Controlled attenuation parameter and liver stiffness measurements using transient elastography by FibroScan in Gaucher disease.

BACKGROUND: Liver involvement in Gaucher disease (GD) is a result of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) infiltration of macrophages. The long-term liver-related complications of GD could include liver fibrosis and cirrhosis. The aim of the study was to evaluate clinical utility and relevance of TE by FibroScan in GD patients by assessing two parameters: controlled attenuation parameter (CAP) and liver stiffness (LS), in regard of GD-related variables, type of GD, age of patients, enzymatic replacement therapy (ERT), and metabolic features. METHODS: 59 Polish patients (55 adults, 4 children) with GD (43 patients with type 1 and 16 patients with type 3) aged 7-86 years, underwent TE by FibroScan; elevated CAP was defined as >250 dB/m and elevated LS as >7 kPa. All patients, except five patients with type 1 GD (patients' refusal), were treated by ERT. RESULTS: Elevated CAP was present in 23% of GD1 patients and 19% of GD3 patients. Elevated LS was present in 21% of GD1 patients and 13% of GD3 patients. CAP was fairly, positively (ρ = 0.356) correlated with BMI. LS was fairly, positively (ρ = 0.4) correlated with patient's age, as well as the age at start of ERT (ρ = 0.326). CAP was strongly, negatively (ρ = -0.52) correlated with the age at start of ERT. LS and CAP were correlated (strongly, positively) only in GD3. CONCLUSIONS: TE by FibroScan could be considered as an additional method for evaluating GD patients for non-invasive assessment of CAP and LS. The investigation of serial TE measurements in untreated as well as treated GD patients is needed to better determine whether this technology should be added to recommendations for monitoring GD patients. TE by FibroScan could be performed in GD patients with increased BMI and especially those with metabolic syndrome as they have other important risks for liver disease. After our analysis we think these risks factors are independent of GD but still very important for their overall health.

Plasma chitotriosidase activity versus plasma glucosylsphingosine in wide spectrum of Gaucher disease phenotypes - A statistical insight.

Deficiency of beta-glucocerebrosidase (GBA) leads to Gaucher disease (GD), an inherited disorder characterised by storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. Macrophages activated by accumulated GlcCer secrete chitotriosidase. Plasma chitotriosidase activity is significantly elevated in patients with active GD and has been suggested to indicate total body Gaucher cell load. There are two biomarkers used to assess the severity of GD - chitotriosidase has been measured for over 20 years, and deacylated GlcCer, known as glucosylsphingosine (GlcSph) is thought to be even more adequate, as it is almost a direct storage substrate. In this paper we focused entirely on statistical analysis, performing a thorough search of possible relations, dependencies and differences in the levels of these two biomarkers in a cohort of 64 Polish GD patients. We found that the treatment of GD with enzyme replacement therapy (ERT) changes the distribution of the disease biomarkers; their levels follow a normal distribution only in untreated patients. The variable "disease biomarker level" was found dependent of the binary variable "treated with ERT or not". It was found independent of the following variables: "disease type", "splenectomized or not", and "heterozygous for 24-bp duplication for CHIT1 variant" or "CHIT1 wild type". An almost perfect linear correlation (coefficient of determination R2 = 0.99) between the chitotriosidase activity and GlcSph level was revealed in splenectomized patients.

A 20-Year Longitudinal Study of Plasma Chitotriosidase Activity in Treated Gaucher Disease Type 1 and 3 Patients-A Qualitative and Quantitative Approach.

Chitotriosidase is an enzyme produced and secreted in large amounts by activated macrophages, especially macrophages loaded with phagocytozed glycosphingolipid in Gaucher disease. Macrophages phagocytose decayed blood cells that contain a lot of sphingolipid-rich cell membranes. In Gaucher disease, due to a deficit in beta-glucocerebrosidase activity, the phagocytozed substrate glucocerebroside cannot undergo further catabolism. In such a situation, macrophages secrete chitotriosidase in proportion to the degree of overload. Gaucher disease (GD) is a recessively inherited disorder resulting in storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. It is directly caused by the deficiency of beta-glucocerebrosidase (GBA) activity. Chitotriosidase has been measured systematically each year in the same group of 49 patients with type 1 and 3 GD for over 20 years. Our analysis showed that chitotriosidase is very sensitive biomarker to enzyme replacement therapy (ERT). The response to treatment introduction is of an almost immediate nature, lowering pathologically high chitotriosidase levels by a factor of 2 in a time scale of 8 months, on average. Long term enzyme replacement therapy (ERT) brings chitotriosidase activity close to reference values. Finally, reducing the dose of ERT quickly boosts chitotriosidase activity, but restoring the initial dose of treatment brings chitotriosidase level of activity back onto the decreasing time trajectory.

Alpha-Synuclein mRNA Level Found Dependent on L444P Variant in Carriers and Gaucher Disease Patients on Enzyme Replacement Therapy.

Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for ß-glucocerebrosidase (GCase, E.C. 3.2.1.45). The condition is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease in both non-neuronopathic type 1 (GD1) and neuronopathic type 3 (GD3). Interestingly, GBA1 variants were found to be one of the most important risk factors for the development of Parkinson's disease (PD) in GD1 patients. We performed a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosine (Lyso-Gb1) and α-synuclein for GD and PD, respectively. A total of 65 patients with GD treated with ERT (47 GD1 patients and 18 GD3 patients), 19 GBA1 pathogenic variant carriers (including 10 L444P carriers), and 16 healthy subjects were involved in the study. Lyso-Gb1 was assessed by dried blood spot testing. The level of α-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. α-synuclein mRNA level was found significantly elevated in GD3 patients and L444P carriers. GD1 patients, along with GBA1 carriers of an unknown or unconfirmed variant, as well as healthy controls, have the same low level of α-synuclein mRNA. There was no correlation found between the level of α-synuclein mRNA and age in GD patients treated with ERT, whereas there was a positive correlation in L444P carriers.

Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up.

BACKGROUND: Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and the attachment of glycans to proteins and lipids. Our study aimed to describe the clinical, biochemical, and molecular findings of CDG patients, and to present the long-term follow-up. MATERIAL AND METHODS: A single-center study (1995-2019 years) of patients with congenital disorders of N-glycosylation and combined N- and O-hypoglycosylation was performed. RESULTS: Among 32 patients included into the study, there were 12 PMM2-CDG, 3 ALG13-CDG, 3 ALG1-CDG, 1 ALG3-CDG, 3 MPI-CDG, 1 PGM1-CDG, 4 SRD5A3-CDG, 1 DPAGT1-CDG, 3 ATP6AP1-CDG, 1 ATP6V0A2-CDG. The phenotypic and genotypic spectrum during long-term (in some cases over 20 years) observation was characterised and several measurements of serum Tf isoforms taken. Statistical analysis revealed strong negative correlation between asialo-Tf and tetrasialo-Tf, as well as between disialo-Tf and tetrasialo-Tf. Within CDG type I, no difference in % Tf isoforms was revealed between PMM2-CDG and non-PMM2-CDG patients. However, these two groups differed significantly in such diagnostic features as: cerebellar ataxia, failure to thrive, hypothyroidism, pericardial effusion, cardiomyopathy, inverted nipples, prolonged INR. The effect of treatment with mannose in 2 patients with MPI-CDG was assessed and we found that % of asialo-Tf, monosialo-Tf, and disialo-Tf was significantly lowered, whereas tetrasialo-Tf and pentasialo-Tf rose, coming closer or falling into the reference range. CONCLUSIONS: The novel finding was an abnormal Tf IEF pattern in two ALG13-CDG patients and normal in one ALG1-CDG patient. Clinical manifestation of presented CDG patients was similar to that reported in the literature. Mannose supplementation in MPI-CDG patients, as well as galactose supplementation in PGM1-CDG patient, improved patients' clinical picture and Tf isoform profiles.

Pediatric Liver Disease Patients and Secondary Glycosylation Abnormalities.

Background: Isoelectric focusing (IEF) of serum transferrin (Tf) is still the method of choice for diagnosis of congenital disorders of glycosylation (CDG). An abnormal glycosylation is also a known phenomenon in adult liver disease patients. The aim of this study was to characterize glycosylation disturbances in pediatric patients with primary liver disease. However, there are no reports of this phenomenon in children. Materials and Methods: Between 1995 and 2019, circa 2,000 serum Tf isoform analyses have been performed in children with primary liver diseases; some of them underwent subsequent analyses. We enrolled in this study 19 patients who developed an acute liver injury (ALI)/failure (ALF) or exhibited a chronic liver disease (CLD) and were evaluated and listed for liver transplantation (LTx) or had just undergone this procedure, and secondary abnormal serum Tf isoform profile. Results: Among 12 patients with ALI/ALF, 10 had an increased percentage of asialo-, monosialo-, and disialo-Tf isoforms. All patients with CLD had an increased percentage of asialo- and monosialo-Tf isoform. Two patients diagnosed with recurrent ALF had very specific serum Tf profile with a huge increase in the asialo- and monosialo-Tf isoform. On follow-up analyses (available in some patients), serum Tf IEF profile normalized in parallel to normalization of liver function tests, spontaneously or during treatment, including glucocorticosteroids in AIH, LTx in CLD. Conclusions: All pediatric patients with primary liver disease had increased asialo-Tf as well as monosialo-Tf isoforms. None of them had elevated percentage of trisialo-Tf isoform.

Transient Elastography for Detection of Liver Fibrosis in Children With Autosomal Recessive Polycystic Kidney Disease.

Introduction: Congenital hepatic fibrosis (CHF) is invariably present in all patients with autosomal recessive polycystic kidney disease (ARPKD) but is usually clinically asymptomatic. The portal hypertension in the course of CHF develops and progresses over time, so an early detection of liver fibrosis remains crucial. Aim: The aim of the study was to evaluate a predictive value of transient elastography for evaluating liver disease progress in pediatric ARPKD patients. Material and Methods: The study group encompassed 21 pediatric patients with ARPKD and 20 healthy children (control group) from The Children's Memorial Health Institute in Warsaw, Poland. Liver fibrosis was determined by assessing the liver stiffness (LS) with transient elastography (FibroScan®, FS) using size-appropriate probes. In ARPKD group the laboratory findings, results of an abdominal ultrasound examination, and an endoscopic gastroduodenoscopy were also analyzed. Results: Compared with healthy controls, patients with ARPKD had significantly increased median LS values (22 vs. 4.25 kPa, p < 0.0001). Based on FS results, ARPKD group was divided into two subgroups: patients (n = 5) with LS results suggestive of no fibrosis or minimal fibrosis (LS < 6.9 kPa, METAVIR fibrosis stage 0-1) and patients (n = 16) with LS results suggestive of at least significant liver fibrosis (LS ≥ 6.9 kPa, METAVIR fibrosis stage 2-4). In the first subgroup (no fibrosis or minimal fibrosis), all patients had no signs of portal hypertension. In the subgroup with at least significant liver fibrosis, splenomegaly was observed in 87.5% of patients and thrombocytopenia in 69% of patients. An endoscopic gastroduodenoscopy was performed in 15 out of 21 ARPKD patients, nine patients (60%) had esophageal varices. All of these patients had LS results suggestive of at least significant liver fibrosis. Conclusions: TE by FibroScan can be used as an additional method for evaluating liver disease progress in pediatric ARPKD patients.