Abstract
Purpose
The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy.
Methods
Fifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes.
Results
In a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches.
Conclusion
Consensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease.
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Introduction
Acromegaly caused by a growth hormone (GH)-secreting pituitary adenoma can deleteriously affect patient quality of life (QOL) and mortality if not diagnosed early and properly treated [1]. Insulin-like growth factor (IGF)-I and GH measurements are commonly used as biochemical markers of disease activity for diagnosis and follow-up of acromegaly [2]: IGF-I levels are reflective of GH action on peripheral tissue, primarily in the liver, while GH levels reflect somatotroph adenoma secretory activity.
The first Acromegaly Consensus Conference held in 1999 in Cortina, Italy, concluded that a diagnosis of acromegaly is excluded if random GH is < 0.4 µg/L and age- and sex-matched IGF-I is normal, or if GH nadir is < 1 µg/L during 75-g oral glucose tolerance test (OGTT) and IGF-I is normal [3]. Biochemical control after treatment of acromegaly was defined as achieving normal IGF-I and, after surgery, nadir GH < 1 µg/L during OGTT (Table 1).
Revisiting this issue in 2010, the 7th Acromegaly Consensus Conference recommendations included two changes [4]: (1) OGTT is not required for diagnosis if IGF-I and GH levels are clearly elevated; and (2) definition of biochemical control could be adjusted to nadir GH < 0.4 µg/L during OGTT if using newer, ultrasensitive assays. In 2014, guidelines from the Endocrine Society further adjusted these criteria [5]. They recommended using IGF-I normalized to age but not sex for the diagnosis of acromegaly, confirmed by lack of suppression of GH < 1 µg/L during OGTT if necessary, and to use age-normalized IGF-I and random GH < 1.0 µg/L as a therapeutic goal.
Following on studies underscoring the challenges of uniformly applying results of GH and IGF-I assays in the clinic [6, 7], the 14th Acromegaly Consensus Conference held in 2022 in Stresa, Italy, once again revisited the question of how to define biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy. Key points from the discussions are presented here and are summarized in Table 2.
Materials and methods
The process for development of consensus recommendations by Acromegaly Consensus Group participants before and during the meeting has been described [8]. Briefly, participants (Table 3) were assigned specific topics related to acromegaly diagnosis and follow-up and conducted comprehensive literature searches for English-language papers published between January 2015 and September 2022. Search terms included “acromegaly” as well as terms associated with each respective topic covered. After brief presentations to the entire group on each topic, breakout groups discussed current practice and recommendations, and a summary of the findings was reported back to the entire group. Consensus recommendations were developed based on all presentations and discussions and all participants voted on each recommendation. After the meeting, members of the Scientific Committee graded both the quality of the supporting evidence and the consensus recommendations based on principles for grading of evidence for guidelines and prior Acromegaly Consensus publications [9,10,11]. Evidence was graded by strength as very low quality (VLQ), low quality (LQ), moderate quality (MQ), or high quality (HQ), and recommendations were classified as discretionary (DR) or strong (SR) as indicated in Table 4.
Diagnostic assessment
Accurate measures of IGF-I and GH are critical to the diagnosis of acromegaly. Therefore, clinicians should know which assay is being used, which factors influence its performance, how normal ranges are obtained (SR), and how it has been calibrated and validated.
IGF-I and GH assays
In a patient with typical clinical signs and symptoms of acromegaly, IGF-I > 1.3 times the upper limit of normal (ULN) for age confirms the diagnosis (MQ). GH measured after overnight fasting may be useful for informing prognosis or complications, but is not required for diagnosis (SR). However, as it is still often used as first line biochemical assessment [12], a need for the use of validated GH assays worldwide is reinforced (SR). For patients with equivocal results, IGF-I measurements can be repeated using the same validated assay, and OGTT might additionally be useful (DR).
Inter-laboratory and inter-assay discrepancies with IGF-I assays are well known [6, 13, 14]; normal reference ranges are specific to each immunoassay, with the greatest differences seen at the highest values [6] (MQ). Well-validated IGF-I should be calibrated to the current international standard (02/254) [15]. Age-stratified reference ranges should be based on adequate numbers of subjects (SR), but sex-stratified reference ranges are likely not required beyond puberty if the normative population is sufficiently large [16] (DR). However, body mass index (BMI) might influence normal IGF-I ranges, such that patients with high BMI have lower IGF-I levels for their age group [16] (MQ). Nutritional, genetic, metabolic, and hepatic factors can also impact IGF-I concentrations, often inducing states of GH resistance [17,18,19,20].
Although mass spectrometry largely eliminates interference from IGF binding proteins that might affect immunoassay results, errors can be introduced during protein concentration and sample preparation, and variability is similar to that seen with immunoassay [21] (LQ). There is currently no evidence that IGF-I measurement by mass spectrometry is superior to measurement by immunoassay (LQ).
Variability in GH immunoassay assessments is commonly encountered because of differences in antibody and epitope binding of GH isoforms, and variability may be greatest with higher values [15] (MQ). Calibration to the current international standard for GH (98/574) should be standard with immunoassays [15], but has not been validated for mass spectrometry methodologies and its use in this setting remains somewhat undefined (DR).
OGTT
GH nadir during OGTT correlates with spontaneous trough inter-pulse GH concentrations [22], which determine the magnitude of IGF-I production [23] (MQ). Thus, glucose-suppressed GH nadir is effectively an indirect assessment of IGF-I and a reflection of preserved GH neuroregulation [24]. However, there is no cutoff for glucose-suppressed GH that definitively excludes a diagnosis of acromegaly (MQ). GH nadirs in healthy adults vary depending on sex, BMI, and estrogen-containing oral contraceptive (OC) use [7], and the range of both spontaneous trough and glucose-suppressed levels in healthy adults can overlap those of acromegaly patients. Thus, glucose-suppressed GH nadirs in acromegaly patients with lower mean 24-hr GH levels can fall into the range of normal adults [25] (VLQ). Furthermore, up to one-third of patients with acromegaly may show a paradoxical increase in GH following OGTT and may demonstrate up to 50% increase or more in GH levels within 120 min after glucose ingestion [26].
In weighing the available evidence, consensus discussions considered that, in most cases, diagnosis is clear without a need for OGTT, and the interpretative difficulties of OGTT therefore outweigh the potential advantages. Thus, the consensus recommended that this test be reserved for patients in whom baseline hormone levels do not clarify the diagnosis (SR).
If OGTT is performed, 75 g glucose should be administered after fasting [27], and GH nadir assessed after 30, 60, 90, and 120 min [7] (SR). BMI-based GH nadir cutoffs can be considered for diagnosis, with < 0.4 µg/L for BMI < 25 kg/m2 and < 0.2 µg/L for BMI ≥ 25 kg/m2 [7], although this may be assay dependent (DR). As healthy premenopausal females on estrogen-containing OC have higher GH nadirs [7], cessation of oral estrogen therapy 4 weeks prior to OGTT may avoid its effects on the GH axis.
OGTT can be safely performed in patients with impaired glucose tolerance or type 2 diabetes mellitus, with some applying BMI-based cutoffs [28, 29] (DR). However, due to the suppressive effect of hyperglycemia on GH levels [30], particularly in patients with uncontrolled diabetes [31], both random and post-OGTT GH levels should be interpreted with caution. Measurement of basal and 120-minute glucose levels during OGTT is useful for detecting disturbances in glucose homeostasis (MQ).
Other assays
A rapid decrease in soluble α-Klotho occurs after adenoma surgical resection, correlating with decreases in IGF-I, and associated with normal IGF-I levels in patients with discordantly elevated random GH levels [32] (LQ). Soluble α-Klotho, but not IGF-I, correlated with GH-dependent symptom scores and disease-specific QOL in patients receiving medical therapy [33] (VLQ)]. However, mechanisms driving soluble α-Klotho secretion in acromegaly as well as assay validation and confirmatory studies are required before it can be considered for use as a biochemical marker in clinical practice (SR).
Clinical examination
A careful history and physical exam in the initial assessment of patients with suspected acromegaly is required as it will often reveal unequivocal signs and symptoms related to local mass effect or secondary features of GH and IGF-I hypersecretion (SR).
Characteristic changes in the face and head, including widening and malocclusion of the jaw and macroglossia, as well as enlarged hands, occur insidiously but are often apparent at initial assessment [2, 17] (HQ). Moreover, due to diagnostic delay, disease comorbidities and complications including hypertension, diabetes mellitus, and kyphosis [34, 35] should not be overlooked (SR). In fact, they are signs of active disease and may be apparent at initial presentation [36] (LQ). (Diagnosis and management of acromegaly comorbidities are extensively discussed in a separate Consensus Statement [8].) Impaired QOL resulting from the clinical and psychological burden of disease may be present at all stages of disease [37] (VLQ).
Imaging
Gadolinium-enhanced pituitary MRI should be performed in all patients at diagnosis using high-quality, high-resolution equipment, such as 1.5T or 3T scanners, where available, including T1- and T2-weighted fast spin echo sequences, with coronal and sagittal planes in 2–3 mm slice thickness with no or minimal spacing (SR). Reporting should be standardized, and include information on invasion into surrounding structures based on modified Knosp grade [38] (SR). Adenoma dimensions; suprasellar and infrasellar extension; presence of cystic components; and T2 hypo-, iso-, or hyperintensity of the adenoma compared with adjacent temporal lobe can all be used to inform likelihood of treatment response [39,40,41] (MQ). Given the proven benefits of expert MRI review in patients with Cushing’s disease microadenomas [42], equivocal diagnosis of acromegaly associated with pituitary microadenomas should be referred for review by an experienced neuroradiologist [43] before considering further imaging studies (SR). Very rarely, cross-sectional imaging and measurement of GH releasing hormone (GHRH) may be needed to identify an ectopic GHRH-secreting neuroendocrine tumor [44] (DR).
PET imaging using 11 C-methionine as a molecular tracer may be useful when MRI cannot identify an adenoma at initial diagnosis or, more commonly, a residual adenoma in patients with persistent GH hypersecretion following primary therapy [45, 46] (DR). However, limited availability of both the imaging technology and the tracer constrain their use.
Pathology
Differentiation of somatotroph, lactotroph, and thyrotroph cells in the pituitary is driven by the PIT1 transcription factor. Somatotroph adenomas are defined on pathology based on immunohistochemistry (IHC) GH expression, and adenomas that secrete/express GH and prolactin may also be seen [47] (HQ). Standard reporting should include IHC assessment for pituitary hormones. Transcription factors can be used to define adenoma lineage and further characterize adenoma cell type when not classifiable on hormone expression alone (SR).
Clinicopathologic classification of pituitary adenomas that considers adenoma invasiveness using Knosp grade and sphenoid sinus invasion as well as proliferation by Ki-67 and mitoses can distinguish adenomas with potentially more aggressive behavior [48], and thus identify patients at increased risk for progression [49, 50] (MQ). Somatostatin receptor immunopositivity, granulation pattern, and AIP mutation status have been reported to identify patients less likely to respond to somatostatin receptor ligand (SRL) therapy (DR) [51, 52]. Clinical implications of the 2022 WHO classification suggesting that pituitary adenomas could also be called pituitary neuroendocrine tumors remain unclear [53] and the clinical ramifications for acromegaly patients are not apparent [54].
Effect of diagnostic delay
Signs and symptoms of acromegaly are nonspecific, and there may be a delay of 5–10 years or more between first symptom onset and diagnosis [55, 56] (HQ). The effect is more pronounced in older patients and in women [57, 58] (MQ) likely due to inappropriate attribution of acromegaly symptoms to normal aging and menopause. Prolonged exposure to excess GH with diagnostic delay leads to increased comorbidity and mortality risks with decreased QOL [55, 59, 60] (HQ).
Importantly, delayed diagnosis also allows for continued adenoma growth as well as invasion into the cavernous sinus, both of which limit successful surgical resection, regardless of surgical expertise [61] (HQ). In these patients, adjuvant medical therapy and/or radiotherapy targeted to the residual mass after debulking surgery might be needed [62] (MQ).
Strategies aimed at reducing diagnostic delay should be implemented worldwide as they may reduce short-term and long-term morbidity and positively impact QOL (SR). All patients with a newly diagnosed pituitary mass should undergo IGF-I measurement (SR). Although widespread screening in the general population is not warranted, IGF-I screening could be considered in individuals with classical signs, symptoms, and comorbidities of acromegaly (DR), including acral enlargement and orofacial changes, particularly if these occur in conjunction with unexplained systemic manifestations such as sleep apnea or ventricular hypertrophy [63]. A systematic approach should be implemented among healthcare practitioners to increase awareness about acromegaly. Outreach strategies in collaboration with patient advocacy groups such as for other rare diseases could also help promote earlier referral for diagnostic testing (SR).
Criteria for remission
Consensus recommendations previously adjusted criteria for therapeutic goals because of improvements in assay sensitivity and our evolving understanding of GH dynamics after glucose suppression [3,4,5] (LQ). Additionally, by definition, postoperative IGF-I normalization is a function of the reference values used for each respective assay [15] (HQ). Therefore, an absolute biochemical threshold to define postoperative “cure” does not seem feasible (DR). “Biochemical control,” indicating no biochemical evidence of adenoma GH hypersecretion, is similarly imprecise as measures of GH and/or IGF-I attenuation might be delayed despite complete adenoma resection (DR). By contrast, the term “remission” indicates that active disease cannot be detected even if it might still be present. This was deemed the most accurate descriptor for biochemical assessment of treatment outcome in acromegaly and was adopted at this 14th Acromegaly Consensus Conference (SR).
Importantly, although biochemical remission is the primary assessment of treatment outcome, it is not the only goal of treatment in acromegaly. In all cases, biochemical findings should be interpreted within the clinical context of acromegaly signs and symptoms (SR). Maintaining serum IGF-I level in the mid to upper half of the age-related reference range could be considered in clinically controlled patients to avoid induction of GH deficiency [64] (HQ).
Postoperative remission
There are no definitive studies on the optimal assessment for postoperative remission, nor of the timing of its evaluation. Remission rates after surgery using OGTT results are influenced by the defined cutoff for GH normalization, timing of measurement, and adenoma characteristics. For example, some studies reported approximately 60% of patients achieve biochemical remission in the immediate postoperative period when defined as nadir GH < 1 µg/L during OGTT, with lower rates in patients with macroadenomas and in those treated with a microscopic approach [65, 66] (MQ). However, remission rates fell to approximately 40% when using stricter criteria of < 0.4 µg/L on postoperative day 2, and 20% of patients achieved GH below threshold after a delayed period of a median of 24 months of observation [ Not applicable. 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J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgad365 The authors dedicate the manuscript to our colleague and friend, the late Marcello Bronstein, in honor of his major contributions to the field. Open access funding provided by SCELC, Statewide California Electronic Library Consortium. The 14th Acromegaly Consensus Conference was supported by unrestricted educational grants from Amolyt Pharma, Amryt Pharma, Basecamp Bio, Crinetics Pharmaceuticals, Ionis Pharmaceuticals, Novo Nordisk, Pfizer, and Recordati Rare Diseases. Supporters were invited to observe the highlight summaries, but did not observe the small group discussions, had no role in the development of consensus recommendations or topics for future research, and did not review the manuscript prior to publication. Steering Committee Members (AG, NM, FFC, MF, PM, CS, AJvdL, JW, and SM) conceptualized the consensus meeting and publication of its conclusions. AG and SM prepared the initial draft manuscript. Steering Committee Members critically revised the initial draft. All authors reviewed, edited, and approved the final manuscript. AB, MB, AG, and RS are Editors of Pituitary. NB, CB, TB, FC, PC, MF, SF, MG, MG, YG, KH, AI, GJ, JOJ, LK, NK, RL, PM, SN, SP, CS, IS, SLS, and AJvdL are Editorial Board Members of Pituitary. SM is Editor-in-Chief of Pituitary. MB has received research support, consultancy, and/or lecture fees from Camurus, Chiasma, Crinetics Pharmaceuticals, Diasorin, IDS, Ionis, IPSEN, Midatech, Novartis, Ono, OPKO, Pfizer, Recordati, Roche, and StrongBridge. CB has received support for investigator-initiated clinical trials from Crinetics and served as speaker or consultant for Ipsen, Recordati, and NovoNordisk. TB has received support for research grants from Pfizer, consultant/speaker agreements with Ipsen and Pfizer, and clinical trials for Crinetics and Debiopharm. PC has received unrestricted research and educational grants from Ipsen, Novartis, and Pfizer, Recordati, and Advanz; has served as an investigator for clinical trials funded by Crinetics, Chiasma, and Debiopharm; is a member of Advisory Boards for Ipsen, Pfizer, Crinetics, Recordati, and Amolyt; and is a speaker for Ipsen, Recordati, and Pfizer. SC has served as an investigator for clinical trials funded by Novartis, Pfizer, Ipsen, and Crinetics; received grants to the institution from Pfizer, Ipsen, and Recordati; and served as an Advisory Board member for Recordati. DE has received lecture fees from Ipsen and Pfizer AB. MF has received grants to the institution from Amryt, Crinetics, Ionis, and Recordati, and occasional consulting fees from Amryt, Camurus, Crinetics, Ipsen, and Recordati. MF has served as an Advisory Board member for Recordati, Crinetics and Ipsen, received speaker fees from Recordati and Ipsen, and served as principal investigator for studies funded by Recordati and Crinetics. SF has received consultancy and speaker fees from Ipsen, Pfizer, Novartis, and Recordati. BG has received research grants to the institution from Amryt/Chiesi and Ionis, and served as an occasional consultant to Amryt/Chiesi and Crinetics. AG has served as a consultant for Ipsen, Pfizer and Recordati and received research grants to the institution from Pfizer and Recordati. MG has served as a member of a speakers bureau for Ipsen Ltd UK and Pfizer. AI has served as principal investigator for institution-directed research grants from Recordati, Xeris and Amryt/Chiesi, and as an occasional consultant for Recordati, Xeris, Amryt/Chiesi, Camurus, and Crinetics. GJ has served as consultant for NovoNordisk and AstraZeneca and received lecture fees from NovoNordisk and Pfizer. JOJ has received lecture fees and unrestricted research grants from Pfizer and Novo Nordisk. PM has received speaker and/or consultancy fees from Pfizer. UBK has served as consultant for ModeX Therapeutics. LK has served as advisor for Camarus, Novo Nordisk, and Strongbridge, and received research funding from Camurus. NK has served as speaker for Pfizer, Ipsen, and Recordati Rare Diseases; as an investigator for Pfizer and Ipsen; and as a Scientific Advisory Board member for Pfizer, Ipsen, and Recordati Rare Diseases. AL has received honoraria for presentations from Pfizer and Ipsen. MM has served on advisory boards and as a speaker for Ipsen, Recordati, and Pfizer. PM has served as principal investigator, and has received consultation fees and research grants from Pfizer, Recordati, and Camurus. SM has received grants to the institution from Recordati and served as an adviser to Recordati, Crinetics, and Ionis. SN has received research grants Pfizer and consultancy grants from Recordati, NovoNordisk, and Crinetics. LP has received congress fees from Merck and Sandoz. SP has served as a speaker at workshops and Advisory Boards for Ipsen, Pfizer, and Recordati. MR has received consulting fees from Crinetics and Ipsen. CS has received speaker fees from Pfizer, and served as an advisor to Debiopharm, NovoNordisk, Chiasma, and Crinetics. IS has served as an investigator for Crinetics, Chiasma, and Debiopharm, and as speaker and consultant for Pfizer, Medison, and NovoNordisk. RS has served as a consultant for NovoNordisk, Amryt, and Camurus. SLS has served as principal investigator and conducted research studies supported by Novartis and Chiasma. ST has received grants to the institution from Crinetics, honoraria for lectures/presentations from Recordati, and support for attending meetings and/or travel from Pfizer, Ipsen, and Recordati, and has served as an Advisory Board member for Pfizer and Recordati. AJvdL has received speaker and/or consultancy fees from Pfizer, Ipsen, Crinetics, Tiburio, and Amolyt Pharma SA. All other authors declare no competing interests. Not applicable. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The original article has been corrected to update funding section. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Giustina, A., Biermasz, N., Casanueva, F.F. et al. Consensus on criteria for acromegaly diagnosis and remission.
Pituitary 27, 7–22 (2024). https://doi.org/10.1007/s11102-023-01360-1 Accepted: Published: Issue Date: DOI: https://doi.org/10.1007/s11102-023-01360-1Data Availability
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06 December 2023
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