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Liver involvement in patients with Gaucher disease types I and III.

ABSTRACT: Background & aims:Gaucher disease (GD) is a multisystemic disease. Liver involvement in GD is not well characterised and ranges from hepatomegaly to cirrhosis and hepatocellular carcinoma. We aim to describe, and assess the effect of treatment, on the hepatic phenotype of a cohort of patients with GD types I and II. Methods:Retrospective study based on the review of the medical files of the Gaucher Reference Centre of the Hospital de Clínicas de Porto Alegre, Brazil. Data from all GD types I and III patients seen at the centre since 2003 were analysed. Variables were compared as pre- ("baseline") and post-treatment ("follow-up"). Results:Forty-two patients (types I: 39, III: 3; female: 22; median age: 35 y; enzyme replacement therapy: 37; substrate reduction therapy: 2; non-treated: 3; median time on treatment-MTT: 124 months) were included. Liver enzyme abnormalities, hepatomegaly, and steatosis at baseline were seen in 19/28 (68%), 28/42 (67%), and 3/38 patients (8%), respectively; at follow-up, 21/38 (55%), 15/38 (39%) and 15/38 (39%). MRI iron quantification showed overload in 7/8 patients (treated: 7; MTT: 55 months), being severe in 2/7 (treated: 2/2; MTT: 44.5 months). Eight patients had liver biopsy (treated: 6; MTT: 58 months), with fibrosis in 3 (treated: 1; time on treatment: 108 months) and steatohepatitis in 2 (treated: 2; time on treatment: 69 and 185 months). One patient developed hepatocellular carcinoma. Conclusions:GD is a heterogeneous disease that causes different patterns of liver damage even during treatment. Although treatment improves the hepatocellular damage, it is associated with an increased rate of steatosis. This study highlights the importance of a follow-up of liver integrity in these patients.

SUBMITTER: Starosta RT

PROVIDER: S-EPMC7026612 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Liver involvement in patients with Gaucher disease types I and III.

Starosta Rodrigo Tzovenos RT Vairo Filippo Pinto E FPE Dornelles Alícia Dorneles AD Basgalupp Suélen Porto SP Siebert Marina M Pedroso Maria Lúcia Alves MLA Cerski Carlos Thadeu Schmidt CTS Álvares-da-Silva Mário Reis MR Schwartz Ida Vanessa Doederlein IVD

Molecular genetics and metabolism reports 20200107

<h4>Background & aims</h4>Gaucher disease (GD) is a multisystemic disease. Liver involvement in GD is not well characterised and ranges from hepatomegaly to cirrhosis and hepatocellular carcinoma. <b>We aim to</b> describe, and assess the effect of treatment, on the hepatic phenotype of a cohort of patients with GD types I and II.<h4>Methods</h4>Retrospective study based on the review of the medical files of the Gaucher Reference Centre of the Hospital de Clínicas de Porto Alegre, Brazil. Data f ...[more]

PMID: 32099816

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Project description:Activator protein (AP), which stimulated fibroblast sphingomyelinase activity, was isolated from the spleen of a patient with Gaucher's disease type I by the combined techniques of heat and alcohol denaturation, DEAE-cellulose column chromatography, gel filtration, preparative polyacrylamide-gel electrophoresis and decyl-agarose chromatography. Urea/sodium dodecyl sulphate (SDS)/polyacrylamide-gel electrophoresis showed two bands, one with an Mr of approx. 3,000 and the other with an Mr of 5,000-6,500. Similarly, SDS/polyacrylamide-gel electrophoresis performed in the absence of urea revealed the presence of two components, one of which adsorbed to a concanavalin A (Con A) column. Both components stimulated sphingomyelinase activity. On a non-denaturing polyacrylamide gel containing Triton X-100, four major components, two of which bound to Con A, were detected with the dye Stains-All. Cross-reacting material (CRM) to polyclonal Gaucher spleen AP antibodies was detected in normal fibroblasts and in fibroblasts from patients with sphingomyelinase and beta-glucocerebrosidase deficiency states (Niemann-Pick and Gaucher's diseases respectively). CRM in normal fibroblasts adsorbed to Con A columns and had the same mobility on SDS/polyacrylamide-gel electrophoresis as Con A-adsorbing Gaucher spleen AP. Normal AP was not observed in mucolipidosis type II (I-cell disease) fibroblasts; instead, extracts from these cells revealed the presence of two closely migrating bands with higher Mr values than normal fibroblast CRM. Furthermore, extracts of media from I-cell fibroblast cultures, but not from control or Gaucher fibroblast cultures, contained AP activity towards sphingomyelinase and beta-glucocerebrosidase. Fibroblasts from a patient with mucolipidosis type III (pseudo-Hurler polydystrophy) showed an intermediate pattern consisting of normal as well as the higher-Mr CRM. Our data provide evidence for the existence of AP in cultured skin fibroblasts and suggest that these proteins may be targetted to the lysosome by post-translational modification in a similar manner to that reported for lysosomal enzymes.

Project description:Investigate the incidence of Parkinsonism among patients with Gaucher disease type 1 (GD1) and describe demographics, genotypes, and Gaucher disease (GD)-related characteristics for affected and non-affected patients.Cohort study with age- and gender-matched nested case-control analysis. Calculation of event incidence, standardized morbidity ratio, and event-free survival (Kaplan-Meier).The International Collaborative Gaucher Group (ICGG) Gaucher Registry data as of June 2010. Study cohort: GD1 patients with any report of Parkinsonism. Pre-matching control group: All GD1 patients with no report of Parkinsonism.The matched study cohort comprised of 68 patients with reports of Parkinsonism and 649 patients without Parkinsonism. Demographic and clinical characteristics suggest a milder GD phenotype in patients with Parkinsonism compared to the control group. The most prevalent GD1 genotype was N370S/N370S (39% for controls; 46% for patients with Parkinsonism). Patients with Parkinsonism were diagnosed with GD1 at a mean age of 37 years compared to 31 years in control patients. The standardized morbidity ratio for the development of Parkinsonism among all GD1 patients indicated an approximately 6 to 17 fold increase over that of 2 reference populations. The mean age of reported Parkinsonism onset was 57 years compared to 60 years in the general population (Lees, Hardy, and Revesz, 2009 [1]). The probability that a patient with GD1 will develop Parkinsonism before age 70 years is 5 to 7% and 9 to 12% before age 80 years.The incidence of Parkinsonism among GD1 patients is significantly increased compared to two reference populations. GD1 patients with Parkinsonism have a later median age at GD diagnosis, later age at the start of treatment, and later age at death than patients with GD1 alone. The Gaucher-related clinical profile of GD1 patients with Parkinsonism is similar to or milder than the GD1 alone group. Therefore, severity of the common GD1 clinical manifestations does not appear to be predictive for the onset of Parkinsonism.

Dataset Information

Liver involvement in patients with Gaucher disease types I and III.

Publications

Liver involvement in patients with Gaucher disease types I and III.

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