Changes in acromegaly comorbidities, treatment, and outcome over three decades: a nationwide cohort study.

Objective: To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer and mortality. Methods: Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation. Results: Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time. Conclusion: Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.

The changing landscape of acromegaly - an epidemiological perspective.

Acromegaly is a rare disease and thus challenging to accurately quantify epidemiologically. In this comprehensive literature review, we compare different approaches to studying acromegaly from an epidemiological perspective and describe the temporal evolution of the disease pertaining to epidemiological variables, clinical presentation and mortality. We present updated epidemiological data from the population-based Danish cohort of patients with acromegaly (AcroDEN), along with meta-analyses of existing estimates from around the world.Based on this, we conclude that the incidence, prevalence and age at acromegaly diagnosis are all steadily increasing, but with considerable variation between studies. An increased number of incidental cases may contribute to the increase in incidence and age at diagnosis, respectively. The clinical features at presentation are trending toward a milder disease phenotype at diagnosis, and advances in therapeutic options have reduced the mortality of patients with acromegaly to a level similar to that of the general population. Moreover, the underlying cause of death has shifted from cardiovascular to malignant neoplastic diseases.

The TRH test provides valuable information in the diagnosis of central hypothyroidism in patients with known pituitary disease and low T4 levels.

Objective: To evaluate the value of the thyrotropin-releasing hormone (TRH) test in the diagnosis of central hypothyroidism (CH) in patients with pituitary disease. Methods: Systematic evaluation of 359 TRH tests in patients with pituitary disease including measurements of thyroxine (T4), TBG-corrected T4 (T4corr), baseline TSH (TSH0) and relative or absolute TSH increase (TSHfold, TSHabsolute). Results: Patients diagnosed with CH (n=39) show comparable TSH0 (p-value 0.824) but lower T4corr (p-value <0.001) and lower TSH increase (p-value <0.001) compared to patients without CH. In 54% (42 of 78 cases) of patients with low T4corr, the CH diagnosis was rejected based on a high TSHfold. In these cases, a spontaneous increase and mean normalization in T4corr (from 62 to 73 nmol/L, p-value <0.001) was observed during the follow-up period (7.6 ± 5.0 years). Three of the 42 patients (7%) were started on replacement therapy due to spontaneous deterioration of thyroid function after 2.8 years. Patients diagnosed with CH reported significantly more symptoms of hypothyroidism (p-value 0.005), although, symptoms were reported in most patients with pituitary disease. The TRH test did not provide clinical relevant information in patients with normal T4 or patients awaiting pituitary surgery (78%, 281 of 359). There were only mild and reversible adverse effects related to the TRH test except for possibly one case (0.3%) experiencing a pituitary apoplexy. Conclusion: The TRH test could be reserved to patients with pituitary disease, low T4 levels without convincing signs of CH. Approximately 50% of patients with a slightly decreased T4 were considered to have normal pituitary thyroid function based on the TRH test results.

Whole-Body and Forearm Muscle Protein Metabolism in Patients With Acromegaly Before and After Treatment.

BACKGROUND: Active acromegaly is characterized by increased lean body mass, but the mechanisms underlying the protein anabolic effect are unclear. AIM: To study if active acromegaly induces reversible changes in whole-body and skeletal muscle protein kinetics. PATIENTS AND METHODS: Eighteen patients with acromegaly were investigated before and 47 ± 10 weeks after disease control by surgery (n = 8) and/or medical treatment (n = 10). Labeled phenylalanine and tyrosine tracers were employed to assess whole-body and regional forearm muscle protein kinetics. Intramyocellular protein signaling was assessed in skeletal muscle biopsies, and whole-body dual-energy X-ray absorptiometry scan and indirect calorimetry assessed lean body mass (LBM) and resting energy expenditure, respectively. RESULTS: Disease control induced a 7% decrease in lean body mass (P < .000) and a 14% decrease in LBM-adjusted energy expenditure. Whole-body phenylalanine breakdown decreased after disease control (P = .005) accompanied by a decrease in the degradation of phenylalanine to tyrosine (P = .005) and a decrease in whole-body phenylalanine synthesis (P = .030). Skeletal muscle protein synthesis tended to decrease after disease control (P = .122), whereas the muscle protein breakdown (P = .437) and muscle protein loss were unaltered (P = .371). Unc-51 like autophagy activating kinase 1 phosphorylation, an activator of protein breakdown, increased after disease control (P = .042). CONCLUSIONS: Active acromegaly represents a reversible high flux state in which both whole-body protein breakdown and synthesis are increased, whereas forearm muscle protein kinetics are unaltered. Future studies are needed to decipher the link between protein kinetics and the structure and function of the associated growth hormone-induced increase in lean body mass.

Gene expression profiling of subcutaneous adipose tissue reveals new biomarkers in acromegaly.

CONTEXT: Active acromegaly is characterized by lipolysis-induced insulin resistance, which suggests adipose tissue (AT) as a primary driver of metabolic aberrations. OBJECTIVE: To study the gene expression landscape in AT in patients with acromegaly before and after disease control in order to understand the changes and to identify disease-specific biomarkers. METHODS: RNA sequencing was performed on paired subcutaneous adipose tissue (SAT) biopsies from six patients with acromegaly at time of diagnosis and after curative surgery. Clustering and pathway analyses were performed in order to identify disease activity-dependent genes. In a larger patient cohort (n = 23), the corresponding proteins were measured in serum by immunoassay. Correlations between growth hormone (GH), insulin-like growth factor I (IGF-I), visceral AT (VAT), SAT, total AT, and serum proteins were analyzed. RESULTS: 743 genes were significantly differentially expressed (P-adjusted < .05) in SAT before and after disease control. The patients clustered according to disease activity. Pathways related to inflammation, cell adhesion and extracellular matrix, GH and insulin signaling, and fatty acid oxidation were differentially expressed.Serum levels of HTRA1, METRNL, S100A8/A9, and PDGFD significantly increased after disease control (P < .05). VAT correlated with HTRA1 (R = 0.73) and S100A8/A9 (R = 0.55) (P < .05 for both). CONCLUSION: AT in active acromegaly is associated with a gene expression profile of fibrosis and inflammation, which may corroborate the hyper-metabolic state and provide a means for identifying novel biomarkers.

Bone parameters in T1D and T2D assessed by DXA and HR-pQCT - A cross-sectional study: The DIAFALL study.

INTRODUCTION/AIM: People with type 1 diabetes (T1D) and type 2 diabetes (T2D) have an increased risk of fractures due to skeletal fragility. We aimed to compare areal bone mineral density (aBMD), volumetric BMD (vBMD), cortical and trabecular measures, and bone strength parameters in participants with diabetes vs. controls. METHODS: In a cross-sectional study, we included adult participants with T1D (n = 111, MA = 52.9 years), T2D (n = 106, MA = 62.1 years) and controls (n = 328, MA = 57.7 years). The study comprised of DXA scans and HR-pQCT scans, biochemistry, handgrip strength (HGS), Timed Up and GO (TUG), vibration perception threshold (VPT), questionnaires, medical histories, alcohol use, and previous fractures. Group comparisons were performed after adjustment for sex, age, BMI, diabetes duration, HbA1c, alcohol, smoking, previous fractures, postmenopausal, HGS, TUG, and VPT. RESULTS: We found decreased aBMD in participants with T1D at the femoral neck (p = 0.028), whereas T2D had significantly higher aBMD at peripheral sites (legs, arms, p < 0.01) vs. controls. In T1D we found higher vBMD (p < 0.001), cortical vBMD (p < 0.001), cortical area (p = 0.002) and thickness (p < 0.001), lower cortical porosity(p = 0.008), higher stiffness (p = 0.002) and failure load (p = 0.003) at radius and higher vBMD (p = 0.003), cortical vBMD(p < 0.001), bone stiffness (p = 0.023) and failure load(p = 0.044) at the tibia than controls. In T2D we found higher vBMD (p < 0.001), cortical vBMD (p < 0.001), trabecular vBMD (p < 0.001), cortical area (p < 0.001) and thickness (p < 0.001), trabecular number (p = 0.024), lower separation (p = 0.010), higher stiffness (p < 0.001) and failure load (p < 0.001) at the radius and higher total vBMD (p < 0.001), cortical vBMD (p < 0.011), trabecular vBMD (p = 0.001), cortical area (p = 0.002) and thickness (p = 0.021), lower trabecular separation (p = 0.039), higher stiffness (p < 0.001) and failure load (p = 0.034) at tibia compared with controls. CONCLUSION: aBMD measures were as expected lower in T1D and higher in T2D than controls. Favorable bone microarchitecture and strength parameters were seen at the tibia and radius for T1D and T2D.

Ectopic lipid deposition and insulin resistance in patients with GH disorders before and after treatment.

OBJECTIVES: Insulin resistance is associated with ectopic lipid deposition. Growth hormone (GH) status also modulates ectopic lipid accumulation, but how this associates with insulin resistance in patients with GH disorders is not well established. DESIGN AND METHODS: Twenty-one patients diagnosed with acromegaly and 12 patients with adult GH deficiency (GHD) were studied at diagnosis and after treatment. A reference group of 12 subjects was included. Each study day comprised assessment of body composition with dual-energy X-ray absorptiometry, ectopic lipid deposition in the liver by MR spectroscopy, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). RESULTS: Disease control of acromegaly decreased lean body mass (LBM) (P < .000) and increased the percentage of total body fat (TBF) (P < .000). GH replacement increased LBM in the GHD patients (P = .007) and decreased the percentage of TBF (P = .010). The intrahepatic lipid (IHL) content increased after disease control in acromegaly (P = .004), whereas IHL did not change significantly after GH replacement in GHD (P = .34). Insulin resistance (HOMA-IR) improved after disease control of acromegaly (P < .000) and remained unaltered after GH replacement in the GHD patients (P = .829). CONCLUSIONS: GH status is a significant modulator of body composition and insulin sensitivity.GH excess reduces total fat mass and intrahepatic lipid content together with induction of insulin resistance.The data support the notion that GH-induced insulin resistance is unassociated with hepatic lipid accumulation.

Sex difference in patients with controlled acromegaly-A multicentre survey.

OBJECTIVE: Active acromegaly is subject to sex differences in growth hormone (GH) and Insulin like growth factor 1 (IGF-I) patterns as well as clinical features but whether this also pertains to controlled disease is unclear. DESIGN: In a cross-sectional, multi-centre study, 84 patients with acromegaly (F = 43, M = 41), who were considered controlled after surgery alone (n = 23) or during continued somatostatin receptor ligand (SRL) treatment (n = 61), were examined. METHODS: Serum concentrations of GH, insulin, glucose and free fatty acid (FFA) were measured during an oral glucose tolerance test (OGTT) together with baseline serum IGF-I and completion of two HR-Qol questionnaires (acromegaly quality of life questionnaire [AcroQol] and Patient-assessed Acromegaly Symptom Questionnaire [PASQ]). RESULTS: The mean age at the time of the study was 57 (±1.1) years and the majority of females (were postmenopausal. Females had significantly higher fasting GH but comparable IGF-I standard deviation scores (SDS). Using fasting GH < 1.0 µg/L as cut off, disease control was less prevalent in females (F: 56% vs. M: 83%, p = .007) whereas a comparable figure was observed using IGF-I SDS < 2 (F:79% vs. M:76%, p = .71). Compared with males, female patients showed impaired AcroQol physical score (p = .05), higher fasting FFA (p = .03) and insulin concentrations during the OGTT (p = .04). CONCLUSION: In patients with acromegaly considered controlled, postmenopausal females exhibited higher GH levels than males despite comparable IGF-I levels, which also translated into impaired metabolic health and well-being. Our findings point to the relevance of including GH measurements in the assessment of disease control and suggest that disease-specific sex differences prevail after treatment.

Impaired postural control in diabetes-a predictor of falls?

New evidence points toward that impaired postural control judged by center of pressure measures during quiet stance is a predictor of falls in people with type 1 and type 2 diabetes-even in occurrence of well-known risk factors for falls. INTRODUCTION/AIM: People with type 1 diabetes (T1D) and type 2 diabetes (T2D) are at risk of falling, but the association with impaired postural control is unclear. Therefore, the aim was to investigate postural control by measuring the center of pressure (CoP) during quiet standing and to estimate the prevalence ratio (PR) of falls and the fear of falling among people with diabetes compared to controls. METHODS: In a cross-sectional study, participants with T1D (n = 111) and T2D (n = 106) and controls without diabetes (n = 328) were included. Study procedures consisted of handgrip strength (HGS), vibration perception threshold (VPT), orthostatism, visual acuity, and postural control during quiet stance measured by CoPArea (degree of body sway) and CoPVelocity (speed of the body sway) with "eyes open," "eyes closed" in combination with executive function tasks. A history of previous falls and fear of falling was collected by a questionnaire. CoPArea and CoPVelocity measurements were analyzed by using a multiple linear regression model. The PR of falls and the fear of falling were estimated by a Poisson regression model. Age, sex, BMI, previous falls, alcohol use, drug, HGS, VPT, orthostatism, episodes of hypoglycemia, and visual acuity were covariates in multiple adjusted analyses. RESULTS: Significantly larger mean CoPArea measures were observed for participants with T1D (p = 0.022) and T2D (0.002), whereas mean CoPVelocity measures were only increased in participants with T2D (p = 0.027) vs. controls. Additionally, T1D and T2D participants had higher PRs for falls (p = 0.044, p = 0.014) and fear of falling (p = 0.006, p < 0.001) in the crude analyses, but the PRs reduced significantly when adjusted for mean CoPArea and mean CoPVelocity, respectively. Furthermore, multiple adjusted PRs were significantly higher than crude the analyses.    CONCLUSION: Impaired postural control during quiet stance was seen in T1D and T2D compared with controls even in the occurrence of well-known risk factors. and correlated well with a higher prevalence of falls.

The prevalence of acromegaly is higher than previously reported: Changes over a three-decade period.

OBJECTIVE: To study time-related changes in the prevalence and patient characteristics of acromegaly, as well as to assess the impact of changes in treatment on disease control. METHODS: A total of 107 patients with acromegaly were identified by healthcare registries and subsequently validated by patient chart review over a three-decade period (1992-2021). A systematic literature review focusing on the incidence and prevalence of acromegaly was performed identifying 31 studies. RESULTS: The prevalence of acromegaly significantly increased throughout the study period (R2 = 0.94, p < .001) and was 122 cases/106 persons in 2021 whereas the annual incidence remained constant at 4.6 cases/106 persons. The age at the first sign of acromegaly and the age at diagnosis significantly increased during the study period, whereas growth hormone and insulin-like growth factor I decreased. Incidentalomas constituted 32% of all cases diagnosed with acromegaly in the last decade. Primary surgery was used in 93% of all cases, and repeated surgery decreased from 24% to 10% during the three decades. The use of first-generation somatostatin analogues (21%-48%) and second-line medical treatment (4%-20%) increased with a concomitant improvement of biochemical disease control (58%-91%). CONCLUSION: The prevalence of acromegaly is higher than previously reported and the clinical presentation has shifted towards a milder phenotype. Modern treatment of acromegaly enables individualized treatment and disease control in the majority of patients.

Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly.

BACKGROUND: Patients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly. METHODS: In a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle. FINDINGS: Disease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat. INTERPRETATION: In conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat. FUNDING: This work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark.

Sodium Glucose Cotransporter-2 Inhibitor Treatment and the Risk of Diabetic Ketoacidosis in Denmark: A Retrospective Cohort Study of Five Years of Use.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been associated with increased risk of diabetic ketoacidosis (DKA) in both people with type 1 and type 2 diabetes mellitus. Few studies using data from high-quality registries exist that attempt to determine the real- world impact of the increasing use of this drug. OBJECTIVE: The aim of this study was to investigate the incidence and risk of DKA in connection with SGLT2i treatment in Denmark between 2013-2017. METHODS: A nationwide retrospective cohort of people with type 2 diabetes mellitus using SGLT2i or glucagon-like peptide-1 receptor agonists (GLP1-RA) was established and analysed using both Cox-proportional hazard regression and Kaplan-Meier survival analysis. RESULTS: The 37,058 individuals included in the cohort, were made up of SGLT2i (10,923), GLP1- RA (18,849), SGLT2i+insulin (2,069), and GLP1-RA+insulin (10,178) users. The incidence rate (IR) of DKA was 0.84 (95% CI 0.49-1.44) and 0.53 (95% CI 0.36-0.77) for the SGLT2i and GLP1-RA groups, respectively. There was no statistically significant increase in the risk for DKA with SGLT2i use (HR 1.02, 95% CI, 0.44-2.36). However, for the SGLT2i+insulin and GLP1- RA+insulin groups, IRs were 3.47 (95% CI 1.92-6.27) and 0.97 (95% CI 0.68-1.37) respectively, and the risk was statistically significantly higher (HR 5.42, 95% CI 2.16-13.56). CONCLUSION: We observed no significant increase in the risk of DKA for SGLT2i users compared to GLP1-RA. However, a significantly higher IR of DKA was observed with concomitant insulin use, and the risk of DKA was considerably higher for the SGLT2 group using insulin.

Sex differences in acromegaly at diagnosis: A nationwide cohort study and meta-analysis of the literature.

OBJECTIVE: Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies. DESIGN: A nationwide cohort study including all incident cases of acromegaly (1978-2010, n = 596) and a meta-analysis on sex differences in active acromegaly (40 studies) were performed. METHOD: Sex-dependent differences in prevalence, age at diagnosis, diagnostic delay, pituitary adenoma size, insulin-like growth factor 1 (IGF-I) and growth hormone (GH) concentrations were estimated. RESULTS: The cohort study identified a balanced gender distribution (49.6% females) and a comparable age (years) at diagnosis (48.2 CI95% 46.5-49.8 (males) vs. 47.2 CI95% 45.5-48.9 (females), p = 0.4). The incidence rate significantly increased during the study period (R2  = 0.42, p < 0.01) and the gender ratio (F/M) changed from female predominance to an even ratio (SR: 1.4 vs. 0.9, p = 0.03). IGF-ISDS was significantly lower in females compared to males, whereas neither nadir GH nor pituitary adenoma size differed between males and females. In the meta-analysis, the weighted percentage female was 53.3% (CI95% 51.5-55.2) with considerable heterogeneity (I2  = 85%) among the studies. The mean age difference at diagnosis between genders was 3.1 years (CI95% 1.9-4.4), and the diagnostic delay was longer in females by 0.9 years (CI95% -0.4 to 2.1). Serum IGF-I levels were significantly lower in female patients, whereas nadir GH, and pituitary adenoma size were comparable. CONCLUSION: There are only a minor sex differences in the epidemiology of acromegaly at the time of diagnosis except that female patients are slightly older and exhibit lower IGF-I concentrations and a longer diagnostic delay.

Increased Risk of Falls, Fall-related Injuries and Fractures in People with Type 1 and Type 2 Diabetes - A Nationwide Cohort Study.

INTRODUCTION: People with diabetes could have an increased risk of falls as they show more complications, morbidity and use of medication compared to the general population. This study aimed to estimate the risk of falls and to identify risk factors associated with falls in people with diabetes. The second aim was to estimate fall-related injuries, such as lesions and fractures, including their anatomic localization in people with diabetes compared with the general population. METHODS: From the Danish National Patient Register, we identified people with Type 1 Diabetes (T1D) (n=12,975) Type 2 Diabetes (T2D) (n=407,009). The cohort was divided into two groups, with respective control groups matched on age and sex (1:1). All episodes of people hospitalized with a first fall from 1996 to 2017 were analyzed using a Cox proportional-hazards model. Risk factors such as age, sex, diabetic complications, a history of alcohol abuse and the use of medication were included in an adjusted analysis. The incidence rate, incidence rate difference and incidence rate ratio (IRR) of falls and the anatomic localization of fall-related injuries as lesions and fractures were identified. RESULTS AND DISCUSSION: The cumulative incidence, of falls requiring hospital treatment, was 13.3% in T1D, 11.9% in T2D. In the adjusted analysis, T1D and T2D were associated with a higher risk of falls [T1D, Hazard Ratio (HR): 1.33 (95% CI: 1.25 - 1.43), T2D, HR: 1.19 (95% CI:1.16 - 1.22), respectively]. Women [group 1, HR 1.21 (CI:95%:1.13 - 1.29), group 2, HR 1.61 (CI:95%:1.58-1.64)], aged >65 years [groups 1, HR 1.52 (CI:95%:1.39 - 1.61), group 2, HR 1.32 (CI:95%:1.58-1.64)], use of selective serotonin receptor inhibitors (SSRI) [group 1, HR 1.35 (CI:95%:1.1.30 - 1.40), group 2, HR 1.32 (CI:95%:1.27-1.38)], opioids [group 1, HR 1.15 (CI:95%:1.12 - 1.19), group 2, HR 1.09 (CI:95%:1.05-1.12)] and a history of alcohol abuse [group 1, HR 1.77 (CI:95%:1.17 - 2.15), group 2, HR 1.88 (CI:95%:1.65-2.15)] were significantly associated with an increased risk of falls in both groups. The IRR of fall-related injuries as hip, radius, humerus and skull/facial fractures were higher in people with T2D than controls [IRR 1.02 (CI:95%:1.01-1.04), IRR 1.39 (CI:95%: 1.18-1.61), IRR 1.24 (CI:95%: 1.12-1.37) and IRR 1.15 (CI:95%:1.07-1.24)]. People with T1D had a higher IRR of hip fractures than controls [IRR: 1.11 (CI:95%:1.02 - 1.23)]. CONCLUSION: People with diabetes have an increased risk of first fall and a higher incidence of fall- related injuries, including fractures. Advanced aging and sex are non-modifiable risk factors, whereas diabetes, the use of SSRIs and opioids and alcohol abuse could be potentially modifiable risk factors for falls. Gaining information on risk factors for falls could guide the management of diabetes treatment, i.e., choice of drugs, which enables us to improve treatment, particularly in people with a high risk of falls and fractures associated with high mortality.

Disease Control and Gender Predict the Socioeconomic Effects of Acromegaly: A Nationwide Cohort Study.

CONTEXT: Acromegaly is an insidious disease associated with severe somatic morbidity but data on socioeconomic status are scarce. OBJECTIVE: To study the socioeconomic status in acromegaly in a population-based follow-up study. METHODS: All incident cases of acromegaly (n = 576) during the period 1977-2010 were included. For every patient, 100 persons were sampled from the general population matched for date of birth and gender (comparison cohort). Cox regression and hazard ratios (HR), conditional logistic regression and linear regression with 95% confidence intervals (CI) were used. OUTCOME MEASURES: Retirement, social security benefit, annual income, cohabitation, separation, parenthood and educational level. RESULTS: The proportion of retired individuals was significantly higher in patients with acromegaly after the time of diagnosis (HR, 1.43; 95% CI, 1.26-1.62) and also during the 5-year pre-diagnostic period (HR, 1.15; 95% CI, 1.03-1.28). More individuals with acromegaly received social security benefit compared with the comparison cohort during the initial period after the time of diagnosis. Among patients who maintained a job, the annual income was similar to the comparison cohort. Compared with the background population, cohabitation was lower (HR, 0.69; 95% CI, 0.50-0.95) as was parenthood (HR, 0.56; 95% CI, 0.39-0.80), whereas neither educational level (HR, 0.61; 95% CI, 0.35-1.06) nor separation (HR, 1.13; 95% CI, 0.86-1.47) were different. Female gender and insufficient disease control were associated with a significantly worse socioeconomic status. CONCLUSIONS: 1) Socioeconomic status is impaired in patients with acromegaly even before a diagnosis of acromegaly. 2) Females and patients without disease remission have worse outcomes. 3) Early diagnosis and effective treatment of acromegaly could be important factors in mitigating the negative impact on socioeconomic factors.

Phenotypic and genotypic features of a large kindred with a germline AIP variant.

CONTEXT: Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with familial pituitary adenoma predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved. OBJECTIVE: To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant. METHODS: The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants. RESULTS: We identified 31 p.R304Q carriers, and based on two cases with somatotropinomas, the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum insulin-like growth factor-I (IGF-I) levels in all family members were above the mean for age and sex (IGF-I SDS: +0.6 [CI95% +0.4-0.9], P < .01). Exome analysis identified two candidate genes: PDE11A, known to be associated with the development of adrenal tumours, and ALG14. Ten asymptomatic p.R304Q family members (age >50 years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons. CONCLUSIONS: This large family adds new information on the p.R304Q AIP variant, and data suggest two new candidate genes could be associated with growth hormone excess.

Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM: To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS: Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, ß-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Total FGF21, active FGF21 and ß-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION: 1) Circulating FGF21 and ß-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION: NCT00647179.

Determinants of the growth hormone nadir during oral glucose tolerance test in adults.

OBJECTIVE: Growth hormone (GH) nadir (GHnadir) during oral glucose tolerance test (OGTT) is an important tool in diagnosing acromegaly, but data evaluating the need to adjust cut-offs to biological variables utilizing today's assay methods are scarce. We therefore investigated large cohorts of healthy subjects of both sexes to define normal GHnadir concentrations for a modern, sensitive, 22 kD-GH-specific assay. DESIGN: Multicenter study with prospective and retrospective cohorts (525 healthy adults: 405 females and 120 males). METHODS: GH concentrations were measured by the IDS-iSYS immunoassay after oral application of 75 g glucose. RESULTS: GHnadir concentrations (µg/L) were significantly higher in lean and normal weight subjects (group A) compared to overweight and obese subjects (group B); (males (M): A vs B, mean: 0.124 vs 0.065, P = 0.0317; premenopausal females without estradiol-containing OC (OC-EE) (FPRE): A vs B, mean: 0.179 vs 0.092, P < 0.0001; postmenopausal women (FPOST): A vs B, mean: 0.173 vs 0.078, P < 0.0061). Age, glucose metabolism and menstrual cycle had no impact on GHnadir. However, premenopausal females on OC-EE (FPREOC) exhibited significantly higher GHnadir compared to all other groups (all P < 0.0001). BMI had no impact on GHnadir in FPREOC (A vs B, mean: 0.624 vs 0.274, P = 0.1228). CONCLUSIONS: BMI, sex and OC-EE intake are the major determinants for the GHnadir during OGTT in healthy adults. Using a modern sensitive GH assay, GHnadir concentrations in healthy subjects are distinctly lower than cut-offs used in previous guidelines for diagnosis and monitoring of acromegaly.

Falls and Fractures in Diabetes-More than Bone Fragility.

PURPOSE OF REVIEW: Based on a systematic literature search, we performed a comprehensive review of risk factors for falls and fractures in patients with diabetes. RECENT FINDINGS: Patients with diabetes have an increased risk of fractures partly explained by increased bone fragility. Several risk factors as altered body composition including sarcopenia and obesity, impaired postural control, gait deficits, neuropathy, cardiovascular disease, and other co-morbidities are considered to increase the risk of falling. Diabetes and bone fragility is well studied, but new thresholds for fracture assessment should be considered. In general, the risk factors for falls in patients with diabetes are well documented in several studies. However, the fall mechanisms among diabetic patients have only been assessed in few studies. Thus, a gab of knowledge exits and may influence the current understanding and treatment, in order to reduce the risk of falling and thereby prevent fractures.