Diagnosis of acromegaly: black, white… and sometimes gray!

Disease definitions often rely on cutoff values chosen to help distinguish a pathological condition from a healthy state. This is particularly true in endocrinology, where hormone hypersecretion or hyposecretion needs to be distinguished from physiological secretion. In general, endocrinological disease states are associated with clearly pathological hormone levels, largely above or below the proposed diagnostic cutoff. In acromegaly for example (¹,²), most patients have obvious clinical signs and IGF-I levels markedly above the upper normal limit (ULN). But how is the ULN determined, and what does it signify? In general, the normal range of a biological marker is based on values observed in the healthy general population. If values follow a Gaussian distribution (with as many values above as below the mean), the ULN is generally set at the 97.5^th percentile, corresponding more or less to the mean + 2 standard deviations (SD), while the lower limit of normal is the 2.5^th percentile, corresponding more or less to the mean - 2SD.

However, it is no simple matter to establish reference values for IGF-I. Indeed, serum IGF-I concentrations rise with age during childhood and puberty, while they fall with age in adults (³). Furthermore, the distribution of IGF-I values in an apparently healthy population is non Gaussian, necessitating the use of complex mathematical transformations to obtain reference intervals for a given age group. For this reason, it is crucial to generate reference values after stratifying a large healthy population into age groups (⁴). Another problem is that IGF-I concentrations are influenced by many factors other than the GH concentration, including nutritional status and BMI, the use of post-menopausal hormone replacement therapy and its route of administration (⁵-⁷), kidney and liver function, and diabetic status (⁸). Reference IGF-I values may therefore be influenced by the inclusion criteria used to select the reference population. Elsewhere, comparisons of IGF-I assay kits show that, even in the same healthy population, IGF-I reference ranges can differ: as a result, some individuals considered to have “high” IGF-I levels measured with one assay kit may have “normal” levels when another kit is used (⁹). Finally, by definition, 5% of the healthy population have IGF-I levels either above the 97.5^th percentile or below the 2.5^th percentile. This means that 2.5% of the normal healthy population may have IGF-I levels above the ULN. All these factors may explain why some of the subjects reported in the article by Rosario and Calsolari were found to have elevated IGF-I levels despite perfectly normal GH secretion (¹⁰). The fact that IGF-I levels were above the ULN not only at the first sampling but also at the subsequent measurement five years later suggests that IGF-I levels, like other biological parameters such as TSH, tend to be “set” at an individual level which varies very little, within a range narrower than that of the reference population (¹¹).

GH levels are also clearly elevated in the vast majority of patients with acromegaly, both at baseline and in the oral glucose tolerance test (OGTT), making the biochemical diagnosis of acromegaly quite straightforward (²,¹²). However, it must be kept in mind that a few patients with clear clinical signs and high IGF-I levels may also have authentic acromegaly despite very low GH secretion, including a nadir of < 1 µg/l in the OGTT (¹³-¹⁸). These patients generally have a microadenoma, which can be difficult to visualize or may even have questionable pituitary MRI. Moreover, when GH output is low (basal level < 4 µg/l), the OGTT may sometimes be misleading, as GH levels can be suppressed below 0.3 µg/l in some patients with true acromegaly (¹⁷,¹⁹). The existence of these very rare cases means that all patients with clinical signs of acromegaly and elevated IGF-I levels should have the OGTT. If GH is suppressed to below 0.3 µg/l, acromegaly is unlikely but cannot be ruled out. As stated by Rosario and Calsolari, the most reasonable attitude is to monitor the patient and to repeat laboratory tests after a few months or years.

For the diagnosis of acromegaly, as in all fields of medicine, one must accept that not everything is black and white, and that there may be many shades of gray. As Osler put it, “medicine is a science of uncertainty and an art of probability” (²⁰).

REFERENCES

• ¹
  Chanson P, Salenave S, Kamenicky P. Acromegaly. Handb Clin Neurol. 2014;124:197-219.
• ²
  Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-51.
• ³
  Frystyk J, Freda P, Clemmons DR. The current status of IGF-I assays--a 2009 update. Growth Horm IGF Res. 2010;20(1):8-18.
• ⁴
  Clemmons DR. Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays. Clin Chem. 2011;57(4):555-9.
• ⁵
  Juul A. Serum levels of insulin-like growth factor I and its binding proteins in health and disease. Growth Horm IGF Res. 2003;13(4):113-70.
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  Leung KC, Johannsson G, Leong GM, Ho KK. Estrogen regulation of growth hormone action. Endocr Rev. 2004;25(5):693-721.
• ⁷
  Meinhardt UJ, Ho KK. Modulation of growth hormone action by sex steroids. Clin Endocrinol (Oxf). 2006;65(4):413-22.
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  Clemmons DR. Value of insulin-like growth factor system markers in the assessment of growth hormone status. Endocrinol Metab Clin North Am. 2007;36(1):109-29.
• ⁹
  Chanson P, Arnoux A, Mavromati M, Brailly-Tabard S, Massart C, Young J, et al. Reference values for IGF-I serum concentrations: Comparison of six immunoassays. J Clin Endocrinol Metab. 2016;101(9):3450-8.
• ¹⁰
  Rosario PW, Calsolari MR. Elevated IGF-1 with GH suppression after an oral glucose overload: incipient acromegaly or false-positive IGF-1? Arch Endocrinol Metab. 2016;60(6):510-4.
• ¹¹
  Borofsky ND, Vogelman JH, Krajcik RA, Orentreich N. Utility of insulin-like growth factor-1 as a biomarker in epidemiologic studies. Clin Chem. 2002;48(12):2248-51.
• ¹²
  Carmichael JD, Bonert VS, Mirocha JM, Melmed S. The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly. J Clin Endocrinol Metab. 2009;94(2):523-7.
• ¹³
  Dimaraki EV, Jaffe CA, DeMott-Friberg R, Chandler WF, Barkan AL. Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up. J Clin Endocrinol Metab. 2002;87(8):3537-42.
• ¹⁴
  Freda PU, Reyes CM, Nuruzzaman AT, Sundeen RE, Bruce JN. Basal and glucose-suppressed GH levels less than 1 microg/L in newly diagnosed acromegaly. Pituitary. 2003;6(4):175-80.
• ¹⁵
  Arafat AM, Mohlig M, Weickert MO, Perschel FH, Purschwitz J, Spranger J, et al. Growth hormone response during oral glucose tolerance test: the impact of assay method on the estimation of reference values in patients with acromegaly and in healthy controls, and the role of gender, age, and body mass index. J Clin Endocrinol Metab. 2008;93(4):1254-62.
• ¹⁶
  Ribeiro-Oliveira A Jr, Faje AT, Barkan AL. Limited utility of oral glucose tolerance test in biochemically active acromegaly. Eur J Endocrinol. 2011;164(1):17-22.
• ¹⁷
  Ribeiro-Oliveira A Jr, Barkan A. The changing face of acromegaly--advances in diagnosis and treatment. Nat Rev Endocrinol. 2012;8(10):605-11.
• ¹⁸
  Subbarayan SK, Fleseriu M, Gordon MB, Brzana JA, Kennedy L, Faiman C, et al. Serum IGF-1 in the diagnosis of acromegaly and the profile of patients with elevated IGF-1 but normal glucose-suppressed growth hormone. Endocr Pract. 2012;18(6):817-25.
• ¹⁹
  Ribeiro-Oliveira A Jr, Faje A, Barkan A. Postglucose growth hormone nadir and insulin-like growth factor-1 in naive-active acromegalic patients: do these parameters always correlate? Arq Bras Endocrinol Metabol. 2011;55(7):494-7.
• ²⁰
  Simpkin AL, Schwartzstein RM. Tolerating Uncertainty – The Next Medical Revolution? N Engl J Med. 2016;375(18):1713-5.

Publication Dates

• Publication in this collection
  Nov-Dec 2016

History

• Received
  10 Nov 2016
• Accepted
  28 Nov 2016