Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature.

Hyperargininemia is caused by deficiency of arginase 1, which catalyzes the hydrolysis of L-arginine to urea as the final enzyme in the urea cycle. In contrast to other urea cycle defects, arginase 1 deficiency usually does not cause catastrophic neonatal hyperammonemia but rather presents with progressive neurological symptoms including seizures and spastic paraplegia in the first years of life and hepatic pathology, such as neonatal cholestasis, acute liver failure, or liver fibrosis. Some patients have developed hepatocellular carcinoma. A usually mild or moderate hyperammonemia may occur at any age. The pathogenesis of arginase I deficiency is yet not fully understood. However, the accumulation of L-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role. This article provides an update on the first patients ever described, gives an overview of the distinct clinical characteristics, biochemical as well as genetical background and discusses treatment options.

[Endoscopic therapy for leaks in the gastrointestinal tract, the bile ducts and the pancreas]. / Endoskopische Therapie von Leckagen im Gastrointestinaltrakt, an den Gallenwegen und im Pankreas.

Surgery has been the mainstay of therapy in patients with gastrointestinal perforations, leakage or fistulas. New techniques for endoscopic closure of gastrointestinal perforations provide tools for an effective treatment by less invasive procedures. Temporary placement of covered self-expanding stents is an established therapy for oesophageal perforations and anastomotic leaks. Using conventional endoclips small perforations and leaks in the oesophagus and gastrointestinal tract may be closed. With the new over-the-scope-clips a more effective endoscopic full wall closure is possible in the upper gastrointestinal tract and the rectum. Endoscopically guided endoluminal vacuum therapy using polyurethane sponges is an established method for treating rectal leaks and is now increasingly used also in oesophageal leaks. Biliary leakage following endoscopic or surgical interventions is effectively treated with temporary bile stenting in most cases, but closure using metal stents or coiling may be necessary. Pancreatic leaks are a major therapeutic problem and may require multimodal therapies.

Different dose-dependent correction of MIP-1beta and chitotriosidase during initial enzyme replacement therapy.

In tissue lesions of type I Gaucher patients, characteristic lipid-laden macrophages, 'Gaucher cells', are surrounded by inflammatory phagocytes. Gaucher cells secrete the elevated plasma chitotriosidase. The elevated plasma MIP-1beta in Gaucher patients stems from the phagocytes surrounding the Gaucher cells. Plasma chitotriosidase and MIP-1beta decrease upon successful enzyme replacement therapy (ERT) with mannose-terminated recombinant glucocerebrosidase (alglucerase). Previous histochemical analysis of Gaucher spleens revealed that Gaucher cells express little mannose receptor, in contrast to surrounding phagocytes. We therefore investigated the corrective effects of ERT on plasma MIP-1beta and chitotriosidase in more detail. We also compared effects of one year of treatment with a relatively low dose and a relatively high dose of ERT. A more rapid correction in plasma MIP-1beta, compared to chitotriosidase, was observed in most patients on low-dose ERT. Correction of plasma MIP-1beta and chitotriosidase levels was more pronounced in the higher-dosed patient group. Upon prolonged treatment, differences in the effects of enzyme dose were no longer significant. Normalization of plasma MIP-1beta and chitotriosidase levels was attained in the majority of patients. In conclusion, ERT with mannose-terminated gluocerebrosidase results in prominent corrections of plasma chitotriosidase, a marker of Gaucher cells, and in particular of plasma MIP-1beta, a marker of inflammatory phagocytes. The sharper response in plasma MIP-1beta to ERT is in line with the observation that especially phagocytes surrounding Gaucher cells express mannose-receptors.

Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring.

Enzyme replacement was introduced as treatment for non-neuronopathic Gaucher disease more than 15 years ago. To ensure the best use of this costly ultra-orphan agent, a systematic disease management approach has been proposed by an international panel; this includes the development, by consensus, of achievable treatment goals. Here we critically review these goals and monitoring guidelines and incorporate emerging experience of the disease in the therapeutic era, as well as contemporary clinical research. This review makes recommendations related specifically to the management of pregnancy; the appropriate use of splenectomy and bisphosphonate treatment; the relevance of biochemical markers to disease monitoring; and the use of semi-quantitative methods for assessing bone marrow infiltration. In addition, we identify key areas for development, including the requirement for a validated index of disease severity; the need to correlate widely used biomarkers with long-term disease outcomes, and the desirability of establishing agreed standards for monitoring of bone disease particularly in infants and children with Gaucher disease.

ESPEN Guidelines on Enteral Nutrition: Liver disease.

Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility to increase or to insure nutrient intake in case of insufficient oral food intake. The present guideline is intended to give evidence-based recommendations for the use of ONS and TF in patients with liver disease (LD). It was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was discussed and accepted in a consensus conference. EN by means of ONS is recommended for patients with chronic LD in whom undernutrition is very common. ONS improve nutritional status and survival in severely malnourished patients with alcoholic hepatitis. In patients with cirrhosis, TF improves nutritional status and liver function, reduces the rate of complications and prolongs survival. TF commenced early after liver transplantation can reduce complication rate and cost and is preferable to parenteral nutrition. In acute liver failure TF is feasible and used in the majority of patients.

Characterization of inositol 1,3,4-trisphosphate phosphorylation in rat liver.

Liver homogenates phosphorylated Ins 1,3,4-P3 to an InsP4 isomer that was distinct from Ins 1,3,4,5-P4. This InsP4 isomer accumulated in vasopressin stimulated hepatocytes prelabeled with myo-[3H]inositol with a time course that lagged behind Ins 1,3,4-P3 formation. The Ins 1,3,4-P3 kinase responsible for its formation was partially purified from rat liver. The enzyme had a Km for Ins 1,3,4-P3 of 0.29 microM, a Km for ATP of 141 microM and was not affected by changes in free Ca2+ in the physiological range. The relationship of this new InsP4 isomer to the inositol phosphate signaling pathway is discussed.

Cell volume is a major determinant of proteolysis control in liver.

Hepatic proteolysis is inhibited by insulin, amino acids and hypoosmotic cell swelling and is stimulated by glucagon. These effectors simultaneously modulate cell volume in the intact liver, as shown by measurements of the intracellular water space. A close relationship exists between the effect on proteolysis and the accompanying cell volume change, regardless of whether hepatic proteolysis was modified by insulin, glucagon, cyclic AMP, glutamine, glycine, barium of hypoosmotic exposure. It is suggested that cell volume changes exerted by hormones and amino acids play a crucial role in the regulation of hepatic proteolysis.

[Gaucher disease: MR evaluation of bone marrow features during treatment with enzyme replacement]. / Morbus Gaucher: Analyse der Knochenmarkveränderungen in der MRT während Enzymersatztherapie.

PURPOSE: Enzyme replacement therapy (ERT) arrests and reverses the hematological and visceral symptoms of adult Gaucher disease, the most frequent lysosomal storage disorder. There are only a few studies available evaluating bone disease during ERT. The aim of this study was to investigate the features of bone marrow (bm) by magnetic resonance imaging (MRI) in these patients during ERT. MATERIALS AND METHODS: MRI was performed prospectively in thirty adult type I Gaucher patients before and during ERT with a mean follow-up of 3 years. Spin-echo sequences (T(1)/T(2)) of the lower extremities were obtained and the reconversion (response) or lack of reconversion (non-response) to fatty marrow during treatment was analyzed. The morphological features of bm involvement, a homogeneous or non-homogeneous distribution of bm changes and focal bone lesions surrounded by a rim of reduced signal intensity (SI), were analyzed. RESULTS: Infiltration of bm by Gaucher cells is characterized by a reduction of SI on both T(1)- and T(2)-weighted sequences. Bone marrow responses were seen in 19 patients (63 %) during treatment. Focal bone lesions, surrounded by a rim of reduced SI, did not respond to ERT and correlated with a non-homogenous distribution of bone involvement and splenectomy. CONCLUSION: In adult patients with type I Gaucher disease receiving ERT, treatment effects on bone disease can be demonstrated by MRI using Spin-echo sequences due to the partial reconversion of fat marrow. A non-homogeneous type of signal appearance and a status post splenectomy correlate with the presence of bone infarcts.

First long-term results of imiglucerase therapy of type 1 Gaucher disease.

BACKGROUND/AIMS: In the early 1990s, enzyme replacement therapy with modified placental glucocerebrosidase (alglucerase, Genzyme Corporation, Cambridge, MA, USA) was shown to arrest or reverse complications and to improve quality of life in patients with type 1 Gaucher's disease. More recently, modified recombinant glucocerebrosidase (imiglucerase, Genzyme Corporation) has been shown to be safe, effective and clinically equivalent to alglucerase by two studies which presented data for 12 months' follow-up. This case report, with 30 months' follow-up, represents the first publication of long-term results of imiglucerase therapy of type 1 Gaucher's disease in Europe. METHODS: Retrospective analysis of safety and efficacy of 30 months' imiglucerase infusions, 40 U/kg body weight every 2 weeks for 17 months, then 60 U/kg every 2 weeks for 13 months, in an elderly male patient with severe type 1 Gaucher's disease. RESULTS: No adverse reactions occurred, and anti-imiglucerase antibody assay was negative at 17 months. Clinically, the patient responded rapidly and markedly. Within several months, bone pain decreased notably, enabling him to abandon crutches. Abdominal pain abated, fatigue decreased and physical fitness and general well-being improved. Nosebleeds and haematomas ceased. Dosage increase massively reduced hepatosplenomegaly and produced much greater improvement in laboratory values, especially platelet count. Bone pain diminished further, so that this formerly disabled patient now walks and climbs stairs without complains. Also of note, aminotransferases, gamma-GT, total protein, and prothrombine time improved, suggesting improvement of liver function. CONCLUSIONS: This case documents long-term safety and efficacy of recombinant enzyme replacement in type 1 Gaucher's disease.

[Diagnosis and therapy of Gaucher disease. Current recommendations of German therapy centers in the year 2000]. / Diagnose und Therapie des Morbus Gaucher. Aktuelle Empfehlungen der deutschen Therapiezentren im Jahr 2000.

BACKGROUND: Gaucher's disease is the autosomally recessively inherited deficiency of the lysosomal enzyme glucocerebrosidase. Increasing storage of glucocerebrosides leads to a multisystem disease, the prevalence of which is about 1:40,000 in central Europe and up to 1:2,000 in some other countries (e.g. Israel). The acute and chronic neuronopathic forms of the disease (formerly defined as Gaucher types 2 and 3) account for only 5 to 10% of all Gaucher patients in Central Europe and Germany and are thus less frequent than the non-neuronopathic disease (formerly defined as Gaucher type 1). Gaucher's disease is usually associated with spleno- and hepatomegaly, fatigue, skeletal complications, and several corresponding hematological and laboratory abnormalities. In 5 to 10% of the patients there are also central nervous symptoms such as myoclonic seizures, oculomotoric apraxia and a slight mental retardation. METHODS: Four specialized centers care for more than 2/3 of all German Gaucher patients today. These centers present their consensus recommendations for state-of-the-art diagnosis and treatment of Gaucher's disease. RESULTS: Recent epidemiological data indicate that only 10 to 20% of all Gaucher patients are correctly diagnosed (and treated) in Germany. The diagnosis today can be done in all patients by noninvasive methods, i.e. determination of the glucocerebrosidase activity in peripheral leukocytes and of the genetic defect. The current enzyme replacement therapy with glucocerebrosidase has proven effective to improve and often normalize hematological abnormalities, hepatosplenomegaly, skeletal complications and quality of life, provided that the therapy is started early and is given at adequate dosages. CONCLUSION: In view of the availability of an effective therapy, efforts should be made to increase the awareness of Gaucher's disease in differential diagnosis, to help to diagnose the disease with noninvasive techniques at early stages, and to provide practical guidelines for adequate treatment.

[MRI bone marrow findings in 63 patients with type I Gaucher disease]. / MRT der Knochenmarkverändungen bei 63 Patienten mit Morbus Gaucher Typ I.

PURPOSE: To determine whether MR bone marrow findings in Gaucher patients may help to identify patients at high risk of developing severe Gaucher bone complications exemplified by avascular necrosis (AVN) of the femoral head. MATERIALS AND METHODS: MR images were obtained in 63 Type I Gaucher patients through a standard protocol using coronal T 1 and T 2-weighted sequences of the lower extremities. The location and extent of infiltrated marrow was established using a semi-quantitative MRI scoring method (Düsseldorf Gaucher score, DGS) and the morphological pattern of bone marrow involvement determined (whether homogeneous type A or non-homogeneous type B). The active marrow process with bone edema and AVN of the femoral head were also analyzed. RESULTS: Bone marrow involvement was observed in femoral sites more than in tibial sites. A high DGS was significantly correlated with type B morphology and femoral AVN (both p < 0.0001). Splenectomized patients showed a significantly higher Düsseldorf Gaucher score and type B morphology than non-splenectomized patients (both p < 0.05). AVN was seen in 46 % of patients with type B morphology versus 3 % in type A morphology (p < 0.0001). DGS and morphology of bone marrow involvement were not significantly correlated with active marrow processes. CONCLUSION: Type B marrow morphology and extensive marrow packing were significantly associated with AVN of the femoral head (both p < 0.0001). These patterns are considered predictive and may be employed in a disease management context to alert physicians to the need for urgent therapeutic measures.

Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature.

Gaucher disease type I, the most common lysosomal storage disorder, is associated with immunoglobulin abnormalities. We studied the prevalence, risk factors, pathogenesis, and effect of enzyme relation therapy (ERT) on gammopathies in an adult Gaucher disease type I cohort (N = 63) and related the results to a review of the currently available literature. Polyclonal gammopathies and monoclonal gammopathy of undetermined significance (MGUS) in our adult GD I cohort were found in 41% and 19% of patients. These results are similar to the data from the literature and correspond to the increased risk of multiple myeloma (MM) that has been described. The prevalence of MGUS in our cohort increased with age but was not associated with disease severity or exposure time. The serum levels of free light chains of immunoglobulins were measured and were not found predictive for the development of MGUS or MM. Levels of pro- as well as anti-inflammatory cytokines, growth factors, and chemokines, especially those involved in inflammation and B-cell function, are disturbed in GD I, with the most impressive and consisting elevations for interleukin-10 and pulmonary and activation-regulated chemokine. A beneficial effect of ERT on the occurrence and progression of gammopathies was suggested from longitudinal data.

Cell hydration and mTOR-dependent signalling.

Insulin- and amino acid-induced signalling by the mammalian target of rapamycin (mTOR) involves hyperphosphorylation of the p70 ribosomal S6 protein kinase (p70S6-kinase) and the eukaryotic initiation factor 4E (eIF4E) binding protein 4E-BP1 and contributes to regulation of protein metabolism. This review considers the impact of cell hydration on mTOR-dependent signalling. Although hypoosmotic hepatocyte swelling in some instances activates p70S6-kinase, the hypoosmolarity-induced proteolysis inhibition in perfused rat liver is insensitive to mTOR inhibition by rapamycin. Likewise, swelling-dependent proteolysis inhibition by insulin and swelling-independent proteolysis inhibition by leucine, a potent activator of p70S6-kinase and 4E-BP1 hyperphosphorylation, in perfused rat liver is insensitive to rapamycin, indicating that at least rapamycin-sensitive mTOR signalling is not involved. Hyperosmotic dehydration in different cell types produces inactivation of signalling components around mTOR, thereby attenuating insulin-induced glucose uptake, glycogen synthesis, and lipogenesis in adipocytes, and MAP-kinase phosphatase MKP-1 expression in hepatoma cells. Direct inactivation of mTOR, stimulation of the AMP-activated protein kinase, and the destabilization of individual proteins may impair mTOR signalling under dehydrating conditions. Further investigation of the crosstalk between the mTOR pathway(s) and hyperosmotic signalling will improve our understanding about the contribution of cell hydration changes in health and disease and will provide further rationale for fluid therapy of insulin-resistant states.

Increased incidence of cancer in adult Gaucher disease in Western Europe.

The adult form of Gaucher disease (type I GD) is associated with a high prevalence of hypergammaglobulinemia and monoclonal gammopathy of undetermined significance (MGUS). A significantly increased risk of cancer, especially of hematological types, has been found in Ashkenazi-Jewish GD type 1 patients. In this study, incidence and mortality of cancer were assessed in a total of 131 GD patients of mixed ancestry in a population from Western Europe, i.e. 2 Gaucher referral centers in Germany (Düsseldorf) and the Netherlands (Amsterdam). Standardized rate ratios were determined by indirect standardization, using age- and sex-specific incidence and mortality rates of the Dutch population. A total of 14 GD patients of non-Ashkenazi-Jewish descent were identified of whom 5 had a hematologic malignancy. These numbers correspond to an increased risk of cancer of 2.5 (95% CI 1.1-4.7) and an increased risk of hematologic cancer of 12.7 (95% CI 2.6-37.0) among GD patients compared to the general population. In particular, the incidences of multiple myeloma and hepatocellular carcinoma in absence of preexisting cirrhosis were highly elevated, with standardized rate ratios of 51.1 (95% CI 6.2-184) and 141.3 (95% CI 17.1-510.5), respectively. These strongly increased risks on developing cancer suggest that measures for early detection and prevention of hematological and hepatic malignancies in patients with Gaucher type I disease are mandatory.

Nutritional state and the swelling-induced inhibition of proteolysis in perfused rat liver.

Recent work indicates that cell volume is an important regulator of proteolysis in liver. The antiproteolytic effects of insulin and some amino acids (e.g., glutamine and glycine) are mediated by increases in cell volume. The purpose of the present study was to assess the role of nutritional state in the cell volume-dependent regulation of proteolysis in isolated perfused rat liver. In rats that had been prelabeled by an intraperitoneal injection of L-[4,5-3H]leucine 16-20 h prior to the perfusion experiment, hepatic proteolysis was studied by determination of [3H]label release into effluent perfusate. In separate perfusion experiments [3H]inulin and [14C]urea, acting as markers for extracellular and the sum of extra- plus intracellular space, were employed for determination of effector-induced cell volume changes. Proteolysis in the perfused rat liver was inhibited by insulin-like growth factor-I (IGF-1) and taurocholic acid. Both agonists increased the intracellular water space. The nutritional state of the livers had marked influence on the hormone- and amino acid-dependent regulation of proteolysis. In livers from food-deprived rats for 24 h, the swelling responses to glycine, glutamine and alanine were enhanced, whereas the insulin- and IGF-1-induced increases of cell volume were diminished. A stronger inhibition of proteolysis was observed in livers from food-deprived rats upon addition of the amino acids, whereas the insulin- and IGF-1-mediated inhibition of proteolysis was attenuated. Independent of the nutritional state, a close relationship between the cellular hydration state and the corresponding inhibition of proteolysis was observed, regardless of whether cell volume was modified by amino acids, hormones, hypoosmotic exposure or bile acids. We conclude that the nutritional state markedly modifies the swelling potency of amino acids and hormones in liver and by this means affects proteolysis.

Experimental methods in hepatology. Guidelines of the German Association for the Study of the Liver (GASL). Liver perfusion--technique and applications.

Perfused rat liver is a well-established model for studies on hepatic metabolism. The different perfusion systems, the technical requirements and the surgical preparation steps are described. A main advantage of liver perfusion is the maintenance of liver architecture-rendering it a feasible model for the study of interactions between parenchymal and non-parenchymal cells. Furthermore, steady-state conditions allow the calculation of metabolic flux rates and the reversibility of agonist-induced effects can be studied within the same preparation. As the polarity of the cells is maintained, sinusoidal uptake, metabolism and biliary excretion of substances can be studied. Some applications of liver perfusion and special techniques are described, the advantages specified and the limitations of this model discussed. Due to recent developments in monitoring of liver hemodynamics, extracellular ion concentrations and changes of liver cell volume, liver perfusion is one of the best-controlled experimental systems in the study of hepatic physiology.