Should We Still Use Glucose-Suppressed Growth Hormone Levels for the Evaluation of Acromegaly?

Abstract

Acromegaly is associated with increased mortality if not adequately treated (1). Currently accepted biochemical criteria for cure of acromegaly include a mean 24-h GH level less than 2.5 g/liter (5 mU/liter) and/or a glucose-suppressed GH level of less than 1 g/liter (2 mU/liter) and a normal IGF-I (2). These criteria wereproposedbyBatesetal. (3)whoshowedthatpatientswithGH levels less than 2.5 g/liter did not show an increase in mortality. Since l993, this GH cutoff has been widely applied based on the relative paucity of data relating normal IGF-I levels to normal life expectancy. More recently, Holdaway et al. (4) demonstrated that IGF-I (expressed as an SD score) was significantly associated with mortality. Specifically, they showed that patients with last follow-up IGF-I of at least 2 SD had a mortality ratio 3.5 times higher than thosewithan SD score less thanzero (4).Theyalso showed that mortality was 1.6 times higher in patients with last follow-up GH levels less than 2 g/liter, whereas mortality was similar to the control population in patients with last follow-up GH levels less than 1 g/liter, suggesting that cure criteria should be modified, at least for levels of GH. No data are available concerning mortality and the GH nadir after glucose, yet it is included in almost all studies examining the efficacy of treatment in acromegaly. There are several areas of debate related to the value of the GH response to glucose. First, the additional diagnostic value over a fasting GH level is limited when the IGF-I level is elevated (5), and additionally, a similar diagnostic accuracy of a GH profile and nadir GH after glucose was demonstrated in a large series of patients (6). Second, the clinical implication of a single unsuppressed GH level in patients studied after surgery and showing normal serum IGF-I levels and GH levels below the threshold of cured patients is still a matter of discussion. In this setting, Freda et al. (7) showed that patients considered cured after surgery (normal IGF-I and postglucose GH nadir 0.14 g/liter) did not demonstrate recurrence of acromegaly in long-term follow-up. These data suggest a very relevant role for assessment of GH after glucose to detect patients with a likelihood for recurrence, which is clearly an important clinical outcome. The threshold GH nadir of no more than 0.14 g/liter is, however, well below that mentioned in the 2000 consensus criteria for cured acromegaly (2); the lower threshold was justified by using a highly sensitive GH assay able to detect levels as low as 0.05 g/liter. Lower nadir GH values of 0.25 and 0.26 g/liter after glucose, also using a highly sensitive GH assay, were reported by Costa et al. (8) and Gullu et al. (9), respectively. Thus, the question as to which GH cutoff value should be used for postglucose GH nadir immediately rises. The assay sensitivity is a crucial aspect of diagnostic accuracy of any biochemical test. It is now known that previously used polyclonal RIAs for GH were insufficiently sensitive to discriminate GH levels around 2 g/liter (5). Modern immunoradiometric assays for GH have a detection limit of 0.05 g/liter, so the ability to discriminate postglucose GH levels in patients with active acromegaly vs. healthy subjects is improved. In this issue of the Journal, Arafat et al. (10) have compared different assays to address further the issue of the appropriate GH nadir after glucose currently used in the treatment evaluation of acromegaly. They measured GH after 75 g glucose in 46 acromegaly patients, 18 with controlled disease and 28 with uncontrolled disease, and in 213 healthy subjects using three commercially available assays (Immulite, Nichols, and DSL) that were calibrated against therecentlyrecommendedGHstandards.Asexpected, their results showed that GH levels measured with all assays were stronglycorrelated(rvalues0.8–0.996)Importantly,however,GH levels assessed with the Immulite assay were, on average, 2.3-fold higher than thoseobtainedwith theNichols assayand6-foldhigher than those obtained with the DSL assay (10). Therefore, in centers where Immulite is thestandardmethod, the likelihoodthatapatient with normal IGF-I will have a discrepant unsuppressed GH after glucose is higher than in centers using other methods. To provide clinical advice, the authors propose that a cutoff GH level of 1 g/liter be used with the Immulite method and 0.5 g/liter with the Nichols method; this allowed the authors to identify 95% of patients with active disease and 78–80% of patients in remission.