ACROMEGALY Abstract and Introduction o Abstract

Disease activity of acromegaly can be measured in many ways. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) concentrations are the main biochemical markers used to measure the response to treatment. Both GH and IGF1 have been associated with prognosis, in particular mortality. In this review, we discuss the available parameters to assess disease activity in acromegaly. o Introduction Acromegaly is a rare disease that is most often caused by a growth hormone (GH) secreting benign pituitary tumour. The autonomous increased production of GH results in increased insulin-like growth factor 1 (IGF1) concentration and both cause signs and symptoms. This disease is characterized by soft tissue enlargement and excessive skeletal growth with characteristic acral enlargement and coarse facial features. Complications related to excessive secretion of GH and IGF1 include cardiomyopathy and sleep apnoea syndrome, and result in a two- to threefold increase in mortality if left untreated.[1] Growth hormone and IGF1 are the "classical" biochemical parameters used to diagnose acromegaly and to assess disease activity during treatment. Several studies have related control of acromegaly, defined by a normal IGF1 and/or a certain GH concentration, to an improved mortality risk and to prevalence of several comorbidities.[210] However, in the near normal range, both biochemical markers have limited ability to discriminate active and adequately controlled acromegaly, because of broad normal ranges, assay limitations and individual factors. Therefore, GH and IGF1 levels may not always adequately reflect disease activity as measured by acromegaly symptoms, while patients may well be subjected to ongoing GH and IGF1 excess, and GH-induced tissue damage. Quality of life (QoL), assessed by questionnaire, is a measure of a patient's perception of their general health, and an important goal to aim for in the treatment of chronic diseases. QoL can be used as a biomarker to study disease control in acromegaly in certain circumstances. In the later section, we will discuss the parameters of disease activity, GH, IGF1 and QoL. Although they will change concordantly in the majority of patients with treatment, in some patients clinical and biochemical markers may dissociate. In this review, we will discuss the relevance and limitations of different disease parameters.

Biochemical Markers, GH and IGF1

Assessment of GH, and sex and age-matched IGF1 concentrations are important biochemical parameters for the diagnosis of acromegaly, and at present are the most accepted measures to monitor treatment response. Suppression of both GH[24] and IGF1 concentrations[57,11] to current valid criteria for cure, that is, normal IGF1 and GH < 25 g/l have been associated with improved "normalised" mortality. As mortality is a hard end-point, the consensus statements seem to focus mainly on normalization of GH and IGF1.[810] In these statements, the biochemical target ranges for GH concentration have changed over time, but this is not the case for IGF1. Controlled IGF1, in these statements, means an IGF1 within the sex- and age-adjusted normal limits. For GH, it is different. According to the earlier criteria, the mean of a 24-h GH profile should be to <25 g/l or a GH nadir after glucose of <10 g/l.[8] Using these limits, Dekkers et al.[11] demonstrated that the standardized mortality rate (SMR) is still slightly increased at 109. The SMR from this meta-analysis is based mainly upon studies conducted in patients with acromegaly treated with transsphenoidal surgery. With current effective medical treatments, the SMR outcome could be different. An important issue concerns the assays used to assess GH and IGF1, as these have changed over the years. Currently, ultra-sensitive assays are used to assess GH. Holdaway et al.[12] have demonstrated in a New Zealand cohort of patients with acromegaly that a single GH of <10 g/l was associated with normalization of mortality. More recent consensus statements introduced new limits to reflect these and other findings (single GH 10 g/l or a GH nadir of <04 g/l).[13] So, when the original Cortina criteria[8] are applied, some patients still have active disease as the measured GH level is perceived to have decreased because of the current use of more sensitive immunoradiometricassays rather than the previous, less sensitive, polyclonal radioimmunoassays. Consequently, the puzzle is not solved by just lowering GH cut-offs. With the more sensitive GH assays, there is a lack of adequate gender-specific normative data, standardization and assay validation.[14,15] Depending on which commercial assay is used, the means of the GH nadirs of healthy volunteers differ from 013 to 0015 g/l. The explanation for the heterogeneity between results of the sensitive assays are variable calibration, epitope specificity of the antibody and variable specificity of antibody recognition of different circulating GH isoforms in the serum.[15] Finally, the lack of adequate standardization in the use of mass units and international units and the variety of conversion factors lead to marked problems of interpretation.[15] The situation is improving, however. A recent report provides consensus statements on the standardization and evaluation of GH and IGF1 assays. This concludes that major improvements are necessary in the areas of assay performance and comparability. The group of involved experts recommended that a commutable standard for each assay be implemented for worldwide use and that its recommendations be applied to accomplish the task of providing reliable and clinically useful results.[16]

The problems for IGF1 are not that different. Circulating serum levels of IGF1 are influenced by age, gender, season, nutritional status and concomitant disease such as diabetes mellitus. Serum IGF1 is mainly bound to IGF1 binding proteins and acid-labile subunit: only approximately 1% is unbound.[17] To assess IGF1 serum levels, these binding proteins need to be displaced. One of the most common methods is functional displacement by IGF2.[18] In diabetes, IGF1 can be glycosylated at the recognition site of the antibody of the IGF1 assay.[19] Also, increased proteolytic activity of IGF1 binding protein 3[20] can influence the assay's results.[20] Acromegaly and diabetes mellitus are associated; therefore, this could influence the assessed IGF1 results in our patients. The assay calibration by the International Reference Reagent (IRR 87/518) is biased because of uncertain purity compared with the available recombinant IGF1 preparation.[21] Additionally, there is a lack of adequate normative data for the commercially available IGF1 assays. The variability in assay performance for GH and IGF1, coupled with the use of inappropriate conversion factors and normative data, undermines the applicability of the consensus criteria to local practice.[22] Practical Aspects After surgery, GH and IGF1 assessment are time-dependent. A long half-life and other factors regulating IGF1 may result in its elevation several months after surgery,[13,23] whereas GH during oGTT is an early predictor of remission or failure.[13,23] During long-acting somatostatin analogue (LA-SRIF) treatment, GH nadir assessment cannot be performed after glucose loading.[14,24] Therefore, IGF1 is considered to be the most feasible assessment. However, if patients still have symptoms of active acromegaly, mean or single GH measurements can still be helpful.[13] During pegvisomant (PEG-V) treatment, IGF1 is the only reliable assessment. PEG-V mimics GH and therefore interferes with most commercially available GH assays making results invalid.[25] So, in everyday practice at the outpatient clinic, IGF1 is the most feasible parameter to assess. Therefore, the aim is to normalize serum IGF1 levels via a reduction of GH action or GH overproduction.[1,8,9,13,26] A tangible advantage of this approach is that the efficacy of different treatments can easily be compared by means of serum IGF1 measurements. This is more practicable than either time-consuming, and costly, 24 h GH measurements[26] or assessment of GH nadir after glucose loading, which is only valid after surgery and not during treatment with LA-SRIF analogues.[24] This also applies to comparisons between the effects of long-acting LA-SRIF analogue therapies, PEG-V and surgery.

By this, we assume that serum IGF1 levels adequately and uniformly reflect disease activity. However, it can be argued that this assumption is not valid. Acromegaly patients with normal IGF1 during LA-SRIF treatment still had elevated nadir GH levels as compared with patients with a normal IGF1 after surgery.[27] The LA-SRIF treated patients also had a reduced disease-specific health status compared with the surgically cured patients.[27] The combination of an elevated IGF1 level and a normal GH level is sometimes seen after radiation therapy because radiotherapy causes a flat GH secretory pattern.[28] On the other hand, several factors have been identified that can result in lower IGF1 relative to GH levels, such as chronic inflammatory disorders and anorexia nervosa (which can impair IGF1 production by the liver), nutritional or gastrointestinal disorders such as hepatic or renal failure, poorly controlled type 1 diabetes, oral oestrogens and hypothyroidism.[14,26] Acromegaly patients with long-term "remission" may have some signs of GH excess. This can be observed as arthralgia, mild hypertension, relative glucose intolerance and numbness of the hands.[2931] By antagonizing this excess of GH, QoL improves.[30] There is also evidence from animal models for this hypothesis of mild GH excess. In mice, GH can have temporal and tissue-specific effects that are independent of IGF1 serum levels. In adipose tissue, kidney and skeletal muscle, local activity of GH can be blocked with relatively low doses of PEG-V that do not change serum IGF1.[32] For example, glomerulosclerosis is caused by high GH levels not by raised IGF1. This was confirmed in mice 20 years ago.[33,34] Finally, in a prospective, double-blind, placebo-controlled, crossover trial of PEG-V treatment in acromegaly patients with "normal" IGF1, QoL was assessed by a disease-specific QoL questionnaire, Acromegaly Quality of Life Questionnaire (AcroQoL)[35,36] and a disease-specific symptom questionnaire (PASQ).[25,37] After 16 weeks of treatment with 40 mg PEG-V weekly, QoL improved, as indicated by an increased AcroQoL score total and AcroQoL score physical dimension. The magnitude of the improvement in AcroQoL score of 64% was equal to the observations of Paisley et al.[38] when elevated IGF-I was reduced to the age-adjusted normal range. This was accompanied by a reduction in symptoms assessed by PASQ, (the total PASQ score and the single PASQ questions, perspiration, soft tissue swelling and overall health status). The same symptoms in the PASQ scores, perspiration and soft tissue swelling, also decrease after PEG-V treatment in previously uncontrolled patients. This seems to occur without a significant correlation with change in IGF1 levels.[39] This clinically relevant improvement also failed to be detected by other currently available biochemical markers.[30] Although auto or paracrine GH or IGF1 effects may explain some of these findings, there is evidence for a new concept called "extra hepatic acromegaly".[26] Normalization of levels of total serum IGF1 and GH do not necessarily reflect optimal QoL, nor relief of symptoms in patients with acromegaly.[5,26,30,4043] From the patient's perspective, QoL is one of the most important parameters of disease control. So the goals of treatment are to normalize IGF1 and GH levels and activity, and improve QoL.

There is a group of patients with active disease who do not have impaired QoL. It is not logical that in these patients, QoL is a good bioassay or could improve more. However, there are a limited number of patients without any symptoms or decreased QoL otherwise they would not have sought medical care. As briefly discussed previously, QoL can be assessed by different questionnaires. There are more general questionnaires, which can be used to study general health concepts and functional status in different situations and there are disease-specific questionnaires. To quantify perceived health, QoL and symptoms in patients with acromegaly, PASQ[25,37] and the AcroQoL are available and are described here in more detail:

Disease-specific Symptom Score and Quality of Life Questionnaires

o Acromegaly Quality of Life Questionnaire (AcroQoL) AcroQoL is a disease-specific quality of life questionnaire, comprising 22 questions. Each question has five possible answers scored 15, with a total maximum score of 110 and quoted as a percentage. The score of 110 reflects the best possible QoL. The 22 questions are divided into two main categories: physical and psychological function. The psychological dimension is subdivided into appearance and personal relationships.[35,36] The AcroQoL has a good internal consistency (Cronbach's > 08),[44] although there is, to some extent, a lack of normative data. The QoL scores of the AcroQoL from different countries are interchangeable, with cure around 80, and active disease 50. This suggests that there is a high homology between countries and patients even though they have a different background. o Patient-assessed Acromegaly Symptom Questionnaire (PASQ) The PASQ is a disease-specific symptom questionnaire, which consists of six questions scoring 08 and the seventh question addressing overall health status, based on the other six questions, scoring 010.[25,37] The first six questions evaluate symptoms of headache, excessive sweating, joint pain, fatigue, soft tissue swelling, and numbness or tingling of the extremities. The maximum score of these six questions is 48 and indicates severe symptoms, with lower scores reflecting milder symptoms. o Quality of Life as Marker of Disease Activity. Despite biochemical control, patients may experience ongoing signs of GH excess, such as mild hypertension, relative glucose intolerance and arthralgia, soft tissue swelling and perspiration.[29,31] These symptoms can be present because of (ongoing) pathological GH secretion, while IGF1 and GH are within the normal range or irreversible changes. Thus, biochemical assessments fail to discriminate perfectly in cases of mild excess.[31] A very important issue is whether quality of life and patients' perceived

health, as assessed by questionnaire, perform better than biochemical assessments and may be of additive value in the detection of disease activity. In general, QoL in patients is influenced by several factors, which may limit the discriminatory value of QoL. These include, firstly, somatic factors: the disease itself, signs and symptoms related to the disease and unrelated co-morbidity. At present, there are no cut-off points for quality of life scores. In previous studies, QoL scores were significantly related to the presence of joint pain, anxiety/depression, but not to obstructive sleep apnoea and cardiomyopathy. Secondly, several psychological factors are known to influence quality of life. For example, anxiety and depression negatively influence quality of life, including physical scales. Also, coping behaviour, personality and understanding of the disease as can be measured by illness perceptions are relevant factors.[45,46] In acromegaly, quality of life has been reported to be significantly reduced in active untreated disease and in controlled treated disease, even after long-term follow-up. Although QoL improves in biochemically cured patients, limitations remain, possibly due to irreversible damage or elevated GH action. QoL has been measured with diseasespecific questionnaires, the AcroQoL, and several general health questionnaires, most frequently by assessing functional status with the SF-36, but also using HADS and MFI20 and EQ-5D.[5,38,4749] Comparative studies within the field of pituitary disease have suggested that acromegaly and Cushing's are the diseases with most impaired QoL, with acromegaly most frequently causing impairments in physical function and pain.[50] To date, the number of longitudinal studies is limited. However, improvements of QoL are generally observed in patients with new treatments, although biochemical changes, GH and IGF1 concentrations, and QoL changes frequently dissociate.[38,42,48,51,52] QoL does relate to patients' perceived symptom scores.[49] Based on quality of life outcomes, there is not a clear preference for any one treatment modality. In Dutch[53] and Danish[27] cohorts of patients with acromegaly, the best QoL was reported in patients with surgical cure without pituitary failure and a progressive decline in QoL score occurred in irradiated patients.[47] Improved QoL was reported after adding pegvisomant to controlled patients during LA-SRIF analogue treatment.[30] Treatment of GHD in patients with acromegaly was also associated with improved QoL in one study, but not in another.[54,55] Pain, especially joint pain, was an important negative factor for QoL. Patients with (clinical) acromegalic arthropathy had decreased QoL in comparison with patients without arthropathy.[5658] By analogy, patients with hypertension, restless legs and a high symptom score also had impaired QoL.[40,49,5760] Patients with acromegaly are at risk for depression and other neuropsychiatric symptoms[61,62] characterized by reduced impulsivity and novelty seeking. Depressive and anxiety symptoms assessed by HADS were associated with more impaired QoL.[53] Currently, little is known about coping strategies and illness perceptions in relation to quality of life in acromegaly. These have been associated with QoL in other chronic

diseases. In an exploratory study, coping strategies in acromegaly appeared to be suboptimal, and coping strategies were related to QoL.[46] Quality of life is an important patient-based outcome measure of treatment[63] and is a component of the quality-adjusted life year (QALY) unit, which is used in costbenefit assessments.[64] Several studies have reported that QoL changes with major changes in disease status. However, in stable disease and during minor changes in disease state within the (near) normal range, biochemical markers and QoL frequently dissociate. This is because of imperfections in the ability of biochemical markers to adequately detect disease status. When all available data are taken into consideration, QoL could add additional value to the current available biochemical markers.

Summary
The definition of normal values, that is, criteria for control, remains a challenge, and adequately suppressed growth hormone/insulin-like growth factor 1 assessed by biochemical means may not reflect abolished growth hormone excess and true normalization of growth hormone and insulin-like growth factor 1 concentrations, for a number of reasons. Firstly, normal growth hormone values are assay dependent. Secondly, normal values are age and sex dependent, and there is probably variation in individual growth hormone receptor sensitivity. Thirdly, serum values may not reflect tissue hormone levels. Fourthly, there are treatment-specific issues, such as altered growth hormone pulsatility during treatment with long-acting somatostatin analogue analogues and the limitation that only insulin-like growth factor 1, not growth hormone, can be used as a reliable marker during pegvisomant treatment. Therefore, there is a need for a bioassay that reliably assesses disease activity. To date, it has not been possible to identify a reliable sign/symptom (score)/biochemical marker with good test characteristics that reflects disease activity. A new biochemical parameter that can assess tissue-specific disease activity is necessary, but not available. The current best bioassays are quality of life and symptom scoring lists, whose effectiveness may be improved by mean outcome measurement. However, Acromegaly Quality of Life Questionnaire must be simplified and patient-assessed acromegaly symptom questionnaire requires validation before they can be used in everyday clinical practice, to achieve a tailored approach to the individual patient