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Biomedical subjects

C E Hollak

Publications and source records attributed to C E Hollak.

At least 19 recordsLinked to original sources
PubMed2005

Plasma chitotriosidase and CCL18: early biochemical surrogate markers in type B Niemann-Pick disease.

Type B Niemann-Pick disease (NPD) is a nonneuronopathic lysosomal storage disorder which is characterized by accumulation of sphingomyelin-laden macrophages. The availability of plasma markers for storage cells may be of great value in facilitating therapeutic decisions. Given the similarity of the storage cells in NPD and Gaucher disease, we studied Gaucher plasma markers (chitotriosidase and CCL18) in two siblings homozygous for the R228C mutation in acid sphingomyelinase (ASM) and a type B course of NPD. The older sibling, first examined at the age of 9 months, showed marked hepatosplenomegaly and pulmonary involvement. The younger sibling has mild asymptomatic hepatosplenomgaly at the age of 5 months. Analysis of plasma specimens revealed markedly increased levels of chitotriosidase and CCL18 in the older sibling. In the younger child also, plasma chitotriosidase and CCL18 were clearly elevated above normal values almost immediately after birth and rapidly increased further. Histochemistry confirmed production of CCL18 by foam cells. In conclusion, plasma chitotriosidase and CCL18 may also serve as markers for the formation of pathological lipid-laden macrophages in type B NPD, in analogy to Gaucher disease. The availability of sensitive plasma surrogate markers may be of great value for monitoring the efficacy of enzyme supplementation therapy that is currently being developed.

Bone Marrow Cells↗
PubMed2001

Clinically relevant therapeutic endpoints in type I Gaucher disease.

The introduction of enzyme supplementation therapy for Gaucher disease has had a great impact on the lives of many patients. Organomegaly, cytopenia and bone disease have been shown to improve in response to treatment, resulting in an improvement in quality of life. However, the assessment of organ system involvement is not always done in such a way that the relationship with clinically relevant endpoints is clear. The lack of adequately validated methods of assessment, especially for bone disease, has hindered the establishment of treatment goals and guidelines for treatment optimization.

Biomarkers↗
PubMed2000

[Fabry's disease; towards a treatment].

Fabry's disease, deficiency of the enzyme alpha-galactosidase A, is an X-linked lysosomal storage disorder. Clinical symptoms are caused by continuous deposition of specific glycolipids in endothelial cells, neural cells, skin and cornea. These depositions give rise to skin (angiokeratoma) and eye abnormalities (cornea verticillata), acroparaesthesias and anhidrosis and later in life cause renal insufficiency and cardiovascular complications. Hemizygous males suffer from Fabry's disease, whereas female carriers (heterozygotes) are usually asymptomatic. Recently, an atypical presentation of Fabry's disease was described in males who only presented with cardiac involvement. Therefore, the actual number of Fabry patients in the Netherlands could be higher than the predicted 300. Diagnosis in males can be established by measuring alpha-galactosidase enzyme activity in plasma, leukocytes or fibroblasts. Apart from kidney transplantation only symptomatic therapy is available today. Enzyme supplementation therapy (as shown in Gaucher's disease) and substrate deprivation are possible ways of treatment in the future.

Cardiomyopathy, Hypertrophic↗
PubMed1998

Oligosaccharide excretion in adult Gaucher disease.

Gaucher disease is a lysosomal storage disease characterized by storage of glucocerebroside due to lysosomal glucocerebrosidase deficiency. Increased urinary excretion of sialyloligosaccharides and mannosylglycoasparagines has been described for two patients with the infantile form of the disease, probably as a consequence of obstruction of lysosomal functioning due to the glycolipid accumulation in lysosomes. By thin-layer chromatography, we found increased urinary oligosaccharide excretion in a series of adult non-neuronopathic patients. Oligosaccharide patterns were comparable between patients and also with the pattern observed in infantile Gaucher disease. Composition was analysed by methanolysis and gas chromatography. Mannose and N-acetylglucosamine are the main carbohydrates in all oligosaccharide bands. A statistically significant correlation was found between oligosaccharide excretion and the severity of the disease expressed as severity score index. Patients treated with enzyme replacement therapy showed a reduction up to 65% of the original oligosaccharide excretion after 1 year of treatment, comparable with the reduction in spleen volume.

Adult↗
PubMed1997

Glucocerebrosidase genotype of Gaucher patients in The Netherlands: limitations in prognostic value.

Gaucher disease is a recessively inherited lysosomal storage disorder that is caused by a deficiency in glucocerebrosidase activity. The clinical expression is markedly heterogeneous with respect to age of onset, progression, severity, and neurological involvement. The relative incidence of glucocerebrosidase (GC) mutations has been studied extensively for Jewish but not for non-Jewish Caucasian patient populations. The present survey on mutant GC genotypes prevalent in Gaucher disease in The Netherlands was taken of 72 patients from different genetic backgrounds. This number is more than half the total number of affected Gaucher patients to be expected on the basis of the incidence of the disorder in this country. Analysis of nine GC mutations led to the identification of 74% of the mutant GC alleles in patients from 44 unrelated Dutch families (i.e., families that have lived in The Netherlands for at least several generations) and of 44% of the mutant GC alleles in patients from nine unrelated families that recently immigrated from both European and non-European countries. The N370S (cDNA 1226G) GC mutation proved to occur most frequently (41%) in the unrelated Dutch patients and less frequently (6%) in the unrelated immigrant patients and was always associated with the nonneuronopathic (Type 1) form of the disease. Apart from the association of the N370S mutation with Type 1 Gaucher disease, the prognostic value of GC genotyping was limited, since a particular GC genotype did not correlate closely to a specific clinical course, or to a specific relative responsiveness to enzyme-supplementation therapy.

Blotting, Southern↗
PubMed1997

Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease.

In type 1 Gaucher disease, decreased activity of glucocerebrosidase results in accumulation of glucosylceramide in macrophages. Infiltration of liver, spleen and bone marrow by lipid-laden macrophages leads to hepatosplenomegaly, bone lesions and cytopenia. These abnormal macrophages may produce and release macrophage derived factors and cytokines, which could contribute to the pathophysiology of the disease. Whether these cytokines and factors are elevated in Gaucher disease is currently unknown. In 29 type 1 Gaucher disease patients we measured serum levels of the macrophage derived cytokines IL8, IL6, TNFalpha, M-CSF and the monocyte/macrophage activation marker sCD14. These factors were studied in relation to disease severity and during treatment with enzyme supplementation therapy. Most patients showed remarkably elevated levels of M-CSF (2-8 fold) and sCD14 (2-5 fold) as compared to normal controls. Levels of IL8 were elevated in all patients (2-20 fold), whereas levels of IL6 and TNFalpha were normal. There was a significant correlation between severity of the disease as determined by the severity score index (SSI), and M-CSF, sCD14 and IL8 levels. M-CSF and sCD14 levels also correlated with the excess liver and spleen volumes. During treatment with alglucerase, levels of M-CSF and sCD14 declined, but IL8 remained unchanged. The relative reduction in excess liver and spleen volume did not correlate with the relative reduction in M-CSF or sCD14 levels. We conclude that serum levels of M-CSF, sCD14 and IL8 are increased in type 1 Gaucher disease. The biological activities of M-CSF and IL8 may add to the pathophysiology of the disease.

Adolescent↗
PubMed1997

Differential effects of enzyme supplementation therapy on manifestations of type 1 Gaucher disease.

BACKGROUND: In type 1 Gaucher disease (GD), the accumulation of glucocerebroside in macrophages, caused by deficient activity of glucocerebrosidase, results in a variety of disease manifestations. In addition to the characteristic features of hepatosplenomegaly, cytopenia, and bone abnormalities, resting energy expenditure (REE) and glucose production are increased. In this study the effects of enzyme supplementation therapy on metabolic parameters in relation to other disease manifestations in type 1 GD patients are investigated. PATIENTS AND METHODS: In 12 adult type 1 GD patients, measurements of REE (by indirect calorimetry), liver and spleen volume (by spiral computerized axial tomography [CT]) and hemoglobin and platelet count were obtained before and after 6 months of alglucerase therapy (15 U/kg per month). In 7 of the 12 patients hepatic glucose production was measured by infusing 3-3H glucose. For comparison, REE and glucose metabolism were studied in 7 weight- and age-matched healthy subjects. RESULTS: REE and glucose production were increased in GD patients as compared with controls (REE: 29.8 kcal/kg/24 h +/- 3.6 and 23.1 +/- 2.3 kcal/kg/24 h, respectively, P < 0.05; glucose production: 14.00 mumol/kg/min +/- 0.51 and 10.77 mumol/kg/min +/- 0.26, respectively, P < 0.03). There were no differences in plasma glucose concentrations. Whereas the elevated REE decreased after 6 months of alglucerase therapy from 129% to 120% of predicted values (P < 0.01), the increase in hepatic glucose production did not change. An increase in weight occurred after 6 months of treatment (1.7 +/- 0.8 kg, P < 0.001), which was accounted for by an increase in fat mass of 1.6 +/- 1.5 kg (P < 0.02). Hemoglobin levels increased from 11.2 mg/dL to 12.1 mg/dL (P = 0.05) and platelet counts rose from 84 x 10(9)/L to 113 x 10(9)/L (P < 0.05). Although liver and spleen volumes decreased by approximately 10% and approximately 20%, respectively, there was no correlation between the decrease in organ volumes and the decrease in REE. CONCLUSIONS: Treatment with alglucerase improves hypermetabolism and organomegaly in GD, whereas the increase in glucose production persists. Therefore, the dose-response effects of alglucerase are variable for the different manifestations of type 1 GD.

Adult↗
PubMed1997

Plasma and metabolic abnormalities in Gaucher's disease.

An overview of the most important plasma abnormalities that can be found in Gaucher's disease is presented in this chapter. Attention is focussed on their practical applications and possible clinical relevance. In addition, the result of studies on metabolic alterations in Gaucher's disease are reviewed.

Gaucher Disease↗
PubMed1997

Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy.

In type 1 Gaucher disease a bleeding tendency occurs which is partly caused by thrombocytopenia due to massive splenomegaly. In addition, low levels of factors IX and XI have been described. The mechanism responsible for these clotting factor abnormalities is unknown. We performed a detailed study of parameters of coagulation and fibrinolysis in 30 type 1 Gaucher disease patients (14 splenectomized) before and after treatment with enzyme supplementation therapy. Pre-treatment aPTT and PT were prolonged in 42% and 38% of patients, respectively. In 30-60% serious deficiencies (< 50%) of coagulation factors XI, XII, VII, X, V and II were observed. The low levels of factor V correlated with platelet count and were inversely associated with splenic volume. Levels of inhibitors were mildly decreased. Markers for activation of coagulation (thrombin-antithrombin (TAT) complex) and fibrinolysis (PAP complex, fibrin cleavage product D-dimer) were significantly elevated, especially in the splenectomized patients, indicating ongoing activation of these processes. After 12 months of enzyme supplementation therapy partial correction occurred. Thus, severe disorders of the coagulation system occur in Gaucher disease, contributing to the bleeding tendency. The deficiencies may be the result of consumption of coagulation factors caused by ongoing low-level coagulation activation. possibly due to mononuclear cell activation.

Adult↗
PubMed1996

Plasma tumor necrosis factor-a (TNF-a) levels in Gaucher disease.

Tumor necrosis factor-a (TNF-a) levels were measured in the plasma of patients with different types of Gaucher disease (GD) and patients with other lysosomal storage diseases. The highest TNF-a levels were observed in the most severe neuronopathic type of GD, exceeding those found in healthy individuals as well as patients with other lysosomal disorders. Type I GD cases showed a wide range of TNF-a levels ranging from normal to 2.5 x the highest control value. TNF-a is a pleiotropic cytokine produced mainly by activated macrophages. Our data suggest that it may play a role in the pathophysiology of GD disease.

Gaucher Disease↗
PubMed1995

Individualised low-dose alglucerase therapy for type 1 Gaucher's disease.

Previous studies have shown that enzyme supplementation therapy with alglucerase for type 1 Gaucher's disease is effective at doses of 30-130 U/kg per month. Since both the clinical presentation and the response to therapy in Gaucher's disease are highly variable, individual dosing seems indicated. This notion, as well as the high costs of alglucerase and the unknown long-term side-effects, led us to investigate the efficacy of an individualised very low dose of alglucerase. Twenty-five adults with symptomatic type 1 Gaucher's disease (thirteen splenectomised) received alglucerase 1.15 U/kg three times a week (15 U/kg per month). Every 6 months, the dose was halved, maintained, or doubled, according to the response (based on haematological variables and liver and spleen volume). After 6 months of treatment, eighteen (72%) patients had a response (seventeen moderate, one good). After 12 months (in nineteen patients) and 18 months (in seven patients), all had sustained improvement. Severe splenomegaly resulted in slower haematological responses. Our results are similar to those obtained by others with higher-dose regimens and better than a low-dose regimen of 10U/kg every 2 weeks. We conclude that very low initial doses of alglucerase, when administered frequently, are effective and cost-saving in the treatment of type 1 Gaucher's disease.

Adult↗
PubMed1995

Elevated plasma chitotriosidase activity in various lysosomal storage disorders.

Recently a striking elevation of the activity of chitotriosidase, an endo beta-glucosaminidase distinct from lysozyme, was found in plasma from patients with Gaucher type I disease (McKusick 230800). Plasma chitotriosidase originates from activated macrophages and this elevation is secondary to the basic defect in Gaucher disease. To investigate the specificity of this phenomenon, we have investigated 24 different lysosomal storage diseases. In 11 different diseases increased chitotriosidase activity in plasma was found (in 28% of the patients). None of these diseases showed elevations as high as in Gaucher disease. Chitotriosidase was not significantly elevated in plasma from 20 different non-lysosomal enzymopathies or in plasma from patients with infectious diseases associated with hepatomegaly. The results show that marked elevation of chitotriosidase activity in plasma appears to be specific for Gaucher disease. The data further suggest that elevated levels of chitotriosidase activity in plasma from patients with unexplained diseases may be indicative for a lysosomal disorder.

Adult↗
PubMed1995

Increased basal glucose production in type 1 Gaucher's disease.

To evaluate the metabolic effects of Gaucher's disease, glucose metabolism and parameters of fat metabolism were studied by indirect calorimetry and primed continuous infusion of [3-3H]glucose in seven clinically stable untreated patients with type 1 Gaucher's disease and in seven healthy matched control subjects. Studies were performed in the postabsorptive state. In Gaucher patients, resting energy expenditure was increased by approximately 24% (29.4 +/- 0.7 vs. 23.7 +/- 0.8 kcal/kg.day; P < 0.01). Glucose production was increased by approximately 30% in patients compared to controls (14.00 +/- 0.51 vs. 10.77 +/- 0.26; P < 0.01), although plasma glucose concentrations and net glucose oxidation were not different. Although C peptide concentrations were not different, insulin concentrations were slightly increased in Gaucher patients (P < 0.05). The differences in basal glucose production were not related to differences in plasma concentrations of insulin or other glucoregulatory hormones. In conclusion, the increase in basal glucose production is a remarkable feature of type 1 Gaucher's disease, which cannot merely be explained by endocrine mechanisms. Because Gaucher's disease is manifested within the liver in macrophages, but not in hepatocytes, altered intrahepatic regulatory mechanisms might be involved in this increase in glucose production.

Adaptation, Physiological↗