70

Praca oryginalna Endokrynol. Ped., 7/2008;3(24):65-70

71

Starzyk J. i inni – Hemoglobinuria in patients with newly diagnosed type 1 diabetes mellitus without glucose 6-phosphate dehydrogenase deficiency...

Vol. 7/2008 Nr 3(24)

Endokrynologia PediatrycznaPediatric Endocrinology

Hemoglobinuria in Patients with a Newly Diagnosed Type 1 Diabetes Mellitus without Glucose 6-phosphate Dehydrogenase Deficiency – a Novel Observation in Two Cases

Hemoglobinuria u chorych ze świeżo rozpoznaną cukrzycą typu 1 bez niedoborudehydrogenazy glukozo-6-fosforanowej – nowe obserwacje na przykładzie dwóch przypadków

1Jerzy Starzyk, 1Małgorzata Wójcik, 1Marta Ciechanowska, 1Małgorzata Stelmach, 1Joanna Nazim, 2Mateusz Jagła

1Klinika Endokrynologii Dzieci i Młodzieży Katedry Pediatrii2Klinika Chorób Dzieci Katedry Pediatrii; Uniwersytet Jagielloński, Collegium Medicum, Kraków

Adres do korespondencji: dr hab. n. med. Jerzy Starzyk; Klinika Endokrynologii Dzieci i Młodzieży; Katedry Pediatrii PAIP UJ CM; ul. Wielicka 265; 30-663 Kraków; tel.: (+48) 012 658 12 77; fax: (+48) 012 658 10 05; e-mail: mistarzy@cyf-kr.edu.pl

Słowa kluczowe: Cukrzyca typu 1,hemoglobinuria, niedobór dehydrogenazy glukozo-6-fosforanowejKey words: Type 1 Diabetes Mellitus, hemoglobinuria, glucose 6-phosphate dehydrogenase deficiency

STRESZCZENIE/ABSTRACT

All cases of hemoglobinuria in patients type 1 diabetes described so far have been caused by the coincidence of hypo-, hyperglycemia and/or ketoacidosis and the deficiency of glucose-6-phosphate dehydrogenase (G6PD). We present two boys, aged 14 (P1) and 17 (P2) years with a newly diagnosed type 1 diabetes (glycemia: 33.3 mmol/l, 11.7 mmol, respectively), who developed hemoglobinuria, epigastric pain, nausea and vomiting 3 (P1) and 12 (P2) hours following IV administration of an isotonic fluid infusion (isotonic dehydration >10% P1, <5% P2), 8.4% bicarbonate solution in P1 (pH 6.9, BE (-)28), IV insulin (Actrapid P1, Humulin R P2), 15% KCl (2-4 mEq/100 ml IV fluid) and IV bolus of Metamizole – 4 mg after 1 hour (P1) and 2 mg after 4 hours (P2). In both cases, glucose-6-phosphate dehydrogenase (G6PD) deficiency – the only described cause of hemoglobinuria in diabetes (13.6 P1, 12.8 P2, N 13.55±2.45 IU/gHb), as well as other known potential hemoglobinuria causes were excluded. This implies that the initial period of diabetes mellitus type 1, even without ketoacidosis, in rare conditions predisposes patients with normal G6PD activity to hemolysis and hemoglobinuria. This might be due to another, not yet defined defect of glycolytic/pentose phosphate pathway or membrane in patients’ red blood cells. Pediatr. Endocrinol. 7/2008; 3(24):71-74.

72

Praca kazuistyczna Endokrynol. Ped., 7/2008;3(24):71-74

73

Starzyk J. i inni – Hemoglobinuria in patients with newly diagnosed type 1 diabetes mellitus without glucose 6-phosphate dehydrogenase deficiency...

Wszystkie opisane dotychczas przypadki hemoglobinurii u chorych z cukrzycą typu 1 wywołane były współistnie-niem hipo-, hiperglikemii i/lub kwasicy ketonowej oraz niedoboru dehydrogenazy glukozo-6-fosforanowej (G6PD). W pracy przedstawiono dwóch chłopców, w wieku 14 (P1) oraz 13 (P2) lat ze świeżo rozpoznaną cukrzycą typu 1 (glikemia odpowiednio: 33.3 mmol/l, 11.7 mmol), u których po odpowiednio 3 (P1) i 12 (P2) godzinach od rozpoczę-cia nawadniania iv (odwodnienie izotoniczne >10% P1, <5% P2), podaniu 8.4% NaHCO3 iv u P1 (pH 6.9, BE (-)28), insuliny iv (Actrapid P1, Humulin R P2), 15% KCl (2-4 mEq/100 ml) oraz jednorazowej dawki iv Metamizolu – 4 mg po 1 godzinie (P1) i 2 mg po 4 godzinach (P2), wystąpiła hemoglobinuria, ból brzucha, nudności i wymioty. W obu przypadkach wykluczono niedobór dehydrogenazy glukozo-6-fosforanowej (G6PD), jedynej dotychczas opisanej przyczyny hemoglobinurii w przebiegu cukrzycy (13.6 P1, 12.8 P2, N 13.55±2.45 IU/gHb). Wykluczo-no również inne, potencjalne przyczyny hemoglobinurii. To sugeruje, że hemoliza i hemoglobinuria może wystąpić u chorych ze świeżo rozpoznaną cukrzycą typu pierwszego, nawet bez kwasicy ketonowej oraz przy prawidłowej ak-tywności G6PD. Może to wynikać z innego, nieokreślonego defektu szlaków glikolizy/pentozofosforanowego lub błony komórkowej erytrocytów. Endokrynol. Ped. 7/2008; 3(24):71-74.

Introduction

All cases of hemoglobinuria in patients with a newly diagnosed type 1 diabetes described so far concerned male patients with congenital, genetic deficiency of glucose-6-phosphate dehydrogenase (G6PD) [1-7]. This enzyme defect, transmitted as a recessive X-linked trait, affects approximately 400 millions of males originating mainly from Africa, Asia and Mediterranean countries [8]. In European countries, it is observed only sporadically. G6PD catalysis is the first stage of the pentosophosphate pathway, responsible for maintaining the appropri-ate concentration of the reduced glutathione form within an erythrocyte, and the cellular membrane integrity under oxidative stress. In G6PD deficient patients, oxidative stress evoked by a variety of factors decreases the concentration of the reduced form of glutathione in red blood cells (RBC) caus-ing prompt hemolysis and hemoglobinuria [8]. In diabetic patients with G6PD deficiency, diabetic ketoacidosis (DKA) and/or rapid alterations of se-rum glucose concentration were postulated as the cause of oxidative stress and hemoglobinuria [1-7]. We present a novel observation of two males with a newly diagnosed type 1 diabetes, in whom mas-sive hemolysis and hemoglobinuria have not been caused by a congenital G6PD deficiency.

Case reports

Patient 1 (P1) A previously healthy 14-year-old boy, with

a 2-week history of polyuria and polydypsia was ad-mitted in a moderately severe state, with circulatory centralization, dehydration and disturbed mental auto and allo-orientation. The medical history of the patient and his family was negative for diabe-

tes, anemia and hemoglobinuria. On admission, he presented with hyperglycemia of 33.3 mmol/l; DKA – pH 6.9, BE (-28); increased acetonuria and glycosuria. The results of other basic tests, includ-ing serum ions and blood cell count, were normal – hematocrit 50.2%, hemoglobin 17.2 g/dl, RBC 5.8 mln/mm3, WBC 19 800/mm3. Administration of isotonic 0.9% NaCl solution was started. Due to epigastric pain with concomitant nausea, the patient received a single IV dose of 4 mg of Metamizole after 1 hour of hospitalization. After subsequent two hours, during an IV infusion of insulin (Ac-trapid) at the dose of 0.1 IU/kg/h, the patient passed red-brownish urine, which was tested and which revealed the presence of free hemoglobin crystals. A repeated blood cell count demonstrated the de-crease in the hematocrit value (36.5%), hemoglobin concentration (12.9 g/dl) and RBC (4.4 mln/mm3).lactate dehydrogenase (1368 IU/1, N: 313-618 IU/1)and bilirubin (38 umol/l, N: 3-22 umol/l) concentra-tion values were elevated. Ultrasonography ruled out any renal abnormalities. Blood smear and os-motic resistance of RBC were normal. No serum immune antibodies against surface antigens of RBC were detected. G6PD activity determined by spectrophotometry was normal, amounting to 13.6 IU/gHb (N: 13.55±2.45 IU/gHb).

Patient 2 (P2) A previously healthy, 17-year-old male, with

a 2-week history of polydypsia, polyuria and weak-ening and a negative personal and family history of diabetes, anemia and hemoglobinuria was ad-mitted in a good general condition, presenting no clear signs of dehydration. His glycemia was 11.7 mmol/l; HbA1c 7.9%, no biochemical determinants of DKA were found – serum pH 7.42, no acetonuria. Other lab results, including blood cell count, were

72

Praca kazuistyczna Endokrynol. Ped., 7/2008;3(24):71-74

73

Starzyk J. i inni – Hemoglobinuria in patients with newly diagnosed type 1 diabetes mellitus without glucose 6-phosphate dehydrogenase deficiency...

normal – hematocrit 47%, hemoglobin 16.6 g/dl, RBC 5.71 mln/mm3, WBC 7100/ mm3. IV hydration with 0.9% NaCl solution was started and followed by an IV insulin (Humulin R) infusion at the dose of 0.01-0.02 IU/kg/h. Approximately 4 hours after the admission, he was administered a single IV dose of 2 mg of Metamizole due to severe epigastric pain. After approximately 12 hours of hospitalization, following an episode of vomiting, the patient passed red-brownish urine, which was tested and revealed the presence of free hemoglobin crystals.

A follow-up blood cell count demonstrated the decrease in the hematocrit value (41%), hemoglobin concentration (14.6 g/dl), RBC (4.9 mln/mm3) and elevated reticulocytosis (9 ‰) Ultrasonography ruled out any renal abnormalities. Blood smear was normal, similarly as osmotic resistance of RBC. No serum immune antibodies against surface antigens of RBC were detected. G6PD activity determined by spectrophotometry was normal, amounting to 12.8 IU/gHb (N: 13.55±2.45 IU/gHb).

Discussion

The only cause of hemolytic anemia and hemo-globinuria in patients with type 1 diabetes described so far is a congenital G6PD defect, which is more frequent in this group of patients in comparison to the general population [9]. G6PD deficiency in such cases was demonstrated, based either on medical history or determinations of the enzyme activity [1-7]. In both of the above-described cases, the activity of G6PD was normal and the other com-mon causes of hemolysis and hemoglobinuria were excluded. Pyruvate kinase deficiency was excluded on the basis of negative history of anemia and hemolysis, no hepatomegaly and splenomegaly, and relatively high reticulocytosis (9‰ in P2, no data available in P1), following the hemolysis episode. Autoimmune hemolysis, congenital and acquired RBC membrane defects and hemoglobinopathies were excluded due to the absence of autoantibod-ies, normal blood smears and osmotic resistance, no evidence of bacterial or viral infection, respec-

tively. Taking into consideration the fact that fluid supplementation and insulin administration were performed in both patients in the standard way and DKA was observed only in one patient, these factors had probably no influence on hemolysis/hemoglobinuria development. Metamizole, an an-algetic administered frequently in the past and only incidentally at present, has never been associated with this adverse event in patients, including those with a newly diagnosed type 1 diabetes. However, a concomitant role of hyperglycemia and/or insulin in hemolysis/hemoglobinuria mechanism in some predisposed patients cannot be excluded. Prolonged intense hyperglycemia results in glycation of surface proteins of erythrocyte membrane, including CD 59 protein, and subsequently facilitates their binding complement elements, causing chronic, but not acute, hemolysis and anemia [10]. Another factor that might potentially weaken the structure of eryth-rocyte membrane in the described patients might be a relative insulin deficiency or its rapid supple-mentation. In normal individuals, insulin increases calcium concentration within a red blood cell with a subsequent increase of the activity of phosphof-ructokinase in the glycolytic pathway, which in-creases ATP production, stabilizes the membrane of a red blood cell and prevents its hemolysis [11]. In turn, glycolysis activation, acting via a feedback mechanism, prevents an excessive increase of calci-um concentration within an erythrocyte, which may also be a cause of hemolysis, especially in the case of insufficient glycolysis activation resulting from any enzymatic defect or a decreased phosphate con-centration in the initial period of intensive treatment of a patient with a newly diagnosed type 1 diabetes [12,13].

The novel observation in two patients suggests that the initial period of diabetes mellitus type 1, even without ketoacidosis, in rare conditions pre-disposes patients with normal G6PD activity to hemolysis and hemoglobinuria. This might be due to another, not yet defined defect of glycolytic/pen-tose phosphate pathway or membrane in patients’ red blood cells.

74

Praca kazuistyczna Endokrynol. Ped., 7/2008;3(24):71-74

[1] Gant F.R., Winks G.F.: Primaquine sensitive hemolytic anemia complicating diabetic acidosis. Clin. Res. 1961: 9, 27.[2] Galli-Tsinopoulou A., Nousia-Arvanitakis S.: Glucose-6-phosphate dehydrogenase deficiency-induced hemolysis in newly diagnosed diabetic monozygotic twins. J. Ped. Endocrinol. Metab., 2000: 13(6), 669-672.[3] Haroun M., G-6-PD Deficiency-Induced Hemolysis in Diabetic Twins. Indian Ped., 2005: 2(17), 705-707.[4] Vanelli M., Lucentini L., Picco P., Galanello R., Chiari G, Adinolfi B., Street M.E.: Blood glucose normalization-induced haemolysis in three adolescents with type 1 diabetes mellitus at onset and unknown G-6-PD deficiency. J. Ped. Endocrinol. Metab., 1996: 9(2), 193-196.[5] Shalev O., Eliakim R., Lugassy G.Z., Menczel J.: Hypoglycemia-induced hemolysis in glucose-6-phosphate dehydrogenase deficiency. Acta Hematol. 1985: 74(4), 227-229.[6] Messsina M.F., Lombardo F., Crisafulli G., Salzano G., Rosano M., Di Giorgio R.M.: Hemolytic crisis In non-ketotic and euglycemic child with glucose-6-phosphate dehydrogenase deficiency and onset of type 1 diabetes mellitus. J Ped. Endocrinol. Metab., 2004: 17(12), 1671-1673.[7] Shalev O., Eliakim R., Menczel J.: Diabetic ketoacidosis does not precipitate hemolysis In patients with the Mediterranean variant of glucose-6-phsphate deficiency. Brit. Med. Journ., 1984: 288, 179-180.[8] Frank J.E., Maj M.C.: Diagnosis and Management of G6PD deficiency. Am. Fam. Phys.: 2005: 72(7), 1277-1282.[9] Niazi G.A.: Glucose-6-phosphate dehydogenase deficiency and diabetes mellitus. Int. J. Hematol. 1991: 54(4), 295-298.[10] Davies C.S., Harris C.L., Morgan P.B.: Glycation of CD59 impairs complement regulation on erythrocytes from diabetic subjects. Immunology 2005: 114, 280-286.[11] Zancan P., Sola-Penna M.: Regulation of human erythrocyte metabolism by insulin: cellular distribution of 6-phosphofructo-1- -kinase and its implications for red blood cell function. Mol. Genet. Metab.,2005: 86(3), 401-411.[12] Assouline-Cohen M., Beitner R.: Effects of Ca 2+ on erythrocyte membrane skeleton-bound phosphofructokinase, ATP levels, and hemolysis. Mol. Genet. Metab., 1999: 66(1), 56-61.[13] Casteels K., Beckers D., Wouters C, Van Geet C.: Rhabdomyolysis in diabetic ketoacidosis. Pediatr. Diabetes, 2003: 4(1), 29-31.

PIŚMIENNICTWO/REFERENCES