Anders F. Mattsson

Serum Insulin-Like Growth Factor I Reference Values for an Automated Chemiluminescence Immunoassay System: Results from a Multicenter Study

Background: Analysis of insulin-like growth factor I in serum (S-IGF-I) is an integral component in the diagnosis of GH-related disorders and is going to be of interest in the diagnosis and follow-up of many disorders. The objective of the present study was to develop cross-sectional reference values for S-IGF-I measured by an automated chemiluminescence immunoassay (Nichols Advantage®). Methods: The study included samples from 3,961 healthy subjects (2,201 males, 1,760 females) aged 1 month to 88 years. Six laboratories were involved in this study and the samples were analyzed by one of seven automated immunoassay systems run in these laboratories. For data analysis, polynomial age and sex-specific models were fitted after transformation of S-IGF-I values. Results: The results show the well-known age dependency of S-IGF-I levels. At ages <20, higher S-IGF-I levels were seen in girls with an estimated mean peak of 410 µg/l at age 14 and an estimated mean peak of 382 µg/l at age 16 in boys. Thereafter, a rapid decrease was seen to approximately 25 years of age, followed by a slow age-dependent decrease. In adulthood, S-IGF-I in males were slightly, but significantly higher than in females. It could be shown that the mean values of some reference sample subgroups differed significantly from the total mean. However, the multicenter approach used in this study reduces the impact of systematic population, sample handling and laboratory differences on the calculated reference mean. Conclusion: The present study establishes age- and sex-specific reference values for a fully automated immunoassay system based on a large population of healthy subjects. The established reference values may be used for this immunoassay system in different laboratories provided that the systematic difference between systems is low.

Deaths Among Adult Patients With Hypopituitarism : Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality

CONTEXT Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. OBJECTIVE To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. DESIGN AND METHODS All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. MAIN OUTCOME MEASURES Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. RESULTS An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. CONCLUSION Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

Overall and cause-specific mortality in GH-deficient adults on GH replacement.

OBJECTIVE Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients. DESIGN In KIMS (Pfizer International Metabolic Database) 13,983 GH-deficient patients with 69,056 patient-years of follow-up were available. METHODS This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05. RESULTS All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04-1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushings disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044). CONCLUSIONS GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.

Growth Hormone Treatment in Children is not Associated with an Increase in the Incidence of Cancer: Experience from KIGS (Pfizer International Growth Database)

OBJECTIVE To assess the incidence of cancer in patients treated with growth hormone (GH) in KIGS - the Pfizer International Growth Database-without cancer or any other condition in medical history known to increase the risk of cancer. STUDY DESIGN Data were analyzed from patients with growth disorders enrolled in an observational survey KIGS who had no known increased risk of developing cancer before starting recombinant human GH treatment. The incidence of cancer in this patient cohort (overall, site-specific, and according to etiology of growth disorder) was compared with the incidence in the general population by using the standardized incidence ratio (ie, relating the observed to expected number of cases with stratification for age, sex, and country). RESULTS A total of 32 new malignant neoplasms were reported in 58 603 patients, versus the 25.3 expected (incidence, 16.4 per 100 000 patient-years; standardized incidence ratio, 1.26; 95% confidence interval, 0.86-1.78). No category of growth disorder showed a statistically significant difference in observed compared with the expected number of cases. CONCLUSION There is no evidence in this series that GH treatment in young patients with growth disorders results in an increased risk of developing cancer relative to that expected in the normal population. However, surveillance for an extended time should continue to allow further assessment.

Assessment of quality of life in adult patients with GH deficiency: KIMS contribution to clinical practice and pharmacoeconomic evaluations

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.

Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA): Comparison of Normative Reference Data for the General Population of England and Wales with Results for Adult Hypopituitary Patients with Growth Hormone Deficiency

Background/Aim:Age- and gender-specific reference values for the quality of life (QoL) measures used in assessing the impact of growth hormone deficiency (GHD) are important. The objective of this study was to develop such data for the QoL-AGHDA instrument for the population of England and Wales and to demonstrate the QoL deficit in patients with GHD. Methods: For the purpose of this study, a questionnaire was developed that contained the EurQoL EQ-5D, QoL-AGHDA, questions recording an individual’s general situation and social functioning, and a self-reported five-point rating scale of general health. The questionnaire was mailed out to a sample of 1,190 individuals drawn from the general population of England and Wales. Corresponding data for 836 patients were retrieved from KIMS (Pfizer International Metabolic Database). The postal survey data were weighted to ensure that they were representative of the general population. Results: The mean weighted QoL-AGHDA scores for the general population were 6.2 and 7.1 for men and women, respectively, compared with 13.6 and 15.7 for patients. For both males and females the differences in mean QoL-AGHDA scores between the general population and patients were statistically significant for all age categories (p < 0.01). In the general population the mean QoL-AGHDA score for each category of self-assessed health status increased progressively, indicating a poorer QoL as health status declined. Conclusions: This study reports QoL-AGHDA normative values for the population of England and Wales and confirms the extent of QoL impairment in patients with GHD in comparison with the general population.

Prevalence and characteristics of the metabolic syndrome in 2479 hypopituitary patients with adult-onset GH deficiency before GH replacement: a KIMS analysis

OBJECTIVE 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. Design 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 Programs Adult Treatment Panel III (NCEP) and the International Diabetes Foundation (IDF). METHODS 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. RESULTS 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. CONCLUSIONS 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.

Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone-deficient subjects during growth hormone replacement therapy: a long-term observational study.

OBJECTIVE Growth hormone (GH) deficiency is associated with insulin resistance and diabetes. The aim of the current study was to determine incidence of diabetes during GH replacement therapy (GHRT) and the effect of GHRT on fasting plasma glucose concentrations and HbA1c in adult patients with GH deficiency. RESEARCH DESIGN AND METHODS A total of 5,143 GH-deficient patients (male 49.9%; mean age ± SD, 49 ± 13 years; BMI 29.1 ± 5.9 kg/m2) were analyzed. Mean observation period was 3.9 years (range 0.01–13). Total number of patient-years was 20,106. Observed number of cases (O) was compared with expected number of cases (E). Reference rates were from Sweden, three additional European regions, and one U.S. region. RESULTS Patients who developed diabetes (n = 523) were older; had higher BMI, waist circumference, triglyceride concentrations, and blood pressure; and had lower HDL-cholesterol concentrations (P < 0.0001) than those who did not develop diabetes. Diabetes incidence was 2.6 per 100 patient-years, equal in both sexes, and significantly increased compared with the Swedish reference (O/E = 6.02; P < 0.0001) as well as with the four other populations (O/E = 2.11–5.22). O/E increased with BMI and decreased with duration of GHRT (P < 0.0001). There was no significant association with GH dose (P = 0.74) or IGF-I SDS (P = 0.47). In subjects not developing diabetes, plasma glucose concentrations increased from 84.4 ± 0.9 mg/dL to 89.5 ± 0.8 mg/dL (0.70 mg/dL/year) and HbA1c increased from 4.74 ± 0.04% to 5.09 ± 0.13% (0.036%/year) after 6 years of GHRT. CONCLUSIONS Diabetes incidence appears to be increased in GH-deficient patients receiving GHRT and exhibiting an adverse risk profile at baseline. Therefore, glucose homeostasis parameters should be monitored carefully in these patients.

Serum insulin-like growth factor I (IGF-I), IGF-binding proteins 2 and 3, and the risk for development of malignancies in adults with growth hormone (GH) deficiency treated with GH: data from KIMS (Pfizer International Metabolic Database).

CONTEXT The association between IGFs and cancer in adults with GH deficiency (GHD) receiving GH replacement requires investigation. OBJECTIVE The objective was to examine the association between IGF-I, IGF-binding protein 2 (IGFBP-2), and IGFBP-3 SD scores (SDSs) in GH-deficient adults receiving GH therapy and the occurrence of de novo malignancies. DESIGN Serum IGF-I, IGFBP-2, and IGFBP-3 levels in GH-deficient patients who developed a malignancy since receiving GH were compared with patients with idiopathic GHD but without malignancy. Measurements were related to age-, sex-, and body mass index-specific SDS reference regions. SETTING The setting included the KIMS (the Pfizer International Metabolic Database). PATIENTS One hundred patients with de novo malignancy during GH therapy were compared with 325 patients with idiopathic GHD without malignancy. INTERVENTION(S) Serum samples were obtained as close as possible to the diagnosis of malignancy, or after approximately 2 yr of GH replacement in KIMS. MAIN OUTCOME MEASURES Associations between relative risk (RR) of malignancy and IGF-I, IGFBP-2, and IGFBP-3 SDSs were assessed in multiple log-linear Poisson working regression models, controlling for age, sex, onset of GHD, and GH naivety at KIMS entry. RESULTS No association between IGF-I SDSs and RR was observed (P = 0.48). Increasing IGFBP-2 and IGFBP-3 SDSs were associated with increasing RRs [18% per unit IGFBP-2 SDSs (95% confidence interval, 7-30%; P = 0.0006), 13% per unit IGFBP-3 SDS (2-26%; P = 0.01)]. CONCLUSIONS IGF-I levels targeted to within normal age-related reference ranges during GH replacement were not associated with the occurrence of malignancies. Higher IGFBP-2 and/or IGFBP-3 SDSs may be associated with increased cancer risk.

Multidimensional reference regions for IGF-I, IGFBP-2 and IGFBP-3 concentrations in serum of healthy adults

CONTEXT The insulin-like growth factor (IGF) system exerts many effects on the growth and differentiation of both normal and malignant cells. The serum concentrations of insulin-like growth factor I (S-IGF-I), insulin-like growth factor-binding protein 2 (S-IGFBP-2) and insulin-like growth factor-binding protein 3 (S-IGFBP-3) and their inter-relations may differ in certain disease states from those seen in healthy individuals. OBJECTIVE To estimate age-, gender- and body mass index (BMI)-specific univariate, bivariate and trivariate 95% reference regions for these components in healthy adults and present indices that will facilitate interpretation of patient observations in relation to these reference regions. DESIGN Blood samples were taken in the morning from 427 healthy, non-fasting German blood donors of both genders (age range, 18-79 years; BMI range, 16-44 kg/m(2)). Reference regions were developed with multivariate regression methods. RESULTS Regression analyses showed that S-IGF-I and S-IGFBP-3 levels decrease with increasing age, whereas S-IGFBP-2 concentrations increase with age (P<0.0001). Females had significantly higher S-IGFBP-3 levels than males (P<0.0001) and similar S-IGF-I and S-IGFBP-2 concentrations. Increasing BMI was associated with decreasing S-IGFBP-2 (P<0.0001), but was not significantly associated with the concentrations of the other two analytes. Controlling for age, gender and BMI, S-IGF-I and S-IGFBP-3 were positively correlated (r=0.58), whereas S-IGF-I and S-IGFBP-2, and S-IGFBP-2 and S-IGFBP-3 were negatively correlated (r=-0.11 and r=-0.18, respectively). Based on the regression models, which were controlled for age, gender and BMI, two- and three-dimensional 95% reference regions with associated patient indices were described for each pair of analytes and for the trio of analytes, respectively. CONCLUSIONS The multivariate reference regions developed in this study should be useful in identifying patients with an abnormal IGF-IGFBP axis. It is suggested that introducing multidimensional reference regions and the described patient indices into clinical practice may aid monitoring of the safety of GH therapy. These patient indices may also be useful in the assessment of cancer risk.