Quality of life (QoL) has emerged as an important construct that has found numerous applications across healthcare-related fields, ranging from research and clinical evaluation of treatment effects to pharmacoeconomic evaluations and global healthcare policy. Impairment of QoL is one of the key clinical characteristics in adult GHD and has been extensively studied in the Pfizer International Metabolic Database (KIMS). We provide summarized evidence on GH treatment effects for both clinical and health economic applications based on the KIMS data. The primary focus is on those aspects of QoL research that cannot be investigated in the traditional clinical trial setting, such as specific patient subgroups, cross-country comparisons and long-term follow-up. First, the impact of age, gender, disease onset, primary aetiology, extent of hypopituitarism, previous radiotherapy and obesity on QoL before and during long-term GH replacement is discussed. Secondly, the studies on QoL in relation to country-specific normative values are reviewed. Finally, health economic data derived from KIMS including both burden of disease and utility assessment are evaluated. We conclude that the wide spectrum of analyses performed on the KIMS data allows for practical application of the results not only to research and clinical practice but also to health policy and global medical decision making.
Maria Koltowska-Häggström, Anders F Mattsson and Stephen M Shalet
Mohamad Maghnie, Anders Lindberg, Maria Koltowska-Häggström and Michael B Ranke
Neuroimaging has become an essential part of the diagnostic process in children with GH deficiency (GHD). The aim of the study was to document the frequency of neuroanatomical abnormalities in a very large cohort of children with GHD and to relate these findings to patient clinical characteristics.
Design and methods
Results of magnetic resonance imaging (MRI) were reported in 15 043 of 43 725 children with non-acquired GHD (idiopathic, neurosecretory dysfunction (NSD) and known congenital cause) who were enrolled in KIGS (Pfizer International Growth Database) between 1987 and 2011. Clinical characteristics of patients before GH treatment with normal MRI (idiopathic GHD (IGHD) and NSD) were compared with those of patients with abnormal pituitaries (hypoplasia, empty sella (ES), HME (hypoplastic anterior pituitary, missing pituitary stalk and ectopic posterior pituitary)).
Abnormal MRIs were found in 4032 (26.8%) children, within which ES (n=1178 (7.8%)) and HME (n=1019 (6.8%)) were the most frequent findings. In 2361 children diagnosed as IGHD or NSD before MRI examination, anatomical abnormalities ((pituitary hypoplasia: n=974); (HME: n=459)) were documented. Patients with anatomical abnormalities had more severe characteristics of GHD: normal MRI < pituitary hypoplasia < ES < HME.
GHD is associated with a great variety of neuroanatomical abnormalities as identified by MRI. The investigation and evaluation of MRI need to be conducted in a structured mode. There is an association between anatomical and functional abnormalities of the pituitary.
Charlotte Hoybye, Peter Jönsson, John P Monson, Maria Kołtowska-Häggström, Václav Hána, Mitchell Geffner and Roger Abs
The impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy.
Design and methods
Data from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement.
GHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement.
The adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.
Chris J Gardner, Anders F Mattsson, Christina Daousi, Márta Korbonits, Maria Koltowska-Haggstrom and Daniel J Cuthbertson
Prevalence of GH deficiency (GHD) caused by traumatic brain injury (TBI) is highly variable. Short-term studies show improvement in quality of life (QoL) during GH replacement (GHR), but long-term data are lacking. The aim of this study was to analyse the clinical characteristics of post-traumatic hypopituitarism and the QoL effects of long-term GHR.
Pfizer International Metabolic Database patients with GHD caused by TBI and by non-functioning pituitary adenoma (NFPA) were compared regarding: clinical characteristics at baseline and 1-year of GHR, and QoL response up to 8-years of GHR (QoL-AGHDA total scores and dimensions) in relationship with country-specific norms.
TBI patients compared with NFPA patients were younger, diagnosed with GHD 2.4 years later after primary disease onset (P<0.0001), had a higher incidence of isolated GHD, higher GH peak, a more favourable metabolic profile and worse QoL, were shorter by 0.9 cm (1.8 cm when corrected for age and gender; P=0.004) and received higher GH dose (mean difference: 0.04 mg/day P=0.006). In TBI patients, 1-year improvement in QoL was greater than in NFPA (change in QoL-AGHDA score 5.0 vs 3.5, respectively, P=0.04) and was sustained over 8 years. In TBI patients, socialisation normalised after 1 year of GHR, self-confidence and tenseness after 6 years and no normalisation of tiredness and memory was observed.
Compared with NFPA, TBI patients presented biochemically with less severe hypopituitarism and worse QoL scores. GHR achieved clinically relevant, long-term benefit in QoL.
Roger Abs, Anders F Mattsson, Maria Thunander, Johan Verhelst, Miklós I Góth, Patrick Wilton, Maria Kołtowska-Häggström and Anton Luger
GH deficiency (GHD) in adults is characterized by a tendency toward obesity and an adverse body composition with visceral fat deposit and may thus predispose to the development of type 2 diabetes mellitus. The aim of this study was to assess the observed prevalence proportion (PP) and observed PP over expected PP ratio (standardized prevalence proportion ratio, SPR) of diabetes according to International Diabetes Federation criteria in a large cohort of GH-untreated adult-onset GHD patients.
Design and methods
Associations between baseline variables and diabetes prevalence in 6050 GHD patients from KIMS (Pfizer International Metabolic Database) were studied and robust Poisson-regression analyses were performed. Comparisons between baseline status and HbA1c categories in the nondiabetic patients were done with covariance analysis. P values <0.05 were considered statistically significant.
PP was 9.3% compared with the expected 8.2%. SPR was 1.13 (95% confidence intervals (95% CIs), 1.04–1.23), which was significantly increased in females (1.23; 95% CI, 1.09–1.38%) but not in males (SPR 1.04; 95% CI, 0.92–1.17%). PP increased significantly by age, familial diabetes, country selection, BMI, waist circumference, number of pituitary deficiencies, and GHD etiology. SPR decreased significantly by age and increased significantly by BMI, waist circumference, and IGF1 SDS. Multiple regression model showed that the most important impact on SPR was from age and BMI. HbA1c values of 6.0–6.5% were found in 9.5% of nondiabetic patients and were associated with higher BMI and waist circumference.
GHD is associated with an increased prevalence of diabetes, largely to be explained by the adverse body composition. These data urge toward early initiation of lifestyle modification measures.
Johan Verhelst, Anders F Mattsson, Anton Luger, Maria Thunander, Miklós I Góth, Maria Kołtowska-Häggström and Roger Abs
An increased risk of cardiovascular morbidity and mortality in adult GH deficiency (GHD) may be related to hypopituitarism but also to the presence of the metabolic syndrome (MetS). Our objective was to investigate the characteristics and prevalence of MetS as well as its comorbidities in adult GHD.
In KIMS (Pfizer International Metabolic Database) 2479 patients with severe adult-onset GHD, naïve to GH replacement, with complete information on all MetS components were found. MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP) and the International Diabetes Foundation (IDF).
The prevalence of MetS was calculated and compared with previously published data from the normal population. Associations were assessed between background variables, baseline variables, comorbidities, and MetS.
MetS was present in 43.1% (NCEP) and in 49.1% (IDF) of patients, clearly higher than data from the normal population (20–30%). MetS prevalence was related to age, GHD duration, and body mass index (BMI), but not to GHD severity, extent of hypopituitarism, or etiology of pituitary disease. Adjusted for age, gender, and BMI, patients with MetS had a higher prevalence ratio for diabetes mellitus: 4.65 (95% confidence interval (CI): 3.29–6.58), for cardiovascular morbidity: 1.91 (95% CI: 1.33–2.75), and for cerebrovascular morbidity: 1.77 (95% CI: 1.09–2.87) than patients without MetS.
MetS is highly prevalent in GHD and is associated with a higher prevalence ratio for comorbidities. The presence of MetS in GHD may therefore contribute to the increased risk of cardiovascular morbidity and mortality found in these patients.
Charlotte Höybye, Oskar Ragnarsson, Peter J Jönsson, Maria Koltowska-Häggström, Peter Trainer, Ulla Feldt-Rasmussen and Beverly M K Biller
Patients in remission from Cushing's disease (CD) have many clinical features that are difficult to distinguish from those of concomitant GH deficiency (GHD). In this study, we evaluated the features of GHD in a large cohort of controlled CD patients, and assessed the effect of GH treatment.
Design and methods
Data were obtained from KIMS, the Pfizer International Metabolic Database. A retrospective cross-sectional comparison of background characteristics in unmatched cohorts of patients with CD (n=684, 74% women) and nonfunctioning pituitary adenoma (NFPA; n=2990, 39% women) was conducted. In addition, a longitudinal evaluation of 3 years of GH replacement in a subset of patients with controlled CD (n=322) and NFPA (n=748) matched for age and gender was performed.
The cross-sectional study showed a significant delay in GHD diagnosis in the CD group, who had a higher prevalence of hypertension, fractures, and diabetes mellitus. In the longitudinal, matched study, the CD group had a better metabolic profile but a poorer quality of life (QoL) at baseline, which was assessed with the disease-specific questionnaire QoL-assessment of GHD in adults. After 3 years of GH treatment (mean dose at 3 years 0.39 mg/day in CD and 0.37 mg/day in NFPA), total and low-density lipoprotein cholesterol decreased, while glucose and HbAlc increased. Improvement in QoL was observed, which was greater in the CD group (−6 CD group versus −5 NFPA group, P<0.01).
In untreated GHD, co-morbidities, including impairment of QoL, were more prevalent in controlled CD. Overall, both the groups responded similarly to GH replacement, suggesting that patients with GHD due to CD benefit from GH to the same extent as those with GHD due to NFPA.
Oskar Ragnarsson, Charlotte Höybye, Peter J Jönsson, Ulla Feldt-Rasmussen, Gudmundur Johannsson, Beverly M K Biller and Maria Kołtowska-Häggström
Cushing's disease (CD) and non-functioning pituitary adenoma (NFPA) are rare in paediatric patients. The aim of this study was to describe long-term consequences in adults with GH deficiency (GHD) treated for CD or NFPA during childhood.
Design, patients and methods
This was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Background characteristics, anthropometry and comorbidity were studied in 47 patients diagnosed with childhood-onset (CO)-CD and 62 patients with CO-NFPA. Data from 100 ACTH-sufficient patients with CO-idiopathic hypopituitarism (CO-Idio) were used for comparison. Cardiovascular risk profile was analysed at baseline and at 1 year on GH treatment in a subgroup of patients (17 CO-CD, 24 CO-NFPA and 55 CO-Idio) not receiving GH treatment at study entry.
The median age at diagnosis of pituitary tumour was 14.0 years (range 10–17) in patients with CO-CD and 13.7 years (range 8–17) in CO-NFPA. In addition to GHD, 41% of patients with CO-CD had three or four other pituitary hormone deficiencies compared with 78% of patients with CO-NFPA (P<0.001). Eighty-nine per cent of patients with CO-CD had height SDS lower than 0 compared with 61% of patients with CO-NFPA (P=0.002). Hypertension was more common in CO-CD compared with CO-Idio (23 vs 9%, P=0.018). At 1 year on GH treatment, total- and low-density lipoprotein-cholesterol decreased significantly in CO-CD but not in CO-NFPA.
Adult patients with GHD following treatment for paediatric CD and NFPA have long-term adverse consequences. Despite more severe hypopituitarism in CO-NFPA, patients with CO-CD have more frequently compromised final stature.
Pat Kendall-Taylor, Peter J Jönsson, Roger Abs, Eva Marie Erfurth, Maria Koltowska-Häggström, David Anthony Price and Johan Verhelst
Background: Craniopharyngioma is a parasellar tumour that, although benign, tends to behave aggressively. It can occur at any age but most commonly presents in childhood or adolescence.
Objectives: To investigate the frequency and severity of problems associated with craniopharyngioma, using the large international database (KIMS) for adult patients with GH deficiency (GHD), and to assess the differences between the adult onset (AO, aged 18 or above) disease and adults with childhood onset (CO) craniopharyngioma.
Design: Inclusion criteria were: an established diagnosis of craniopharyngioma, severe GHD and no recent GH treatment. These criteria were fulfilled by 393 (184 female, 209 male) patients; 241 had AO (mean age 28.7±8.7 years) and 152 had CO disease (age 42.0±12.3 years). Disease history, clinical features and anthropometric data were recorded at the time of enrolment in the database, and body composition, serum IGF-I, serum lipids and quality of life (QoL) were assessed.
Results: Peak age at onset of craniopharyngioma was 15–20 years. Ninety percent of patients had been treated surgically. CO patients were shorter than AO patients and had much lower IGF-I standard deviation scores (SDS). The majority had hypopituitarism and over 60% had diabetes insipidus. Body mass index (BMI) was higher in AO males (30.2±5.5) than in CO males (28.5±7.5); waist circumference was also greater. Obesity was more common in AO patients (51.8% vs 39.1%). Body composition did not differ between groups. Cholesterol and triglycerides were higher in AO than in CO patients, but high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol did not differ. Quality of life, assessed by Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) and the Nottingham Health Profile, was markedly reduced in all groups with no significant differences between them; the QoL-AGHDA score correlated with age at onset of both craniopharyngioma and GHD, and also with BMI in AO patients.
Conclusions: These data emphasise the generally poor state of health of patients treated for craniopharyngioma, with respect to endocrine and metabolic function, and also the markedly reduced quality of life. In addition to GHD, most patients have evidence of hypothalamic damage with associated obesity, diabetes insipidus and hypopituitarism. Adults with CO craniopharyngioma were shorter, had lower IGF-I, lower BMI, less obesity and slightly lower blood lipid levels than patients with AO craniopharyngioma.
Thierry Brue, Frederic Castinetti, Frida Lundgren, Maria Koltowska-Häggström, Patrick Petrossians and on behalf of all ACROSTUDY investigators
Pegvisomant (Somavert, Pfizer Inc.) is the first and only available GH receptor antagonist. ACROSTUDY is an international surveillance study that offers inclusion in a web-based registry to all patients with acromegaly treated with pegvisomant; it aims at monitoring long-term safety and efficacy of this compound.
Patients and methods
This report summarizes the main baseline characteristics of this particular population of patients. In February 2009, over 300 centres in 10 countries had contributed 792 patients. A gradual increase in cumulative patient recruitment was observed since the launching of ACROSTUDY in 2004: from 116 patients in 2005, it steeply increased to 792 at the latest data freeze in February 2009. At the time of enrolment, 91.8% of patients were already treated with pegvisomant but baseline was considered at the time of pegvisomant start. IGF1 concentrations were measured at local laboratories.
Of all patients, 80% were reported to have had surgery and 33% to have received radiation therapy. Of the 792 patients, 14% had received no prior medical treatment before pegvisomant start, 65.9% had received somatostatin analogues and 18.6% dopamine agonists. Interestingly, 66.7% had received only pegvisomant at study start, while it was taken in association with dopamine agonists in 5.7%, with somatostatin analogues in 23.4% and with both types of agents in 3.8%. Mean IGF1 at baseline was 522 ng/ml.
Analysis of the baseline features of these patients treated with pegvisomant and reported in the ACROSTUDY database underscores the severity of the disease in this subset of the population of patients with acromegaly previously unresponsive to several medical, surgical or radiation treatment approaches.