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Acromegaly—Consensus, What Consensus?

Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom

Address all correspondence and requests for reprints to: Peter J. Trainer, M.D., FRCP, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: . peter.trainer{at}man.ac.uk

Acromegaly is a disfiguring and disabling illness that, when inadequately treated, reduces life expectancy by a decade, on average. Large strides have been made in the treatment of acromegaly such that we are now entering on an era when it should be possible to achieve biochemical disease control in all, or at least virtually all, patients with acromegaly. The prospect of curative surgery has improved with advances in surgical technique (for example, the endoscope and the greater awareness of the need for transsphenoidal surgery to be performed by specialist pituitary surgeons), whereas refinements in radiotherapy make it a safe and effective option for patients not cured by the surgeon. The majority of patients with acromegaly require medical treatment at some point, and this field has been one of the fastest developing areas of clinical endocrinology. The newer, better-tolerated, and more potent dopamine agonists, such as cabergoline, plus the availability of the long-acting somatostatin analogs octreotide and lanreotide, allow biochemical disease control to be achieved in the majority of patients. The prospects of new somatostatin analogs, together with the imminent availability of the GH receptor antagonist pegvisomant, means that the challenge in the future will be optimizing therapeutic algorithms to ensure that individual patients achieve disease control while controlling tumor volume, preserving pituitary function, and relieving symptoms (1). An implication of the ability to offer effective treatment is the increased onus on physicians of all sorts to ensure acromegaly is diagnosed and treated as early as possible. To this end, the accompanying paper by Dimaraki et al. (2) has highlighted a diagnostic difficulty in patients with biochemically mild disease and thereby challenges the diagnostic criteria proposed in the consensus statement of Giustina et al. (3) published in this journal 2 yr ago.

The consensus states that "if a random GH is <0.4 µg/liter and IGF-I in the age- and gender-related reference range the diagnosis of acromegaly is excluded. If either of these levels is not achieved, a glucose tolerance test should be performed with 75 g oral glucose and subsequent measurements of glucose and GH every 30 min for over 2 h. During this time, the GH level should fall to 1 µg/liter or less for acromegaly to be excluded." It is also stated that a mean integrated 24-h GH level of less than 2.5 µg/liter excludes acromegaly.

Dimaraki et al. (2) report 16 patients with newly diagnosed acromegaly in whom GH and IGF-I results are discrepant when judged by the consensus criteria. All have an elevated serum IGF-I, but at least one measure of GH secretion does not fulfill the consensus criteria. A chemiluminometric assay with a sensitivity of 0.01 µg/liter was used to measure GH during a 75-g oral glucose tolerance test (OGTT) and at 10-min intervals for 24 h. GH suppressed to less than 1 µg/liter during an OGTT in 8 patients, and mean 24-h integrated GH levels were less than 2.5 µg/liter in 12 of the 16 patients. All patients had 24-h mean plasma GH values that overlapped with those of the 46 healthy controls. The patients reported by Dimaraki et al. (2) were not necessarily typical because they had biochemically mild disease and, in contrast to most series, the majority (10 of 16) had microadenomas; but in the opinion of the authors such patients account for up to 25% of patients with acromegaly and "the diagnosis could be missed if existing GH-based criteria are used."

The rationale for the choice of a nadir during a 75-g OGTT of 1 µg/liter requires exploration, particularly when it is appreciated that this value represents an increase on previously proffered cut-offs. While not necessarily referencing peer-reviewed journals, major textbooks of endocrinology have advocated a nadir value of less than 0.5 µg/liter (1 mU/liter), and the choice of 1 µg/liter by Giustina et al. is similarly unreferenced (4, 5). There is a dearth of data exploring the merits of the OGTT using highly sensitive GH assays in the diagnosis of acromegaly. The best data available come from Freda et al. (6) who performed a 100-g OGTT in 60 postoperative patients with acromegaly, 22 patients with active disease (defined by raised serum IGF-I), and 38 patients in remission (posttreatment normal serum IGF-I) (Fig. 1). Twenty-five healthy controls were also studied, and GH was measured by a highly sensitive immunoradiometric assay capable of measuring as low as 0.05 µg/liter. The highest nadir GH value in the control group was 0.13 µg/liter and in the patients with active acromegaly GH suppressed as low as 0.33 µg/liter, and in 50% (11 of 22) was less than 1 µg/liter. Nadir GH values ranged between 0.05 and 0.9 µg/liter in the patients in remission and in 39% of this group failed to suppress normally (<0.14 µg/liter). Future reports on this latter cohort of patients in remission are eagerly awaited to see which, if any, relapse. Freda et al. (6) conclude a cut-off of 1 µg/liter will fail to identify 50% of patients with active disease.

View larger version (16K): [in this window] [in a new window]   Figure 1. Nadir GH values after a 100-g OGTT in healthy controls and patients with acromegaly postsurgery and a normal IGF-I (remission) and a raised IGF-I (active disease). [Modified with permission from P. U. Freda et al.: J Clin Endocrinol Metab 83:3808–3816, 1998 (6 ). ©The Endocrine Society.]

Calculation of mean 24-h GH levels is not practicable for the routine care of patients with acromegaly and is a research tool. While acknowledging that mean 24-h GH values is not a cost-effective means of assessing the disease, the consensus statement suggests a value of less than 2.5 µg/liter excludes acromegaly. However, 12 of 16 patients of Dimaraki et al. (2) had mean 24-h integrated GH values of 2.5 µg/liter or less, and there was complete overlap between patients and controls, which although not a novel observation (7), further emphasizes the fallacy of using mean GH values to diagnose acromegaly. In normal adults GH secretion is pulsatile, and at times basal (interpulse) secretion rates approach zero. In contrast, GH secretion rates are consistently elevated throughout the 24-h period in patients with active acromegaly (7). Therefore, as the data of Dimaraki et al. (2) indicate, in both the patient with mild acromegaly and healthy controls the mean integrated 24-h GH may be the same. The diagnostic value of multiple GH measurement lies in studying the nadir values. In keeping with this notion, Dimaraki et al. (2) documented both the nadir and 24-h trough plasma GH values to be significantly higher in patients than controls, with overlap in only two patients. The principal value of multiple GH measurement is as a measure of disease activity and is the basis of much of the epidemiological evidence relating disease activity to mortality (8). Typically, the mean is calculated from five measurements from a single day, and such data have suggested that it is patients with posttreatment mean GH values greater than 2.5 µg/liter in whom mortality is increased and that lowering GH under 2.5 µg/liter restores mortality to normal (9, 10, 11). It should be remembered that there are no data correlating the means of monitoring disease activity favored by the consensus statement (a post-OGTT GH nadir <1 µg/liter) to morbidity or mortality.

With all the problems associated with establishing robust GH criteria for the diagnosis and monitoring of disease activity, the question might be posed as to whether GH measurement should be abandoned and IGF-I used as the sole measure of disease activity. It can be said in favor of IGF-I that most of the actions of GH are mediated by IGF-I and monitoring disease activity with serum IGF-I has the virtue of convenience. However, the pitfalls of over-dependence on a single parameter must be borne in mind. Melmed (12) has drawn attention to the limitations of the available IGF-I assays and highlighted the need for good gender- and age-related reference ranges, particularly as GH secretion diminishes by approximately 14% per decade during adult life. Even in a detailed study of acromegaly such as that of Dimaraki et al. (2), a single value for each gender for the upper limit of the normal range for IGF-I is quoted. The diagnosis is not in doubt in their patients; however, in a less well documented group, an IGF-I of 300 µg/liter in a 30-yr-old man would be against a diagnosis of acromegaly, whereas the same value in a 70 yr old would support the diagnosis. Furthermore, in defense of GH measurement, as discussed above, there is much evidence from epidemiological studies relating GH values to long-term morbidity and mortality, and consistently indicating a posttreatment mean GH value of less than 2.5 µg/liter to be the goal of treatment, whereas there is only one study claiming that a normal posttreatment IGF-I value restores life expectancy to normal, although actual IGF-I data are absent (13). The merits of IGF-I are not in question, and ongoing studies and various acromegaly databases will with time produce further evidence of the value of controlling IGF-I levels, but it must be appreciated that although serum GH and IGF-I levels are closely correlated, they cannot be assumed to provide exactly the same information and are discrepant in a significant minority of patients. Holly et al. (14) demonstrated results to be discrepant in 27% of patients, with a normal GH being associated with an elevated IGF-I in 19% and elevated GH being associated with a normal IGF-I in 8% (15). Gender, age, and prior radiotherapy are all known to alter the relationship between GH and IGF-I, with women and the elderly having lower IGF-I values for a given GH, whereas in irradiated patients GH falls faster than IGF-I (16, 17, 18).

Establishing robust guidelines for the diagnosis or assessment of disease activity of acromegaly is a major challenge, and exceptions to rules will inevitably occur. Many questions remain unanswered, and various inconsistencies exist. To name but two, the post-OGTT GH nadir is known to be higher in women than men (19), and GH secretion declines by approximately 14% per decade, but age- and gender-dependent reference ranges are not advocated for GH but are for IGF-I. However, what is clear from the reports of Freda et al. (6) and Dimaraki et al. (2) is that the post-OGTT GH nadir of 1 µg/liter is inappropriately high for the diagnosis and probably for assessment of posttreatment disease activity, and there is a need for this topic to be re-explored and the consensus statement revised. To initiate the debate, I propose an initial random GH and IGF-I estimation, and if both the GH is less than 0.3 µg/liter and the IGF-I is normal, then acromegaly is excluded, but if either the GH is 0.3 µg/liter or greater or serum IGF-I is above the age- and gender-related reference range, then the patient should proceed to have a 75-g OGTT and repeat IGF-I measurement. Failure of GH to suppress less than 0.3 µg/liter and an elevated IGF-I is diagnostic of acromegaly, suppression of GH below this limit and a normal IGF-I excludes acromegaly, and the rare patient with GH suppression and an elevated IGF-I requires following and reassessment. Mean 24-h integrated GH has no part in the diagnosis of acromegaly, although the nadir value during multiple, say five, unstimulated GH measurements may have a role in the rare patient in whom doubt persists after an OGTT. Such a strategy is within the capability of modern assays.

Acknowledgments

Footnotes

Abbreviation: OGTT, Oral glucose tolerance test.

Received June 11, 2002.

Accepted June 11, 2002.

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