The aetiology of NICTH could be as follows: increased glucose consumption by the tumour, decreased glycogenolysis and gluconeogenesis because of the liver metastases, and suppression of the counter-regulatory hormones for insulin or insulin-like factor secreted by the tumour.
NICTH is mediated via IGF-II (molecular weight 7.5 kDa), which exhibits a high degree of structural homology to proinsulin.5,6
Only one case of ACC with NICTH has been reported.8
In that case, Cushing’s syndrome was not evident: the serum IGF-II concentration was elevated and the hypoglycaemia improved after removing the tumour; ACC tissue was positive for IGF-II immunohistochemically, but no evidence of big IGF-II associated with ACC was seen.
We report the first case of ACC presenting with both Cushing’s syndrome and NICTH in whom big IGF-II protein was demonstrated in both the serum and tumour using western blotting; the molecular weight of the IGF-II was 15–20 kDa, which is heavier than normal.
IGF-II exists in three different forms in serum: 20–30% of total IGF-II is bound to a 50 kDa IGF-binding protein (IGFBP), 70–80% of total IGF-II occurs in a 150 kDa complex, and free IGF-II is <1%. In NICTH, 70% of the patients have high molecular weight IGF-II, so-called “big” IGF-II (11–18 kDa), although the total IGF-II values are within the normal range.9
Big IGF-II forms binary complexes with IGFBP, instead of the normal ternary 150 kDa complex, and these small complexes reach insulin target organs through the capillaries. Delivered big IGF-II could increase glucose uptake and inhibit hepatic gluconeogenesis.10,11
Comprehensive gene expression profiling using DNA microarrays showed that IGF-II is expressed abundantly in ACC.12
As the ACC develops, big IGF-II is generated by abnormal processing of an IGF-II precursor.7,13
In addition, posttranslational modifications such as O-glycosylation of the residues in the first 21 positions of the proIGF-II E-domain have been suggested to be involved in the generation of big IFG-II.14
Indeed, we found variable sized protein blotted with antibody to IGF-II in both the tumour and serum of our patient.
In the clinical setting, diagnosing NICTH is difficult because the total IGF-II is within the normal range. Hizuka et al
suggested that the IGF-II/IGF-I ratio in serum is useful for detecting NICTH with big IGF-II.9
They reported that the IGF-II/IGF-I ratio in serum exceeded 20 in patients with NICTH.15
In these patients, IGF-I production could be suppressed by an insulin-like factor, big IGF-II. In our case, the IGF-II/IGF-I ratio increased to 84 in the terminal phase.
Therapeutic treatment with glucocorticoids is reported to suppress big IGF-II production.16
Notably, our case developed Cushing’s syndrome because the ACC produced excessive cortisol autonomously. However, our patient required large amounts of glucose to keep her plasma glucose within normal limits.
This is the first case of ACC in which big IGF-II was identified in both the serum and tumour using western blotting. To our knowledge, the natural clinical course of ACC is not well known because of the poor prognosis. Our case might present the natural clinical course of ACC. In the initial stage, our patient needed oral hydrocortisone; subsequently, the tumour produced superabundant cortisol resulting in Cushing’s syndrome; and finally, it caused hypoglycaemia by NICTH. With the current progress in cancer therapy, patients with ACC will live longer, resulting in more big IGF-II being produced to cause more severe hypoglycaemia. Further study will contribute to the therapy for hypoglycaemia caused by NICTH in ACC.
- The typical natural course of patients with adrenocortical carcinoma (ACC) might involve adrenal failure, Cushing’s syndrome and hypoglycaemia caused by ACC associated big IGF-II.
- Stage specific care is needed for such patients.