrhosis at age 43 and with LAL-D at age 53, but he has never been treated with sebelipase alfa for economic reasons. During the coronavirus disease 2019 (COVID-19) pandemic, he lost follow-up and missed three 6-month ultrasound exams for liver cancer screening.Diagnosis: At age 58, a remarkable deterioration in liver function was observed and he was diagnosed with hepatocellular carcinoma (HCC) outside the Milan Criteria (two nodules measuring 48mm and 25mm). Three other individuals with LAL-D and progression to liver cancer have been reported so far and none of them underwent enzyme replacement therapy: an 11-year-old girl with HCC, a 51-year-old male with cholangiocarcinoma, and a 21-year-old male with hepatocellular-cholangiocarcinoma. The latter had the same mutation in the gene LIPA as our patient, but a relationship between this variant and malignancies has not yet been established. Lessons:We emphasize how important is to treat LAL-D patients after diagnosis in order to avoid worsening liver function and progression to neoplasms. Untreated individuals should be considered at a higher risk but the most appropriate liver cancer screening program for this subgroup is still unknown.

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Section: Case Presentationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…LAL-D is underrecognized and some patients present with cirrhosis and signs of portal hypertension at diagnosis. [ 1 , 2 ]…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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15-Year progression to liver cancer in the lack of treatment for lysosomal acid lipase deficiency: A case report

et al. 2022

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Lipid-based nanoparticles deliver mRNA to reverse the pathogenesis of lysosomal acid lipase deficiency in a preclinical model

Zadory,

Lopez-Vince,

Haddouch

et al. 2024

Preprint

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Lysosomal acid lipase (LAL) is the only known enzyme that degrades cholesteryl esters (CEs) and triglycerides (TGs) in the lysosomes. LAL deficiency (LAL-D) results in hepatosplenomegaly with extensive accumulation of CEs and TGs, and can in the most severe cases be a life-threatening condition in early infancy. Using messenger ribonucleic acid (mRNA) for protein replacement is an innovative approach for the treatment of genetic disorders, but is challenged by a safe and efficient mRNA delivery. Here, we generated a combinatorial library of lipid-based nanoparticles (LNPs) for mRNA delivery and screened it in vitro and in vivo, which yielded a new formulation with a superior potency than an FDA-approved nanoformulation. This formulation efficiently delivered LAL mRNA and restored LAL activity in liver and spleen, mediating significant reversal of the pathological progression in an aggressive preclinical model of LAL-D. In vivo, the new formulation also promoted a more sustained and quantitatively higher LAL expression. In addition, repeated administration regimen mitigated hepatosplenomegaly, and targeted lipidomic analysis revealed strong diminution of CEs and TGs and of toxic lipid species in the liver and spleen. Transcriptomic analysis showed significant attenuation of inflammatory processes, fibrosis and several pathological pathways associated to LAL-D. These findings provide strong evidence that the intracellular production of LAL via mRNA-LNP is a very promising approach for the chronic treatment of LAL-D and support the clinical translation of mRNA therapy to overcome the challenges associated with traditional enzyme replacement therapies.

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Lysosomal Acid Lipase Deficiency in the Etiological Investigation of Cryptogenic Liver Disease in Adults: A Multicenter Brazilian Study

Candolo,

Cançado,

Zitelli

et al. 2023

Gastroenterology Insights

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Background: Lysosomal acid lipase deficiency (LAL-D) is a rare genetic disease associated with the deregulation of lipid metabolism, leading to atherosclerosis, dyslipidemia, and hepatic steatosis, with potential progression to cirrhosis. Our study aims to assess the role of LAL-D in the setting of cryptogenic liver disease. Methods: A large multicenter cross-sectional study was conducted, which included 135 patients with cryptogenic liver disease from four liver centers in Brazil. All patients were submitted to the investigation of LAL enzyme activity on dried blood spots. Results: Three patients (two female) presented levels of LAL below the reference limit, compatible with LAL-D (2.2%). They had a mean age of 43.9 ± 10.1 years and a mean body-mass index (BMI) of 23.1 ± 1.7 kg/m2. The mean serum levels of glucose, HDL-cholesterol, and triglycerides were 89.7 ± 3.2, 21.7 ± 3.2, and 206.7 ± 25.5 mg/dL, respectively. All patients had duodenal polyposis with xanthomatous macrophages. LAL-D investigation should be considered for individuals with chronic liver disease of an unknown etiology, especially with a normal BMI, high triglycerides, and low-HDL-cholesterol levels. The identification of LAL-D patients is extremely important since enzyme replacement therapy with Sebelipase Alfa significantly increases their survival.

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Lysosomal Acid Lipase Deficiency Leading to Liver Cirrhosis: a Case Report of a Rare Variant Mutation

Cited by 3 publications

References 25 publications

15-Year progression to liver cancer in the lack of treatment for lysosomal acid lipase deficiency: A case report

15-Year progression to liver cancer in the lack of treatment for lysosomal acid lipase deficiency: A case report

Lipid-based nanoparticles deliver mRNA to reverse the pathogenesis of lysosomal acid lipase deficiency in a preclinical model

Lysosomal Acid Lipase Deficiency in the Etiological Investigation of Cryptogenic Liver Disease in Adults: A Multicenter Brazilian Study

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