Two originally prepubertal girls suffering from glycogen storage disease type Ia and short stature were treated with low-dose diazoxide (3-4.8 mg/kg per day) for 7 and 4 years, respectively. Both showed an impressive catch-up growth following this treatment. This appeared to be due to prolongation of normoglycaemia after meals and reduction of fasting lactic acidosis by diazoxid

Mullis, P.

Nuoffer, J.

Wiesmann, U.

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J. Inher. Metab. Dis. 20 (1997) 790È798SSIEM and Kluwer Academic Publishers. Printed in the Netherlands(Treatment with low-dose diazoxide in twogrowth-retarded prepubertal girls withglycogen storage disease type Ia resulted incatch-up growthJ. M. NUOFFER, P. E. MULLIS and U. N. WIESMANN*Division of Endocrinology and Metabolism, University ChildrenÏs Hospital, Bern,Switzerland* Correspondence : ChildrenÏs University Hospital, Inselspital, CH, 3010 Bern,SwitzerlandMS received 6.2.97 Accepted 14.4.97Summary : Two originally prepubertal girls su†ering from glycogen storagedisease type Ia and short stature were treated with low-dose diazoxide (3È4.8mg/kg per day) for 7 and 4 years, respectively. Both showed an impressivecatch-up growth following this treatment. This appeared to be due to prolonga-tion of normoglycaemia after meals and reduction of fasting lactic acidosis bydiazoxide.Growth retardation is a well-known complication in patients with glucose-6-phos-phatase deÐciency (glycogen storage disease (GSD) type Ia ; McKusick 232200)(Fernandes and Berger 1987). It is almost universal in infancy but responds variablyto di†erent types of therapies for reasons that are not yet clear. Introduction ofuncooked cornstarch during night time as well as nocturnal gastric tube feedingpartially improved height velocity (Wolfsdorf et al 1990 ; Chen et al 1993) but not inall patients. The use of diazoxide in patients with GSD type Ia was Ðrst describedby Rennert and Mukhopadhyay (1968) for the improvement of glucose homeostasis.The treatment was of short-term duration because of skin rashes and was laterforgotten. Unaware of this early observation, we started to treat a female patientwith diazoxide in 1987. In this paper, we report as a new Ðnding a catch-up growthin two prepubertal female patients with GSD type Ia following prolonged treatmentwith low doses of diazoxide (3È4.8 mg/kg per day) for 7 and for 4 years, respectively.Since diazoxide therapy prolongs normoglycaemia in the patients, it signiÐcantlyreduces elevated blood lactate concentrations. We therefore speculate that bloodlactic acidosis is a major cause of growth retardation in GSD type Ia and thatgrowth retardation may be alleviated by long-term diazoxide treatment.790Diazoxide in glycogen storage disease Ia 791Table1E†ectsofdiazoxideaPatient1Patient2BeforeOntreatmentBeforeOntreatment(n)(mean^SD)(n)(mean^SD)(p-value)(n)(mean^SD)(n)(mean^SD)Lactate77.73^0.5893.69^1.220.01847.89^0.9833.66^0.64(mmol/L)Cholesterol86.66^0.54116.86^0.490.575510.65^5.939.48^1.03(mmol/L)HDL-cholesterol100.67^0.11101.11^0.140.00530.45^0.2820.79^0.23(mmol/L)Triglycerides88.01^1.48113.94^1.010.011511.87^8.33312.1^2.32(mmol/L)One-yearheightb7[2.7,[1.110[1.1,9.40.0183[3.5,[1.43[1.9,5.6velocitySDSaBloodlactateandlipidsweredeterminedbetween08:00and09:00after2hfasting.p-ValueswerecalculatedwiththeWilcoxonsignedranktest.Becauseofthesmallnumberofdata,nostatisticsweredoneonpatient2databGrowthdataaregiveninone-yearheightvelocitystandarddeviationscores(Praderetal1989).Sincethedistributionofthesegrowthdataisnotnormalweindicatetherange,ratherthanmeanandSDJ. Inher. Metab. Dis. 20 (1997)792 Nuo†er et alFigure 1 (a) Growth chart (Prader et al 1989) of patient 1. Start of diazoxide therapy andadaptation of dosage for increased weight, on two occasions, are indicated by arrows. A fewmonths after introduction of diazoxide therapy an impressive catch-up growth started. Boneage remained retarded throughout the treatment with diazoxide and, as indicated in the(L)lower part of the chart, there was a delayed pubertal developmentCASE REPORTSThe Ðrst patient, a girl, was born as the third child to unrelated parents after a41-week normal pregnancy, birth weight 3920 g (50thÈ90th centile), length 51 cm(50thÈ90th centile), head circumference 35 cm (50th centile). At the second day oflife, the child was referred to our hospital because of a transient tachypnoea of thenewborn (TTN) with metabolic acidosis (pH 7.35, 21.3 mmHg, base excesspCO2[10). Lactate measured 9 days later was 2.98 mmol/L. In addition a hepatomegaly(5.5 cm below costal margin) and a functional systolic murmur were found. Hyper-insulinism causing hypoglycaemia was excluded. There was no rise in blood glucoseconcentrations but an increase in lactate after intravenous glucagon. Diagnosis ofglucose-6-phosphatase deÐciency was established at 4 weeks of age by liver biopsy.A diet consisting of 6È8 meals per day restricted in galactose and fructose butenriched in glucose and polyunsaturated fat was initiated. Uncooked cornstarch wasintroduced at the age of 3 months (2 g/kg body weight distributed over all mealsinitially, later during night time). Oral therapy with was started at 3NaHCO3J. Inher. Metab. Dis. 20 (1997)Diazoxide in glycogen storage disease Ia 793Figure 1 (b) Growth chart (Prader et al 1989) of patient 2. Start of diazoxide therapy isindicated by an arrow. A few months after introduction of diazoxide therapy an impressivecatch-up growth started. There was a delayed pubertal development, as indicated in the lowerpart of the chart, and bone age remained retarded during the Ðrst year of catch-up(L)growth. Later, growth and bone age were probably a†ected by advancing pubertal develop-mentmonths of age and at 10 months allopurinol was added. This medication has contin-ued up to the present time.The patient was seen at regular intervals in our outpatient clinic. She was admit-ted several times to our hospital because of recurrent urinary tract infections withpoor control of glycaemia. A malformation of the urinary tract could be excluded.Urinary tract infections subsided after the age of 10 years. Preprandial hyper-lacticacidaemia was repeatedly measured at 08 :00 to 09 :00 (Table 1). It still persist-ed when uncooked cornstarch was given during night time.Initially (according to the Swiss growth charts, Prader et al (1989)), the girl grewbetween [0.3 and [1 SDS. After the age of 5 years, the growth gradually droppeduntil it was below [2 SDS at 8 years of age (Figure 1a).At the age of years a trial with diazoxide (initially 4.8 mg/kg per day divided101112in three doses) was started. The drug was given with the main meals. Following thistreatment a signiÐcant reduction of both blood lactate concentrations and hyperlip-idaemia was achieved. At the age of and of 15 years respectively, the dosage of13 412J. Inher. Metab. Dis. 20 (1997)794 Nuo†er et alFigure 2 E†ects of diazoxide (open circles and broken curve) on blood lactate (solid squaresand solid curve) in patient 1. Start of diazoxide therapy is indicated with an arrow. Diazoxidewas given in three divided doses with the main meals. The dosage was adapted for increasedweight on two occasions because the metabolic parameters (lactate and lipids) again becameless favourable. Blood lactate was determined between 08 :00 and 09 :00 after 2 h fastingdiazoxide was adapted for increased weight, because the metabolic parameters(lactate and lipids) again became less favourable (Figure 2).Following this observation, we decided to treat another prepubertal Swiss patientwith GSD type Ia. Her growth pattern had followed the curve [0.5 to [1 SDS onthe Swiss growth chart (Prader et al 1989) until 2 years and dropped below [2 SDSat 3 years of age (Figure 1b). A trial with diazoxide (3.3 mg/kg per day taken inthree doses together with the main meals) was started at years of age. Previous11 412to treatment bone age was retarded by 4 years according to Greulich and Pyle(1959). Since this patient lives in Asia, controls were possible only once a yearduring vacations in Switzerland. Apart from frequent meals, a special diet was notfollowed but she had uncooked cornstarch during the night time.EFFECTS OF DIAZOXIDE TREATMENTShortly after the introduction of diazoxide therapy, lactic acidaemia signiÐcantlydecreased in both patients. Furthermore, after 12 months on treatment an impres-sive increase in the 1 year height velocity (cm/year) SDS was noted (Figure 3). Thedi†erence of height velocities SDS (pretreatment and on treatment) was signiÐcant(Table 1). Bone age assessed according to the method by Greulich and Pyle (1959)remained retarded by 2È3 years in the Ðrst patient, and her pubertal developmentwas still clearly delayed during the Ðrst years of her catch-up growth (Figure 1a). Inthe meantime, puberty started. In case 2, delay of bone age had lessened at the timeJ. Inher. Metab. Dis. 20 (1997)Diazoxide in glycogen storage disease Ia 795of the last clinical control in our outpatient clinic and pubertal development prog-ressed to maturity. The initial catch-up growth, however, did not occur at theexpense of advance in bone age.As shown in Table 1, there was a signiÐcant amelioration of HDL-cholesterol andtriglycerides in patient 1, whereas total cholesterol remained elevated. In patient 2,values of blood lipids remained abnormally high despite diazoxide therapy. Therewere no signiÐcant changes of plasma pH and bicarbonate following diazoxidetherapy ; a reduction of negative base excess in both patients was suggested but notstatistically validated.In both patients, liver size diminished during diazoxide administration. In the Ðrstpatient, liver size before treatment was 12.3^ 0.5 cm below costal margin. After 1year of therapy, the liver size reduced to 8.0 cm and has remained 8.8^ 1 cm up tothe present time. In the second patient, the liver size before treatment was 13.5 ^ 0.5cm; during 3 years of treatment it was 11.5^ 0.5 cm. Following treatment withdiazoxide, a signiÐcant weight gain was experienced from initially the 25th to the97th centile over a period of 7 years in the Ðrst case, and from the 25th to the 50thcentile over a period of 3 years in the second case.No signiÐcant side-e†ects, such as hypertrichosis, water retention, change inblood pressure or worsening of hyperuricaemia, were noted in either patient. Tomonitor the risk of diazoxide administration producing hyperglycaemic insulino-penia in the patients, fructosamine and were measured regularly. These para-HbA1cmeters remained normal in both patients.Figure 3 Growth versus blood lactate (patient 1). Blood lactate (broken curve) was deter-mined between 08 :00 and 09 :00 after 2 h fasting. Growth data are given in one-year heightvelocity standard deviation scores (open circles, solid curve) (Prader et al 1989). Diazoxidetherapy was started at the age of years. The dosage was adapted for increased weight on101112two occasions, because the metabolic parameters (lactate and lipids) again became lessfavourableJ. Inher. Metab. Dis. 20 (1997)796 Nuo†er et alIn case 1, oral glucose tolerance test (45 g/m2) was performed after 2 h fasting andadministration of 25 mg diazoxide. Blood sugar concentrations prior to the testwere 4.92 mmol/L (norm 4.23^ 0.49) ; at 30 min 9.74 mmol/L (norm 7.4^ 1.3) ; at60 min 8.01 mmol/L (norm 6.4^ 1.1) ; at 120 min 6.88 mmol/L (norm 5.3^ 0.8) ;and at 180 min 3.88 mmol/L (norm 4.0^ 0.9), respectively. The correspondinginsulin concentrations were at the mean level for healthy controls : at the beginning13 mU/L (norm 9.5 ^ 7.1) ; at 30 min 46 mU/L (norm 49 ^ 25.7) ; at 60 min 53mU/L (norm 47.7 ^ 36.3) ; at 120 min 35 mU/L (norm 31.3 ^ 26) ; and at 180 min 6mU/L (norm 16.7 ^ 13.5). C-Peptide values remained at the lowest norm through-out the test. Lactate at the beginning of the test was only slightly elevated (2.73mmol/L).DISCUSSIONIn GSD type Ia the release of free glucose from glucose 6-phosphate from the liverinto the blood is greatly impaired, although glycogenolysis and glycogenesis arenormal. This results in early hypoglycaema 2È3 h after a meal. Since glycolysis ofglucose 6-phosphate is intact or even intensiÐed under hormonal counterregulationsimilar to a fasting state, production of pyruvate and lactate is increased. Lacticacidosis becomes more severe whenever postabsorptive sources of glucose areexhausted. The resulting chronic acidosis is usually treated by alkalinization withoral doses of NaHCO3 .Chronic metabolic acidosis is an important growth-inhibiting factor as shown byChalla and colleagues (1993) and in clinical studies by Mehls and colleagues (1992).A severe lactic acidaemia exceeding 5 mmol/L seems to impair normal growth (Smit1993). Therefore, short stature and growth retardation are common features of GSDtype Ia, especially in pre- and pubertal patients, although postpubertal catch-upgrowth seems possible (Smit 1993).Therapy with diazoxide was started with the idea of avoiding early and prolongedhypoglycaemic states between meals as well as to reduce excessive production oflactate. Diazoxide was introduced for therapy of idiopathic hypoglycaemia in child-hood (Goodman et al 1968). It was equally successful in preventing hypoglycaemiain patients a†ected with hypopituitary dwarÐsm (Ventura et al 1983). In 1968,Rennert and Mukhopadhyay suggested treatment with diazoxide in patients withGSD type Ia. Only a few other clinicians (Bartolozzi et al 1975 ; Gardoni and Giran-zani 1978) took up this proposition. All reported an improved glucose, lipid andacid homeostasis and a marked reduction in hepatomegaly in several patients. Inmost patients, however, diazoxide had to be stopped because of various cutaneousallergic reactions. To our knowledge there are no reports on long-term treatmentwith diazoxide in GSD patients, and more speciÐcally e†ects on growth retardationin GSD Ia.The mode of action of diazoxide seems to be linked to K`-ATP channel activa-tion. The resulting hyperpolarization of the membranes decreases insulin release(Dunne et al 1987 ; Edwards and Weston 1990). Diazoxide is usually given in 3È4doses at meal times. Its half-life in the body after oral administration is 24È36 h ;J. Inher. Metab. Dis. 20 (1997)Diazoxide in glycogen storage disease Ia 797elimination is through the kidneys. In spite of its rather slow excretion, it appearsreasonable to give it at the beginning of meals and eventually before going to bed.The drug is usually well tolerated and allergic reactions to the presently com-mercially available preparation are rare.Following diazoxide therapy, lactic acidaemia in both patients improved and inpatient 1 triglycerides and HDL-cholesterol levels nearly normalized. Althoughthere were no signiÐcant changes of plasma pH and in bicarbonate concentrations,negative values of base excess ameliorated in both patients, suggesting a reductionin acid load. The impressive increase of height velocity SDS came with a delay ofseveral months and without simultaneous advance in bone age. There was no indi-cation that this initial increase was related to a pubertal growth spurt. Pubertalmaturation was delayed in both patients as usually seen in GSD Ia, but in themeantime it has started in both girls.The diminution of the liver size in both patients on diazoxide therapy was impres-sive. Diazoxide may lessen fatty inÐltration of the liver and hyperlipidaemia throughindirect inhibition of peripheral lipolysis. Hyperlipidaemia results fromhypoglycaemia-induced lipolysis and increased triglyceride synthesis from plasmafree fatty acids in the liver.We conclude from our observations that diazoxide prolonged the postprandialeuglycaemia, preventing early fasting hypoglycaemia. It successfully reduced lacticacidosis and thereby induced the impressive catch-up-growth in our patients. Sinceshort stature is a psychological problem during childhood, we consider that diaz-oxide may be an alternative add-on treatment, to allow a normal growth during thisperiod in patient with GSD type Ia.REFERENCESBartolozzi G, Bernini G, Marianelli L, Nasi P (1975) Two cases of type-1 glycogenosis withhyperuricemia. Minerva Pediatr 27 : 1229È1241.Challa A, Krieg RJ Jr, Thabet MA, Veldhuis JD, Chan JD (1993) Metabolic acidosis inhibitsgrowth hormone secretion in rats : mechanism of growth retardation. Am J Physiol 265 (4Pt 1) : E547È553.Chen YT, Bazzarre CH, Lee MM, Sidbury JB, Coleman RA (1993) Type I glycogen storagedisease : nine years of management with cornstarch. Eur J Pediatr 152 (supplement 1) :S56ÈS59.Dunne MJ, Illot MC, Peterson OH (1987) Interaction of diazoxide, tolbutamide and ATP4on nucleotide-dependent K` channels in an insulin-secreting cell line. J Membr Biol 99 :215È224.Edwards G, Weston AM (1990) StructureÈactivity relationships of K` channel openers.T rends Pharmacol Sci 11 : 417È422.Fernandes, J, Berger R (1987) Urinary excretion of lactate, 2-oxoglutarate, citrate, and glyc-erol in patient with glycogenosis type I. Pediatr Res 21 : 279È282.Gardoni L, Giranzani F (1978) Treatment of a case of type-1 glycogenosis with diazoxide.Minerva Pediatr 30 : 1535È1542.Goodman HG, Morishima A, Grumbach MM (1968) The use of diazoxide in hypoglycemiain childhood. Ann NY Acad Sci 152(2) : 367È372.Greulich WW, Pyle SI (1959) Radiological Atlas of Skeletal Development of the Hand andW rist. Stanford CA: Stanford University Press.J. Inher. Metab. Dis. 20 (1997)798 Nuo†er et alMehls O, Blum WF, Schaefer F, Tonsho† B, Scharer K (1992) Growth failure in renaldisease. Clin Endocrinol Metab 6 : 665È685.Baillie`reÏsPrader A, Largo RH, Molinari L, Issler C (1989) Physical growth of Swiss children frombirth to 20 years of age. First Zurich longitudinal study of growth and development. HelvPaediatr Acta Suppl 52 : 1È125.Rennert OM, Mukhopadhyay D (1968) Diazoxide in Von GierkeÏs disease. Arch Dis Child 43 :358È361.Smit GPA (1993) The long-term outcome of patients with glycogen storage disease type Ia.Eur J Pediatr 152 (supplement 1) : S52ÈS55.Ventura A, Canciani M, Tamaro P (1983) Efficacy of diazoxide in preventing hypoglycemia ina child a†ected by hypopituitary dwarÐsm. Acta Paediatr Scand 72 : 309È311.Wolfsdorf JI, Rudlin CR, Crigler JF Jr (1990) Physical growth and development of childrenwith type 1 glycogen-storage disease : comparison of the e†ects of long-term use of dextroseand uncooked cornstarch. Am J Clin Nutr 52 : 1051È1057.J. Inher. Metab. Dis. 20 (1997)

Treatment with low-dose diazoxide in two growth-retarded prepubertal girls with glycogen storage disease type Ia resulted in catch-up growth

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Treatment with low-dose diazoxide in two growth-retarded prepubertal girls with glycogen storage disease type Ia resulted in catch-up growth

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