Therapy-related Hypoglycaemia and Liver Changes Including Iron Overload in Children with Acute Lymphoblastic Leukaemia

Abstract

Tutkimuksen tarkoituksena oli selvittää lasten akuutin lymfoblastileukemian (ALL) hoidon vaikutuksia verensokerin säätelyyn ja maksaan.

Akuutin lymfoblastileukemian ylläpitohoitoa saavien lasten paastonsietokykyä tutkittiin yön yli kestävällä, enintään 16 tunnin mittaisella paastokokeella. 54%:lla (19/35) tutkituista todettiin matala verensokeri eli hypoglykemia ylläpitohoidon aikana tehdyssä paastokokeessa. 3-4 kk kuluttua hoidon päättymisestä paastonsietokyky oli jo parantunut. Tutkimus osoitti, että yöpaaston jälkeinen matala verensokeri on leukemian ylläpitohoidon mahdollinen sivuvaikutus. Suurin riski matalaan verenoskeriin on alle 6-vuotiailla.

Toisena tutkimuslinjana oli selvittää akuutin lymfoblastileukemian nykyhoidon vaikutuksia maksaan. Hoidon aiheuttamaa maksaärsytystä tutkittiin verikokein ja ottamalla maksasta koepala hoidon päättyessä. Kohonneita maksaentsyymiarvoja verikokeissa esiintyi useimmilla lapsilla hoidon aikana. Hoidon loputtua maksa-arvot kuitenkin normaalistuivat. Pääasialliset muutokset maksan koepaloissa hoidon lopussa olivat rasvamuutokset ja rautakuorma. Rautakuorma on seurausta hoidon aikana annetuista punasolusiirroista. Rasvamuutoksia, jotka kokemuksen mukaan ovat yleensä ohimeneviä, oli 93%:lla (25/27),ja rautakuormaa 70%:lla (19/27)tutkituista. Rautakuorman kohtaloa tutkittiin mittaamalla verikokein rautaparametreja 1-3 vuotta hoidon loppumisesta. Useimmilla lapsilla rautaparametrit olivat tuolloin normaalit, mutta 14%:lla (3/22) oli verikokeissa rautaylimäärää.

The aims of the present study were to investigate glucose homeostasis and fasting tolerance during therapy, and to evaluate the severity of liver disease and iron overload after therapy for childhood acute lymphoblastic leukaemia (ALL). To study fasting tolerance an overnight fasting test lasting for up to 16 hours was performed on 35 children and adolescents receiving maintenance therapy (MT) for standard risk and intemediate risk ALL. The MT consisted of daily oral mercaptopurine and weekly oral methotrexate. Nineteen out of 35 patients reached ketotic hypoglycaemia during 11 to 16 hours of fasting. Children under the age of 6 years were especially prone to hypoglycaemia. Reduced plasma levels of alanine and abnormal liver tests were associated with hypoglycaemia. No exact single etiological mechanism was revealed. Three to 4 months after cessation of chemotherapy the tendency for fasting hypoglycaemia was improved. In conclusion, hypoglycaemia after prolonged overnight fasting is a potential and insidious adverse effect during MT for ALL. However, it is reversibe, and can be prevented.

Liver disease after modern ALL therapy was studied by obtaining a liver biopsy and by measuring serum liver tests at the end of therapy in 27 children and adolescents with ALL. The main liver histological findings were microvesicular fatty change and siderosis, which occurred in 93% and 70% of the patients respectively. Liver siderosis was most often grade II/IV or III/IV. Liver fibrosis was detected less frequently than expected, in only 11% of the patients. Serum alanine aminotransferase (liver enzyme) levels reached temporarily high levels in most patients during therapy. The long-term sequelaeof liver microvesicular fatty change and siderosis, which could be associated with more severe liver histopathology like steatohepatitis and fibrosis, were not ascertained in the present study. Iron overload was evaluated histologically from liver biopsy specimens taken from 30 patients at the end of ALL therapy, and by measuring serum iron status at the end of therapy, and 1 to 3years after cessation of therapy. At the end of therapy mild, moderate and severe liver iron overload were detected in 10%, 40% and 23% of the patients respectively. In most cases iron overload seemed to be reversible. However, it was long-term in 14% of the re-studied patients. Serum ferritin was a good marker for iron overload. We recommend that serum iron status is measured at the end of ALL therapy, and followed up whenever iron overload is detected. In cases of severe iron overload treatment should be considered.