Stephan vom Dahl

Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?

EPATIC ENCEPHALOPATHY (HE) iS a frequent COmH plication of chronic liver disease. Its pathogenesis is not understood, although there is agreement on the important role of neurotoxins, especially ammonia (1). In the brain of HE patients, neurons appear morphologically normal, but astrocytes exhibit signs of Alzheimer type II degeneration with nuclear enlargement, peripheral margination of chromatin and prominent nucleoli. Functional alterations in HE include selective alterations of blood-brain barrier permeability, changes in cerebral energy metabolism, an increased GABA-ergic tone and changes in several other neurotransmitter systems and their receptors (for reviews see (2-8)). However, previous hypotheses about the pathogenesis of HE were unable to explain all the facets of this clinical syndrome. Clearly, pathogenetic models have to explain the functional nature and reversibility of HE symptoms, and their precipitation by heterogeneous factors, such as infections, diuretics, sedatives, trauma, bleeding or high protein intake.

Proton magnetic resonance spectroscopy studies on human brain Myo-inositol in hypo-osmolarity and hepatic encephalopathy

BACKGROUND/AIMSnRecent in vivo studies using proton magnetic resonance (1H-MR) spectroscopy showed low levels of myo-inositol in the brain in hepatic encephalopathy; the pathogenetic relevance of this observation is unclear.nnnMETHODSnMyo-inositol and glutamine levels in the brain were studied in vivo by 1H-MR spectroscopy in patients with hypo-osmolarity and hepatic encephalopathy.nnnRESULTSnA patient with severe plasma hypo-osmolarity (222 mOsm/L) had almost undetectable signals for myo-inositol and glutamine/glutamate in the brain. Both signals reappeared after normalization of plasma osmolarity, suggesting that both myo-inositol and glutamine were released as organic osmolytes from the brain. A decreased cerebral myo-inositol signal is also found in low-grade hepatic encephalopathy but is accompanied by an increased glutamine signal. Cirrhotics without hepatic encephalopathy have near-normal inositol signals, and patients with acquired immunodeficiency syndrome encephalopathy have increased inositol signals.nnnCONCLUSIONSnThe 1H-MR spectroscopic myo-inositol signal in the human brain predominantly reflects an osmosensitive inositol pool. It is hypothesized that its depletion in latent hepatic encephalopathy points to a disturbance of cell volume homeostasis in the brain as an early pathogenetic event. This may partly be caused by a hyperammonemia-induced glutamine accumulation in the brain.

Involvement of p38MAPK in the regulation of proteolysis by liver cell hydration

BACKGROUND & AIMSnLiver cell hydration is a major determinant of proteolysis control; however, the underlying mechanisms are unknown.nnnMETHODSnThe role of mitogen-activated protein kinases for proteolysis control was studied in perfused rat liver.nnnRESULTSnHyposmolarity led to a rapid activation of Erk-2 and p38(MAPK), but not of c-Jun-N-terminal kinase 1. Likewise, isosmotic cell swelling induced by insulin, ethanol, or glutamine/glycine activated p38(MAPK). Inhibition of hyposmotic Erk activation by pertussis or cholera toxin, erbstatin, or genistein had no effect on the swelling-induced inhibition of proteolysis. Likewise, wortmannin, rapamycin, and okadaic acid were ineffective, but proteolysis recovery from hyposmotic inhibition was okadaic acid sensitive. SB203580, an inhibitor of p38(MAPK), abolished both the antiproteolytic effect of hyposmotic cell swelling and the hyposmolarity-induced inhibition of autophagic vacuole formation. Also, the antiproteolytic effect of isotonic cell swelling induced by ethanol, glutamine/glycine, or insulin was abolished by SB203580, but not the swelling potency of these agents. SB203580 had no effect on the cell hydration-independent control of proteolysis exerted by NH4Cl, asparagine, or phenylalanine.nnnCONCLUSIONSnThe data suggest an important role of p38(MAPK) in the regulation of autophagic proteolysis by cell volume in liver.

Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis

BACKGROUND & AIMSnStimulation of canalicular secretion by tauroursodeoxycholate (TUDC) involves dual activation of p38 mitogen-activated protein kinase (p38(MAPK)) and extracellular signal-regulated kinase (ERK). This study investigates the sensing and upstream signaling events of TUDC-induced choleresis.nnnMETHODSnTUDC and hypo-osmolarity effects on protein kinase activities and taurocholate excretion were studied in perfused rat liver.nnnRESULTSnTUDC induced a rapid activation of focal adhesion kinase (FAK) and Src, as shown by an increase in Y418 phosphorylation and a decrease in Y529 phosphorylation of Src. Inhibition of Src by PP-2 abolished the TUDC-induced activation of p38(MAPK) but not of FAK and ERKs. An integrin-inhibitory peptide with an RGD motif blocked TUDC-induced FAK, Src, ERK, and p38(MAPK) activation, suggesting that integrin signaling toward FAK/Src is required for TUDC-induced MAPK activation. The RGD peptide and PP-2 also abolished the stimulation of taurocholate excretion in perfused rat liver in response to TUDC. Integrin-dependent Src activation was also identified as an upstream event in hypo-osmotic signaling toward MAPKs and choleresis.nnnCONCLUSIONSnTUDC-induced stimulation of canalicular taurocholate excretion involves integrin sensing, FAK, and Src activation as upstream events for dual MAPK activation. Integrins may also represent one long-searched sensor for cell hydration changes in response to hypo-osmolarity.

Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1

Purpose: To determine whether enzyme therapy with imiglucerase/alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients.Methods: Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to <29 U/kg/2 weeks), Group B (29 U to <48 U/kg/2 weeks), Group C (48 U to <75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (Emax) and half-time to Emax (T50) of enzyme therapy for each parameter were compared across dosing groups.Results: Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to Emax and T50 over 96 months for each disease parameter.Conclusions: Enzyme therapy with imiglucerase/alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries.

Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment

We studied the effect of long‐term alglucerase/imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematological, visceral, and bone manifestations of Gaucher disease type 1 (GD1).ObjectiveWe studied the effect of long-term alglucerase/imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematological, visceral, and bone manifestations of Gaucher disease type 1 (GD1).MethodsThe International Collaborative Gaucher Group (ICGG) Gaucher Registry identified GD1 patients treated with alglucerase/imiglucerase who had dose and clinical data at first infusion and after 10xa0years of follow-up. Data for hemoglobin, platelet count, organ volumes, bone pain, and bone crisis were analyzed. Tests of the null hypothesis (no change from first infusion to 10xa0years) were performed using t tests for within-patient absolute change in continuous measurements and McNemar/chi-square tests for change in distributions using categorical values. An alpha level of 0.05 designated statistical significance.ResultsAs of October 2011, 557 nonsplenectomized and 200 splenectomized patients met the inclusion criteria. The majority of GD1 patients had at least one N370S allele. Compared with nonsplenectomized patients at first infusion, splenectomized patients had lower percentages of anemia (26.0xa0% vs. 42.8xa0%) and thrombocytopenia (14.2xa0% vs. 76.3xa0%), similar percentages of moderate or severe hepatomegaly (81.2xa0% vs. 80.0xa0%), and higher percentages of bone pain (88.9xa0% vs. 52.4xa0%) and bone crises (38.3xa0% vs. 16.0xa0%). After 10xa0years, both groups showed significant (pu2009<u20090.05) improvements in mean hemoglobin levels, platelet count, liver, and spleen (nonsplenectomized) volumes, and bone crises. Initial dosing in both groups ranged from <15 U/kg to ≤90 U/kg every 2xa0weeks. After 10xa0years, the majority was receiving 15 to ≤45 U/kg every 2xa0weeks.ConclusionTen years of imiglucerase treatment results in sustainable improvements in all GD1 parameters.

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.

Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease.

Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously - usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase - and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed.

A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase.

To assess the extent to which patients with type 1 Gaucher disease (GD1) receiving individualized enzyme replacement therapy with imiglucerase attain six defined therapeutic goals. One hundred and ninety‐five GD1 patients enrolled in the ICGG Gaucher Registry, all of whom had data available for hemoglobin, platelet count, liver volume, spleen volume, bone pain, and bone crises at first infusion and after 4 years of therapy with imiglucerase, were evaluated for achievement of published therapeutic goals. The proportion of patients who met all six therapeutic goals increased from 2.1% at first infusion to 41.5% at 4 years; ≥5 goals from 12.8% to 76.9%; ≥4 goals from 37.4% to 92.8%; ≥3 goals from 70.8% to 99.0%; and ≥2 goals from 95.4% to 99.5%. All patients met at least one goal at first infusion and after 4 years of treatment. The proportion of patients meeting specific therapeutic goals increased for all parameters between first infusion and 4 years of therapy: platelet count (24.6%–79.5%), spleen volume (25.6%–78.5%), liver volume (45.6%–90.8%), bone pain (62.6–70.3%), hemoglobin (68.2–91.8%), and bone crises (91.8–99.0%). On average, patients who received higher doses of imiglucerase achieved a greater number of therapeutic goals. This analysis provides a benchmark for evaluating the utility of a disease management approach for GD1 based on monitoring achievement of therapeutic goals after treatment with imiglucerase. Am. J. Hematol. 83:890–895, 2008.

Evidence-based recommendations for monitoring bone disease and the response to enzyme replacement therapy in Gaucher patients

ABSTRACT Background: Bone disease is a serious complication of Gaucher disease. Untreated, it can result in pain, permanent bone damage and disability. Enzyme replacement therapy reverses many of the clinical signs of Gaucher bone disease but early assessment and treatment, and regular monitoring, are essential in optimising outcomes. Scope: In September 2005, a group of European experts met to review current knowledge and identify best practice and unmet needs in the monitoring of Gaucher bone disease and the response to enzyme replacement therapy. Methods: Medline searches of peer-reviewed literature (no date restrictions) were conducted and supplemented by additional information considered relevant by panellists to furthering discussions. Findings and conclusions: The groups recommendations included: currently used biochemical bone markers are not clinically practical or reliable; plain X‐rays should not be the sole method of assessing bone disease; MRI is the most sensitive method for monitoring bone marrow infiltration by Gaucher cells; semi-quantitative methods for assessing bone marrow infiltration in routine clinical practice should use readily available technology, include an assessment of Gaucher cell infiltration in the lumbar spine and femur, and be validated for inter-rater reliability and in comparison to other methods; a multidisciplinary approach is required for the treatment of Gaucher patients; all Gaucher patients should receive a comprehensive initial radiologic evaluation for bone disease and ongoing radiological monitoring at least once every 2 years.