Objective: Arthropathy is an invalidating complication of acromegaly. Although acromegalic arthropathy shares features with primary osteoarthritis, joint spaces are widened rather than narrowed in... Show moreObjective: Arthropathy is an invalidating complication of acromegaly. Although acromegalic arthropathy shares features with primary osteoarthritis, joint spaces are widened rather than narrowed in patients with long term cure of acromegaly. The late effects of acromegaly on hand joints have not been characterized. Therefore the objective of the current study was to assess joint space widths of hand joints in patients with long-term control of acromegaly and to identify factors associated with joint space width.Design: Cross-sectional studyMethods: Cross-sectional study in 89 patients(age 58±12yr, 49% women) with long-term controlled acromegaly and 471 controls without hand symptoms(age 46±12yr, 42% women). Radiological joint space widths of individual hand joints were measured by automated image analysis.Results: Patients had wider mean joint spaces than controls: MCP-joints were ~24%, PIP-joints ~21%, and DIP-joints ~20% wider (patients vs controls; p<0.001 for all joints). Mean joint space width exceeded the 95th percentile of the values obtained in controls in 64% of patients. Higher IGF-1 and GH concentrations at diagnosis were associated with larger joint space widths (adjusted ß for pretreatment GH in tertiles:0.09(95%CI 0.03-1.84) and for IGF-1 in tertiles 0.14(95%CI 0.05-0.23) at the MCP-joints in acromegalic patients. In male, but not in female, patients increased joint space widths were associated with more self-reported pain(p=0.02).Conclusions: Using a new semi-automated image analysis of hand radiographs, acromegalic patients with long-term disease control appeared to have increased joint spaces of all hand joints. Joint space widths were positively related to disease activity at diagnosis, but not to duration of follow-up, suggesting irreversible cartilage hypertrophy. Irreversible cartilage hypertrophy may partly explain persisting hand complaints, despite long-term disease control. Show less
Objective: To establish the prevalence of osteoporosis, vertebral fractures (VFs), and non-VFs in acromegaly patients with long-term controlled disease and factors potentially influencing fracture... Show moreObjective: To establish the prevalence of osteoporosis, vertebral fractures (VFs), and non-VFs in acromegaly patients with long-term controlled disease and factors potentially influencing fracture risk. Design: Case-control study. Patients and measurements: Eighty-nine patients (46% male, mean age: 58 years) were included. We studied VFs and non-VFs, bone mineral density (BMD), and markers of bone turnover. In 48 patients, BMD assessment was also obtained 7 years prior to the current study. To compare VF prevalence, data from a sample of the Dutch population (n=3469) were used. Results: VF prevalence was 59% (men 64% and women 54%), significantly increased when compared with controls (odds ratio up to 6.5), and independent of the duration of disease control, BMD, markers of bone turnover, and acromegalic disease characteristics. Mean number of VFs per patient was 3.4 +/- 0.3 (range 1-8). There was no relationship between the number and severity of fractures, parameters of bone turnover, and follow-up BMD measurements. BMD did not change during prolongation of follow-up by 7 years of controlled acromegaly. Conclusion: There is a very high prevalence of VFs in acromegaly patients with long-term controlled disease, independently of BMD. In view of the significant morbidity and mortality associated with VFs in general and the inability of BMD to predict fracture risk in acromegalic patients, we propose to include VF assessment, for example by lateral conventional radiographs of the spine in the screening of patients with acromegaly, both at diagnosis and during follow-up after establishment of disease control. Show less
Objective To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the... Show moreObjective To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the pathophysiological process of growth hormone (GH) and insulin-like growth factor type I (IGF-I)-mediated osteoarthritis. Methods We utilised radiographs of the knee and hip joints of 84 patients with controlled acromegaly for a mean of 14.0 years with 189 patients with primary generalised osteoarthritis. Hips and knees with with doubtful or definite osteoarthritis (Kellgren-Lawrence score of >= 1) were compared in the current study. For a semiquantitative assessment of radiological osteoarthritis (range 0-3) osteophytes and JSN of the medial and lateral tibiofemoral and hip joints were scored according to the Osteoarthritis Research Society International atlas. Logistic regression analysis was performed with adjustment for age, sex, body mass index and intrapatient effect. Results Knee and hip osteoarthritis in patients with cured acromegaly was characterised by more osteophytosis (OR 4.1-9.9), but less JSN (OR 0.3-0.5) in comparison with patients with primary osteoarthritis. Patients with acromegaly and osteoarthritis had significantly less self-reported functional disability than patients with primary osteoarthritis (p < 0.001). Self reported functional disability was associated with JSN rather than with osteophytosis. Conclusion Arthropathy caused by GH oversecretion results in osteophytosis and to a lesser extent in JSN. This observation suggests that the GH-IGF-I system is mainly involved in bone formation resulting in osteophytosis, but may possibly protect against cartilage loss. Show less
OBJECTIVE To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the... Show moreOBJECTIVE To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the pathophysiological process of growth hormone (GH) and insulin-like growth factor type I (IGF-I)-mediated osteoarthritis. METHODS We utilised radiographs of the knee and hip joints of 84 patients with controlled acromegaly for a mean of 14.0 years with 189 patients with primary generalised osteoarthritis. Hips and knees with with doubtful or definite osteoarthritis (Kellgren-Lawrence score of ≥ 1) were compared in the current study. For a semiquantitative assessment of radiological osteoarthritis (range 0-3) osteophytes and JSN of the medial and lateral tibiofemoral and hip joints were scored according to the Osteoarthritis Research Society International atlas. Logistic regression analysis was performed with adjustment for age, sex, body mass index and intrapatient effect. RESULTS Knee and hip osteoarthritis in patients with cured acromegaly was characterised by more osteophytosis (OR 4.1-9.9), but less JSN (OR 0.3-0.5) in comparison with patients with primary osteoarthritis. Patients with acromegaly and osteoarthritis had significantly less self-reported functional disability than patients with primary osteoarthritis (p < 0.001). Self reported functional disability was associated with JSN rather than with osteophytosis. CONCLUSION Arthropathy caused by GH oversecretion results in osteophytosis and to a lesser extent in JSN. This observation suggests that the GH-IGF-I system is mainly involved in bone formation resulting in osteophytosis, but may possibly protect against cartilage loss. Show less
Objective: To establish the prevalence of osteoporosis, vertebral, and non-vertebral fractures in acromegaly patients with long-term controlled disease and factors potentially influencing fracture... Show moreObjective: To establish the prevalence of osteoporosis, vertebral, and non-vertebral fractures in acromegaly patients with long-term controlled disease and factors potentially influencing fracture risk. Design: Case-control study Patients and measurements: Eighty-nine patients (46% male, mean age: 58 years) were included. We studied vertebral and non-vertebral fractures, bone mineral density (BMD), and markers of bone turnover. In 48 patients BMD assessment was also obtained 7 years prior to the current study. To compare vertebral fracture prevalence, data from a sample of the Dutch population (n=3469) was used. Results: Vertebral fracture prevalence was 59% (men 64%, women 54%), significantly increased when compared with controls (odds ratio up to 6.5), and independent of the duration of disease control, BMD, markers of bone turnover, and acromegalic disease characteristics. Mean number of vertebral fractures per patient was 3.4 ± 0.3 (range 1-8). There was no relationship between the number and severity of fractures, parameters of bone-turnover, and follow-up BMD measurements. BMD did not change during prolongation of follow-up by 7 years of controlled acromegaly. Conclusion: There is a very high prevalence of vertebral fractures in acromegaly patients with long-term controlled disease, independently of BMD. In view of the significant morbidity and mortality associated with vertebral fractures in general and the inability of BMD to predict fracture risk in acromegalic patients, we propose to include vertebral fracture assessment, for example by lateral conventional radiographs of the spine in the screening of patients with acromegaly, both at diagnosis and during follow-up after establishment of disease control. Show less
Tiemensma, J.; Biermasz, N.R.; Mast, R.C. van der; Wassenaar, M.J.E.; Middelkoop, H.A.M.; Pereira, A.M.; Romijn, J.A. 2010
Objective: Active acromegaly is associated with psychopathology, personality changes, and cognitive dysfunction. It is unknown whether, and to what extent, these effects are present after long-term... Show moreObjective: Active acromegaly is associated with psychopathology, personality changes, and cognitive dysfunction. It is unknown whether, and to what extent, these effects are present after long-term cure of acromegaly. Aim: The aim of the study was to assess psychopathology, personality traits, and cognitive function in patients after long-term cure of acromegaly. Design: This was a cross-sectional study. Patients and Methods: We studied 68 patients after long-term cure (13 +/- 1 yr) of acromegaly and 68 matched controls. We compared these data with 60 patients treated for nonfunctioning pituitary macroadenomas (NFMAs) and 60 matched controls. Psychopathology was assessed using the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form, and personality was assessed by the Dimensional Assessment of Personality Pathology short-form (DAPPs). Cognitive function was assessed by 11 tests. Results: Compared with matched controls, patients cured from acromegaly scored significantly worse on virtually all psychopathology questionnaires and on several subscales of the DAPPs. Compared with NFMA patients, patients cured from acromegaly scored worse on negative affect (P = 0.050) and somatic arousal (P = 0.009) and seven of 18 subscales of the DAPPs (P < 0.05). Cognitive function in patients cured from acromegaly did not differ from matched controls or patients treated for NFMA. Conclusion: Patients with long-term cure of acromegaly show a higher prevalence of psychopathology and maladaptive personality traits but not cognitive dysfunction, compared with matched controls and patients treated for NFMA. These results suggest irreversible effects of previous GH excess, rather than effects of pituitary adenomas per se and/or their treatment, on the central nervous system. (J Clin Endocrinol Metab 95: E392-E402, 2010) Show less
Bijsterbosch, J.; Wassenaar, M.J.E.; Cessie, S. le; Slagboom, P.E.; Rosendaal, F.R.; Huizinga, T.W.J.; Kloppenburg, M. 2010
Objective: To determine reliability, feasibility, and validity of the Doyle Index (DI), a pain score proposed for osteoarthritis (OA). Methods: The DI was performed in 260 patients with OA at... Show moreObjective: To determine reliability, feasibility, and validity of the Doyle Index (DI), a pain score proposed for osteoarthritis (OA). Methods: The DI was performed in 260 patients with OA at multiple sites (mean age 64.9 years, 84% women) by grading pain (0-3) in 48 joints and joint groups by pressure or passive movement. Reliability and feasibility were determined in a random sample of 18 patients, by examining them twice using four raters. Intraclass correlation coefficients (ICCs) for intra- and interrater reliability were calculated, as well as the mean time to perform the DI. Validity was assessed in 260 patients, by correlating DI total scores and DI scores for the hand and knee/hip joints separately, to the pain and function subscales of the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), using Spearman's rank coefficient (r). Results: In the total population the median (interquartile range) DI score was 11.0 (5.0-19.0). Intraobserver ICCs [95% confidence interval (CI)] ranged from 0.94 (0.84, 0.98) to 0.97 (0.93, 0.99). Interobserver ICC was 0.88 (0.77, 0.94). The mean time to perform the total DI was 5.1 min (range 2.4-7.8). DI total scores as well as scores for the hand and knee/hip joints separately were related to AUSCAN (r range 0.61-0.65) and WOMAC (r range 0.43-0.51), although the level of correlation was moderate. Conclusion: The DI is a reliable, easy to perform, and valid measure for OA pain during physical examination and therefore a promising additional outcome measure not only for OA research but also for clinical practice. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Context and Objective: Active Cushing's disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushing's disease results in irreversible... Show moreContext and Objective: Active Cushing's disease is associated with cognitive impairments. We hypothesized that previous hypercortisolism in patients with Cushing's disease results in irreversible impairments in cognitive functioning. Therefore, our aim was to assess cognitive functioning after long-term cure of Cushing's disease. Design: Cognitive assessment consisted of 11 tests, which evaluated global cognitive functioning, memory, and executive functioning. Patients and Control Subjects: We included 74 patients cured of Cushing's disease and 74 controls matched for age, gender, and education. Furthermore, we included 54 patients previously treated for nonfunctioning pituitary macroadenomas (NFMA) and 54 controls matched for age, gender, and education. Results: Compared with NFMA patients, patients cured from Cushing's disease had lower scores on the Mini Mental State Examination (P = 0.001), and on the memory quotient of the Wechsler Memory Scale (P = 0.050). Furthermore, patients cured from Cushing's disease tended to recall fewer words on the imprinting (P = 0.013), immediate recall (P = 0.012), and delayed recall (P = 0.003) trials of the Verbal Learning Test of Rey. On the Rey Complex Figure Test, patients cured from Cushing's disease had lower scores on both trials (P = 0.002 and P = 0.007) compared with NFMA patients. Patients cured from Cushing's disease also made fewer correct substitutions on the Letter-Digit Substitution Test (P = 0.039) and came up with fewer correct patterns on the Figure Fluency Test (P = 0.003) compared with treated NFMA patients. Conclusions: Cognitive function, reflecting memory and executive functions, is impaired in patients despite long-term cure of Cushing's disease. These observations indicate irreversible effects of previous hypercortisolism on cognitive function and, thus, on the central nervous system. These observations may also be of relevance for patients treated with high-dose exogenous glucocorticoids. (J Clin Endocrinol Metab 95: 2699-2714, 2010) Show less
Wassenaar, M.J.E.; Biermasz, N.R.; Kloppenburg, M.; Klaauw, A.A. van der; Tiemensma, J.; Smit, J.W.A.; ... ; Romijn, J.R. 2010
Objective: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess... Show moreObjective: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess the impact of joint-specific complaints, clinical and radiological signs of arthropathy on different aspects of quality of life (QoL) in patients with acromegaly after long-term disease control. Design: Cross-sectional study. Methods: We studied 58 patients (31 males), mean age 60 years (range 32-81 years), with strict biochemical control of acromegaly for a mean duration of 15 years. QoL was assessed by four health-related QoL questionnaires (HADS, MFI-20, NHP, SF-36) and one disease specific QoL questionnaire (AcroQoL). The outcomes of these questionnaires were compared with joint-specific self-reported complaints of pain/stiffness, clinical osteoarthritis based on American College of Rheumatology (ACR) and radiological osteoarthritis based on the Kellgren-Lawrence (KL) scoring method. Results: Long-term cured acromegaly patients had high pain scores of the spine, knee, and hip which limited physical functioning (mean difference -27.0, 95%-CI -9.5, -41.0) and psychological well-being (mean difference -44.4, 95%-CI -26.1, -60.9) (SF-36). Clinical osteoarthritis of the spine was associated mostly with impaired QoL scores, on physical, social, and emotional functioning, and on anxiety and depression. Remarkably, radiological osteoarthritis was not associated with impaired QoL. Conclusion: These findings accentuate the importance of recognition of the clinical manifestations of arthropathy in patients with acromegaly despite long-term disease control. (C) 2010 Elsevier Ltd. All rights reserved. Show less
This thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the... Show moreThis thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the considerable prevalence of diverse morbidity in these patients, during the active phase of the disease but even more so after 17 years of disease cure, we suggest the screening of acromegalic patients on highly frequent comorbidities, such as osteoarthritis, vertebral fractures, colonic polyps, and colonic diverticulae. It is of great concern to recognize the long-term consequences of the disease in order to offer the patients adequate follow-up and multidisciplinary care. The aim should be to control the persisting complex morbidity as much as possible in order to prevent the patients from a further decrease in quality of life. The patients__ physician as well as the patient itself should be aware of the long-term consequences of acromegaly in order to eliminate surreal expectations concerning recovery of certain comorbidities. Show less
Wassenaar, M.J.E.; Cazemier, M.; Biermasz, N.R.; Pereira, A.M.; Roelfsema, F.; Smit, J.W.A.; ... ; Romijn, J.A. 2010
Objective: In acromegaly, overproduction of GH and IGF-I causes abnormal extracellular matrix regulation. We hypothesized that this may predispose to the development of colonic diverticula. Because... Show moreObjective: In acromegaly, overproduction of GH and IGF-I causes abnormal extracellular matrix regulation. We hypothesized that this may predispose to the development of colonic diverticula. Because the relation between acromegaly and colonic diverticula is unknown, the study aim was to assess the prevalence of colonic diverticula in patients with cured acromegaly. Design: This was a case-control study. Methods: We screened reports of colonoscopies performed for the purpose of screening for polyps in 107 patients with cured or biochemically controlled acromegaly and in 214 age- and sex-matched controls for the presence of diverticula, dolichocolon, and polyps. In patients, the findings were related to GH/IGF-I concentrations at the time of diagnosis of acromegaly and to the duration of GH/IGF-I excess. Results: In acromegaly, colonic diverticula were present in 37% of patients, dolichocolon in 34%, and adenomatous polyps in 34%, which was increased compared with controls (odds ratio 3.6, 95% confidence interval 1.4, 5.7; 12.4, 95% confidence interval 6.8, 18.0; 4.1, 95% confidence interval 1.9, 6.4, respectively). The presence of colonic diverticula was associated with both GH and IGF- I concentrations at the time of diagnosis of acromegaly, when adjusted for the duration of active disease. The presence of dolichocolon and adenomatous polyps was associated with higher IGF-I concentrations at diagnosis. Conclusions: Acromegaly is associated with an increased prevalence of colonic diverticula. In addition to the known irreversible effect of GH excess on collagen of joints and cardiac valves, this observation indicates an irreversible effect of GH and/or IGF-I on the collagen in the colon. (J Clin Endocrinol Metab 95: 2073-2079, 2010) Show less
Wassenaar, M.J.E.; Biermasz, N.R.; Kloppenburg, M.; Klaauw, A.A. van der; Tiemensma, J.; Smit, J.W.A.; ... ; Romijn, J.R. 2010
OBJECTIVE: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess... Show moreOBJECTIVE: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess the impact of joint-specific complaints, clinical and radiological signs of arthropathy on different aspects of quality of life (QoL) in patients with acromegaly after long-term disease control. DESIGN: Cross-sectional study. METHODS: We studied 58 patients (31 males), mean age 60years (range 32-81years), with strict biochemical control of acromegaly for a mean duration of 15years. QoL was assessed by four health-related QoL questionnaires (HADS, MFI-20, NHP, SF-36) and one disease specific QoL questionnaire (AcroQoL). The outcomes of these questionnaires were compared with joint-specific self-reported complaints of pain/stiffness, clinical osteoarthritis based on American College of Rheumatology (ACR) and radiological osteoarthritis based on the Kellgren-Lawrence (KL) scoring method. RESULTS: Long-term cured acromegaly patients had high pain scores of the spine, knee, and hip which limited physical functioning (mean difference -27.0, 95%-CI -9.5, -41.0) and psychological well-being (mean difference -44.4, 95%-CI -26.1, -60.9) (SF-36). Clinical osteoarthritis of the spine was associated mostly with impaired QoL scores, on physical, social, and emotional functioning, and on anxiety and depression. Remarkably, radiological osteoarthritis was not associated with impaired QoL. CONCLUSION: These findings accentuate the importance of recognition of the clinical manifestations of arthropathy in patients with acromegaly despite long-term disease control. Show less
Objective: Traumatic brain injury (TBI) has emerged as an important cause of hypopituitarism. However, considerable variations in the prevalence of hypopituitarism are reported. These can partly be... Show moreObjective: Traumatic brain injury (TBI) has emerged as an important cause of hypopituitarism. However, considerable variations in the prevalence of hypopituitarism are reported. These can partly be explained by severity of trauma and timing of hormonal evaluation, but may also be dependent on endocrine tests and criteria used for diagnosis of hypopituitarism. Methods: Systematic review of studies reporting prevalence of hypopituitarism in adults >= 1 year after TBI focusing on used (dynamic) tests and biochemical criteria. Results: We included data from 14 studies with a total of 931 patients. There was considerable variation in definition of hypopituitarism. Overall, reported prevalences of severe GH deficiency varied between 2 and 39%. Prevalences were 8 20% using the GHRH-arginine test (cutoff < 9 mu g/l), 11-39% using the glucagon test (cutoff 1-5 mu g/l), 2% using the GHRH test (no cutoff), and 15-18% using the insulin tolerance test (ITT; cutoff < 3 mu g/l). Overall, the reported prevalence of secondary adrenal insufficiency had a broad range from 0 to 60%. This prevalence was 0-60% with basal cortisol (cutoff < 220 or < 440 nmol/l), 7-19% using the ACTH test, and 5% with the ITT as first test (cutoff < 500 or < 550 nmol/l). Secondary hypothyroidism was present in 0-19% (free thyroxine) or 5-15% (thyroid-releasing hormone stimulation). Secondary hypogonadism was present in 0-29%. Conclusion: The reported variations in the prevalence rates of hypopituitarism after TBI are in part caused by differences in definitions, endocrine assessments of hypopituitarism, and confounding factors. These methodological issues prohibit simple generalizations of results of original studies on TBI-associated hypopituitarism in the perspective of meta-analyses or reviews. Show less
