The effect of growth hormone treatment on the insulin-like growth factor axis in a child with nonislet cell tumor hypoglycemia

We have previously described a case of tumor-associated hypoglycemia secondary to the production of high molecular weight insulinlike growth factor (IGF)-II in a child with congenital neuroblastoma. The child's hypoglycemia resolved with GH therapy and has continued to be well controlled for 1 yr. This represents one of the first cases of nonislet cell tumor hypoglycemia (NICTH) treated successfully with long-term exogenous GH. We now present an in-depth analysis of the IGF axis in this patient, before and after GH treatment. Although IGF-II levels at presentation were in the normal range, they were inappropriate for the patient's low GH state. Furthermore, the percentage of ''big'' IGF-II was elevated, as was the level of the IGF-IIE peptide, which is normally cleaved in the processing of the mature peptide. On the initial evaluation, GH levels failed to rise in response to hypoglycemia, IGF-I levels were low, IGF binding protein-3 (IG-FBP-3) levels were suppressed, and IGFBP-2 levels were elevated. We have shown that baseline IGFBP-3 levels were low by RIA and immunoblotting and have demonstrated that this decrease was not associated with IGFBP protease activity. We have also demonstrated the baseline suppression of the acid labile subunit (ALS) of the 150K ternary complex by a novel immunoblot assay. The ratio of IGFs to IGFBP-3 was dramatically elevated, presumably leading to hypoglycemia. Furthermore, the percentage of serum IGF-I and IGF-II present as part of a binary (50K) complex with IGFBPs was also increased. GH therapy resulted in a normalization of the levels of blood sugars, IGFBP-3, ALS, IGFBP-2, and IGF-I, as well as the IGF/IGFBP-3 ratio. In summary, we have presented evidence that the hypoglycemia in this patient resulted from tumor production of high molecular weight IGF-II, which suppressed GH secretion, leading to the described derangements in the IGF binding proteins. We speculate that as a result of the decreased IGFBP-3 and ALS levels, the IGF population was shifted from the stable 150K complex to lower molecular weight complexes with IGF binding proteins, increasing IGF availability to tissues due to rapid turnover of these low molecular weight complexes. We demonstrated the reversal of the abnormalities in the IGFBP levels with GH treatment, corresponding to the clinical response of euglycemia.