Etiology of common childhood acute lymphoblastic leukemia: the adrenal hypothesis

Abstract

The pattern of infections in the first years of life modulates our immune system, and a low incidence of infections has been linked to an increased risk of common childhood acute lymphoblastic leukemia (ALL). We here present a new interpretation of these observations -the adrenal hypothesis -that proposes that the risk of childhood ALL is reduced when early childhood infections induce qualitative and quantitative changes in the hypothalamus-pituitary-adrenal axis that increase plasma cortisol levels. This may directly eliminate leukemic cells as well as preleukemic cells for the ALL subsets that dominate in the first 5-7 years of life and may furthermore suppress the Th1-dominated proinflammatory response to infections, and thus lower the proliferative stress on preexisting preleukemic cells.

Implications of infectious diseases and the adrenal hypothesis for the etiology of childhood acute lymphoblastic leukemia

“…Although access to health care has gradually improved the identification of pediatric malignancies, the scenario re-garding age and incidence of ALL remains unchanged when we compare the present data with previous publications (9,10). The age-peak profile today seems to be the same as a decade ago, supporting the assumption of Schmiegelow et al (1) that the lower registration of childhood ALL is not simply the result of underreporting or misdiagnosis notifications. This dataset analysis has also demonstrated that there was a 3-fold increase in the diagnosis of acute leukemia from 2000-2007 compared to 1990-1999 (7).…”

“…In a recent publication Schmiegelow et al (1) proposed the important role of plasma cortisol level in the etiology of common-acute lymphoblastic leukemia (c-ALL), which they called "adrenal hypothesis". This hypothetical etiology of c-ALL emerged from several lines of evidence obtained from descriptive epidemiological data around the world (2), and from clinical evidence of the mechanism of adrenocorticotropic hormone therapy (3).…”

“…The combination of ethnic homogeneity, free and easily accessible public health care, and unparalleled registration of all children diagnosed with leukemia has made the Nordic countries an excellent setting to test the hypothesis that supports the protective role of infections in c-ALL pathogenesis (5). Infections can stimulate the hypothalamus-pituitary-adrenal axis, leading to increased plasma cortisol levels sufficient to eliminate clonal leukemic cells originating during fetal life (1).…”

Allergy and the risk of childhood leukemia: a meta-analysis

“…Furthermore, according to the adrenal hypothesis by Schmiegelow, an increase in plasma cortisol levels in early childhood may destroy leukemic and preleukemic cells. 3 Two recent studies have shown that children with an atopic predisposition (parental atopy) have an increased cortisol response to stressful stimuli compared with non-predisposed children. 9,10 This increased responsiveness of the hypothalamus-pituitary-adrenal axis in children with atopic dispositions could hypothetically lead to an elimination of ALL cells, because of their high glucocorticorticosteroid sensitivity and explain the protective role of allergy.…”

“…Greave's 2 delayed infections hypothesis proposes that childhood acute lymphoblastic leukemia (ALL) is caused by two independent mutations; the first mutation occurs in utero, and if the child has limited exposure to early childhood infections, such infections willFwhen they occur later during childhoodFlead to an excessive proliferative stress on the preleukemic cells, which cause the necessary additional leukemogenic chromosomal aberrations. Finally, the adrenal hypothesis of Schmiegelow et al 3 claims that the risk of childhood ALL is reduced, when early childhood infections increase plasma cortisol levels, as this may eliminate both leukemic and preleukemic cells for the ALL subsets that dominate in the first 5-7 years of life, and may further suppress the Th1-dominated (proinflammatory) response to infections, and thus lower the proliferative stress on preexisting preleukemic cells.…”