Granulocyte colony-stimulating factor in glycogen storage disease type 1b. Results of the European Study on Glycogen Storage Disease Type 1

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Granulocyte colony-stimulating factor in glycogen storage disease type 1b. Results of the European Study on Glycogen Storage Disease Type 1
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  See discussions, stats, and author profiles for this publication at: Granulocyte colony-stimulating factor inglycogen storage disease type 1b. Results of theEuropean Study on Glycogen Storage DiseaseType 1. Eur J Pediatr DOI 10.1007/s00431-002-10...  ARTICLE   in  EUROPEAN JOURNAL OF PEDIATRICS · OCTOBER 2002 Impact Factor: 1.89 · DOI: 10.1007/s00431-002-1010-0 · Source: PubMed CITATIONS 41 READS 32 9 AUTHORS , INCLUDING:Gepke VisserUniversity Medical Center Utrecht 124   PUBLICATIONS   1,236   CITATIONS   SEE PROFILE Philippe LabruneUniversité Paris-Sud 11 274   PUBLICATIONS   2,860   CITATIONS   SEE PROFILE Kurt UllrichUniversity of Hamburg 205   PUBLICATIONS   4,422   CITATIONS   SEE PROFILE Udo WendelHeinrich-Heine-Universität Düsseldorf  287   PUBLICATIONS   4,934   CITATIONS   SEE PROFILE Available from: Philippe LabruneRetrieved on: 14 January 2016  ORIGINAL PAPER Gepke Visser  Æ  Jan Peter Rake  Æ  Philippe LabruneJames V. Leonard  Æ  Shimon Moses  Æ  Kurt UllrichUdo Wendel  Æ  Klaas H. Groenier  Æ  G. Peter A. Smit Granulocyte colony-stimulating factor in glycogen storagedisease type 1b. Results of the European Study on Glycogen Storage Disease Type 1 Published online: 17 July 2002   Springer-Verlag 2002 Abstract  Patients with glycogen storage disease type 1b(GSD-1b) have neutropenia and neutrophil dysfunctionthat predispose to frequent infections and inflammatorybowel disease (IBD), for which granulocyte colony-stimulating factor (GCSF) is given. To investigate theuse and the value of GCSF treatment in GSD-1b, aretrospective registry of GSD-1 patients born between1960 and 1995 in 12 European countries was established.Included were 57 GSD-1b patients. UnglycosylatedGCSF was given to 18 patients, median age of startingtherapy was 8 years, longest duration of therapy 7 years.Dose varied between 2–10  l g/kg, with a frequency fromdaily to twice per week. Neutropenia (defined as anabsolute neutrophil count <0.5 · 10 9 /l) was found in 49patients. In untreated patients, a significant decreaseof haemoglobin, platelet counts and leucocyte countswith increasing age ( P  <0.032,  P  <0.04 and  P  <0.001respectively) was noted, whereas neutrophil countsremained low but stable with increasing age. In ninepatients who were treated longer than 1 year, medianneutrophil counts increased significantly and simulta-neously median leucocyte counts and platelet countsdecreased significantly. In all patients treated, thenumber and severity of infections decreased and theseverity of IBD improved subjectively. The most seriouscomplication of GCSF treatment was marked spleno-megaly (four patients).  Conclusion:  in this retrospectivestudy a significant haematological effect was docu-mented and a subjective improvement of infections andinflammatory bowel disease. In view of the uncertainty,prospective controlled trials seem warranted to clarifythe indication for the use of granulocyte colony-stimu-lating factor in this disease. Keywords  Gylcogen storage disease type 1b  Æ Granulocyte colony-stimulating factor  Æ Neutropenia  Æ  Treatment Abbreviations  ESGSD  European study onglycogen storage disease  Æ  GCSF   granulocyte colonystimulating factor  Æ  GSD  glycogen storage disease  Æ IBD  inflammatory bowel disease Introduction Glycogen storage disease type 1 (GSD-1) (McKusick232200), is caused by inherited defects of the glucose-6-phosphatase complex. This complex has a key role inboth glycogenolysis and gluconeogenesis, convertingglucose-6-phosphate to glucose. The clinical featuresare hepatomegaly, growth retardation, osteopenia andkidney enlargement with hypoglycaemia, hyperlactaci-daemia, hyperlipidaemia and hyperuricaemia [10].Based on the most plausible molecular model, glucose- Eur J Pediatr (2002) 161: S83–S87DOI 10.1007/s00431-002-1010-0G. Visser ( & )  Æ  J.P. Rake  Æ  G.P.A. SmitBeatrix Children’s Hospital, University Hospital,Groningen, The NetherlandsP. LabruneHospital Antoine-Be ´cle `re, Clamart, France J.V. LeonardInstitute of Child Health,Great Ormond Street Hospital, London, UKS. MosesDepartment of Paediatrics,Soroka Medical Centre, Beersheva, IsraelK. UllrichDepartment of Paediatrics,University Hospital, Hamburg, GermanyU. WendelDepartment of Paediatrics,University Hospital, Du ¨sseldorf, GermanyK.H. GroenierDepartment of General Practice,University Hospital Groningen, The Netherlands Present address:  G. VisserWilhelmina Children’s Hospital,University Hospital Utrecht, PO Box 85090,3508 AB Utrecht, The Netherlands,Tel.: +31-30-2504000, Fax: +31-30-2505350,e-mail:  6-phosphatase is a multicomponent complex with a hy-drolytic unit, glucose-6-phosphatase, and one or moremembrane transporters [3,4]. Inborn errors of the cata-lytic unit of glucose-6-phosphatase are called GSD-1a.Defects of the putative transporters were named GSD-1b, GSD-1c and GSD-1d [20], but molecular geneticstudies have shown that patients who had been diag-nosed as GSD-1b, 1c and the putative 1d, all had mu-tations in the G6P transporter [2]. Recently a GSD-1cpatient without mutations in G6P transporter gene wasdescribed suggesting the existence of a distinct GSD-1clocus [18]. In the present study, the term GSD-1b is usedto include patients formerly diagnosed as GSD-1b, 1cand 1d. This corresponds to the clinical observations, asGSD-1 divides in two types: GSD-1a patients have‘classical’ signs and symptoms as listed above, and GSD-1 non-a patients may also have neutropenia and neutr-ophil dysfunction that predisposes to severe infectionsand to inflammatory bowel disease (IBD).Neupogen (Filgrastim), a recombinant granulocytecolony-stimulating factor (GCSF), has identical biolog-ical activity as endogenous GCSF, but contains a N-terminal methionine residue and is not glycosylated.Lenograstim is glycosylated GCSF and in vitro seems tobe more potent and stable than Filgrastim. The clinicalsignificance of these differences still has to be established[12,13]. During recent years, this growth factor has beenused to accelerate the recovery of neutrophil counts afterchemotherapy and also in patients with neutropenia dueto other causes. In addition to its enhancing effect on theproduction of neutrophils, GCSF also modulates severalneutrophil functions [15, 16, 24,25].Patients with GSD-1b and neutropenia have beentreatedwithGCSFsince1989.Thisresultedinanincreasein neutrophil count and regression of the IBD [16, 21,22],but this effect has not been evaluated systematically. Thisis important because some of the complications of treat-ment with GCSF could be especially harmful to GSD-1bpatients. Significant osteopenia has been described inpatients with congenital neutropenia treated with GCSF[11] and there is an increased risk of osteopenia in IBD[7,26]. Osteopenia is a well recognised complication of GSD-1 [17,23] so patients with GSD-Ib on GCSF may beat particularly high risk of this complication. Malignanttransformation during long-term treatment with GCSFhas been reported in congenital neutropenia, but mainlyin those patients with a GCSF receptor mutation [6,8].The aim of the study was first to evaluate the use of GCSF treatment in GSD-Ib patients and second to in-vestigate the value of GCSF treatment in GSD-Ib. AsGSD-Ib is a rare disorder, this has been studied as partof the collaborative European Study on GlycogenStorage Disease Type 1 (ESGSD). Patients and methods Patients were identified from hospital records of 16 metaboliccentres in 12 European countries. Patients were coded by initialsand date of birth to check for duplication. Retrospective patientrecords were discussed in a multicentre meeting and filled in byeither the treating physician or by one of the investigators (JPR).All patients known in the participating centres born after 1960 wereincluded. Clinical details of the patients are described elsewhere[27]. The diagnosis of GSD-1b was established by absent or verylow glucose-6-phosphatase-activity in intact microsomes and(sub)normal glucose-6-phosphatase-activity in disrupted micro-somes [20], most times in combination with identification of mu-tations in the glucose-6-phosphate transporter.Mean haematological values per patient were calculated overeach year in all GSD-1b patients. Height measurements were ex-pressed as SD score adjusted for age, sex and ethnic group. Spleensize was documented by ultrasound measurements and related toappropriate standards for age. In two patients treated with GCSFfor >1 year bone mineral density of the lumbar spine (L1-L4) wasstudied longitudinally, using dual-energy X-ray absorptiometry.Z-scores for bone mineral density were obtained by comparing withage-matched (3–16 years) reference values. Although bone mineraldensity is negatively influenced by skeletal size, so bone mineraldensity in smaller subjects, such as GSD-1 patients with a stuntedheight, is underestimated. However, as the difference between theindividual measurements was analysed, the patients acted as theirown control.StatisticsAll data were analysed using non-parametric tests although somedata had a normal distribution. The Mann-Whitney test was usedto compare the haematological data of GSD-1b patients with andwithout GCSF test. The Wilcoxon signed rank was used to com-pare haematological data of GSD-1b patients before and during>1 year GCSF treatment. Haematological data in different age-groups were analysed using the Jonckheere-Terpstra test which ismost appropriate for data with a natural order. Box-and-whiskerplots were used as a graphical means of summarising the data. Thebox indicates the lower and upper quartiles and the centre line isthe median. The points at the end of the whiskers are the 2.5% and97.5% values and outliers points indicate the extreme values [1]. A P   value of <0.05 was considered statistically significant. Results The ESGSD includes 288 patients with GSD-1, of whom57 had GSD-1b. The GSD-1b patients were born be-tween 1964–1995; 30 males and 27 females, of whom 49are still alive. The median age when data were collectedwas 8.7 years. In most patients (51), the diagnosis wasconfirmed by liver biopsy. In six patients the diagnosiswas based on clinical symptoms and a sibling with adiagnosis in enzyme assay.Unglycosylated GCSF was used in 18 patients, onepatient was given both unglycosylated and glycosylatedGCSF. GCSF was always given subcutaneously. Themedian age of starting therapy was 8 years, with thelongest duration of therapy 7 years. The indications forstarting GCSF were severe IBD in seven patients (con-firmed by colonoscopy and bowel biopsies), frequent orserious infections in seven patients (sepsis two, deepabscess two, respiratory tract infections five, pyogenousskin infections four, gastrointestinal infections four,urinary tract infections three), a combination of bothinfections and IBD in three other patients and preop-erative one gift in one patient. Neutropenia alone was S84  not a reason to start treatment. The dose used variedfrom 0.5–3  l g/kg (four patients) to 4–5  l g/kg (11patients) to 6–10  l g/kg (three patients). The frequencyof GCSF administration was daily in eight patients,2–4/week in seven patients, and intermittent in threepatients.Before any treament, the haematological values of untreated patients ( n =38) (haemoglobin, platelets, totalleucocytes, neutrophils, all non-significant) did not differsignificantly from those who were subsequently treatedwith GCSF for more than 1 year ( n =11). The haema-tological data in patients not receiving GCSF showed asignificant decrease in haemoglobin, platelet counts andleucocyte counts with increasing age ( P  <0.032,  P  <0.04and  P  <0.001 respectively), whereas neutrophil countsremained low but stable (not significant) (Fig. 1). Bycontrast, during treatment median neutrophil countsincreased significantly (p<0.043), and platelet countsand leucocyte counts also decreased significantly( P  <0.028 and  P  <0.015 respectively) (Fig. 2).In all treated patients there was a positive clinicalresponse as both the frequency and the severity of theinfections and the IBD improved as subjectively doc-umented by the treating physicians. One patient hadstill serious relapses of IBD, requiring hospitalisationand parenteral feeding, for which glycosylated GCSFwas added to the treatment scheme. Despite this thepatient still had recurrent infections and relapses of IBD. Although some individual patients treated withGCSF had catch-up on height, when the whole groupwas compared with an age and sex matched group of patients not treated with GCSF, there was no differ-ence.In GSD-1b patients no fractures were reported. Bonemineral density of the lumbar spine in two GSD-1bpatients using GCSF >1 year were investigated longi-tudinally and decreased from SD –2.6 to –2.9 and fromSD –2.8 to –2.9 after 4.3 and 1.5 years respectively.Splenomegaly was reported in 20 of the 57 GSD-1bpatients (35.1%), whereas this was only reported in 11 of the 198 GSD-1a patients (5.5%). Progressive spleno-megaly was noted in four patients, most marked in twopatients with pre-existing splenomegaly. One patientdeveloped hypersplenism and the spleen size regressedwhen the frequency of GCSF was reduced from daily totwice per week. Transient bone pain was reported in twopatients, transient fever and arthralgia in one patient.No side-effects were noted in ten patients. Discussion In this study, all GSD-1b patients treated with GCSFresponded haematologically to low doses of unglycosy-lated GCSF (2–10  l g/kg per day). In patients treated forlonger than 1 year, median neutrophil counts increasedsignificantly and median platelet counts and totalleucocyte counts decreased. Furthermore, there was asubjective by the treating physician reported, but not welldocumented, reduction in the frequency and severity of the infections and the severity of IBD. Thus the decreasein platelet and leucocyte counts might be a sign of  Fig. 1.  Haematogical valuesper age group in GSD-1bpatients. The box indicates thelower and upper quartiles andthe centre line is the median.The points at the end of thewhiskers are the 2.5% and97.5% values and outlierspoints indicate the extremevalues. In the figures of theplatelets and the leucocytes, dotted lines  represent bordersof the normal valuesS85  diminished inflammation. Haematological data of un-treated patients showed a decrease in haemoglobin,platelets and total leucocyte counts with increasing age,but neutrophil counts which were low remained stable.The decrease in platelet and leucocyte counts in those onGCSF might therefore also represent in part the normalnature course.Based on the retrospective data, the effect of GCSFon infection rate and IBD could not be quantified. Thiscould, however, in part be due to the fact that retro-spective data were used, in which the IBD was under-diagnosed and thus not sufficiently monitored [27]. Twopatients with cyclic neutropenia and Crohn ileocolitiswere described, who remained in complete remissionduring GCSF therapy [9]. In GSD-1b no complete re-mission of the IBD was found, despite the increase inneutrophil counts. However, GCSF does not correctneutrophil function completely [19]. The mechanism bywhich GCSF might have a beneficial effect on the IBD inGSD-1b is not clear. From studies in rats it is knownthat an inhibitor of neutrophil activation is effective inreducing colonic injury in both acute and reactivatedcolitis [28]. In experimental colitis high dose GCSFtherapy resulted in a decrease of pro-inflammatory me-diators [14].In the present study, two treated patients studiedlongitudinally showed slightly progressive osteopenia.However, no untreated patients have been studied lon-gitudinally, so the decrease might be the effect of aging.None have had severe bone complications so far. Thenature of osteopenia in GSD-1 is still unknown: bothdeficient bone matrix formation (osteoporosis) and ab-normal bone mineralisation (osteomalacia) have beensuggested.A serious adverse effect of GCSF treatment wassplenomegaly, especially if there was pre-existingsplenomegaly, which was also found in a recent report of 12 patients on GCSF [5]. One patient (not included inthe study) developed splenomegaly on GCSF therapyfor which splenectomy was performed but the patientdied of postoperative complications. Autopsy showedmassive extramedullary haematopoiesis, especially in thespleen. In view of the risk of hypersplenism, carefulmeasurement of spleen size before and during treatmentwith GCSF is indicated.Based on this retrospective study, apart from hema-tological effects no unequivocal improvement in out-come on GCSF in GSD-1b could be established. In viewof the uncertainty prospective controlled trials seemwarranted to clarify the indication for the use of GCSFin this disease. A proposal for treatment and follow-upof GSD-1b patients is found in this same issue. Acknowledgements  Part of this study has been made possible bygrants from Amgen, Breda, The Netherlands and Aventis Pharma,Amstelveen, The Netherlands. Participating centres: Austria (Prof W Endres, Dr D Skladal, Innsbruck), Belgium (Dr E Sokal,Brussels), Czech Republic (Dr J Zeman, Prague), France (Prof PLabrune, Clamart), Germany (Dr P Bu ¨hrdel, Leipzig, Prof KUllrich, Hamburg, Dr G Da ¨ublin, Prof U Wendel, Du ¨sseldorf),Great Britain (Prof JV Leonard, Dr P Lee, Prof G Mieli-Vergani,London), Hungary (Dr L Szo ¨nyi, Budapest), Italy (Dr P Gandullia,Prof R Gatti, Dr M di Rocco, Genova, Prof G Andria, Dr D Melis,Napoli), Israel (Prof S Moses), Poland (Prof E Pronicka, Dr J Fig. 2.  Haemoglobin, platelet,leucocyte and neutrophil countsin GSD-1b patients withoutGCSF ( I  ) and with GCSF ( II  ).Of group II on the left side arevalues prior to treatment andon the right side are values>1 year of GCSF treatment. P   values comparing group Iwith group II prior to treatmentare printed near I,  P   valuescomparing group II patientsbefore and on treatment areprinted above group II. Thebox indicates the lower andupper quartiles and the centreline is the median. The points atthe end of the whiskers are the2.5% and 97.5% values andoutliers points indicate theextreme valuesS86
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