Automated image analysis of hand radiographs reveals widened joint spaces in patients with long-term control of acromegaly: relation to disease activity and symptoms.

OBJECTIVE: 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 (JSWs) of hand joints in patients with long-term control of acromegaly and to identify factors associated with JSW. METHODS: A cross-sectional study was carried out in 89 patients (age 58 ± 12 years, 49% women) with long-term controlled acromegaly and 471 controls without hand symptoms (age 46 ± 12 years, 42% women). Radiological JSWs of individual hand joints were measured by automated image analysis. RESULTS: Patients had wider mean joint spaces than controls: metacarpo-phalangeal (MCP) joints were ~24%, proximal interphalangeal joints ~21%, and distal interphalangeal joints were ~20% wider (patients vs controls; P < 0.001 for all joints). Mean JSW exceeded the 95th percentile of the values obtained in controls in 64% of patients. Higher IGF1 and GH concentrations at diagnosis were associated with larger JSWs (adjusted ß for pretreatment GH in tertiles: 0.09 (95% confidence interval (CI) 0.03-1.84) and for IGF1 in tertiles: 0.14 (95% CI 0.05-0.23) at the MCP joints in acromegalic patients. In male patients, but not in female patients, increased JSWs 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. JSWs 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.

Low prevalence of hypopituitarism after traumatic brain injury: a multicenter study.

OBJECTIVE: Hypopituitarism after traumatic brain injury (TBI) is considered to be a prevalent condition. However, prevalence rates differ considerably among reported studies, due to differences in definitions, endocrine assessments of hypopituitarism, and confounding factors, such as timing of evaluation and the severity of the trauma. Aim To evaluate the prevalence of hypopituitarism in a large cohort of TBI patients after long-term follow-up using a standardized endocrine evaluation. Study design Cross-sectional study. PATIENTS AND METHODS: We included 112 patients with TBI, hospitalized for at least 3 days and duration of follow-up >1 year after TBI from five (neurosurgical) referral centers. Evaluation of pituitary function included fasting morning hormone measurements and insulin tolerance test (n=90) or, when contraindicated, ACTH stimulation and/or CRH stimulation tests and a GH releasing hormone-arginine test (n=22). Clinical evaluation included quality of life questionnaires. RESULTS: We studied 112 patients (75 males), with median age 48 years and mean body mass index (BMI) 26.7±4.8 kg/m(2). Mean duration of hospitalization was 11 (3-105), and 33% of the patients had a severe trauma (Glasgow Coma Scale <9) after TBI. The mean duration of follow-up was 4 (1-12) years. Hypopituitarism was diagnosed in 5.4% (6/112) of patients: severe GH deficiency (n=3), hypogonadism (n=1), adrenal insufficiency (n=2). Patients diagnosed with pituitary insufficiency had significantly higher BMI (P=0.002). CONCLUSION: In this study, the prevalence of hypopituitarism during long-term follow-up after TBI was low. Prospective studies are urgently needed to find reliable predictive tools for the identification of patients with a significant pre-test likelihood for hypopituitarism after TBI.

High prevalence of vertebral fractures despite normal bone mineral density in patients with long-term controlled acromegaly.

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 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.

Arthropathy in long-term cured acromegaly is characterised by osteophytes without joint space narrowing: a comparison with generalised osteoarthritis.

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 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.

Doyle Index is a valuable additional pain measure in osteoarthritis.

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 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 5.1min (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.

Acromegaly is associated with an increased prevalence of colonic diverticula: a case-control study.

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 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.

Clinical osteoarthritis predicts physical and psychological QoL in acromegaly patients.

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 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.

The exon-3 deleted growth hormone receptor polymorphism predisposes to long-term complications of acromegaly.

OBJECTIVE: The aim of the study was to evaluate the impact of the genomic deletion of exon 3 of the GH receptor (d3GHR) on long-term clinical outcome of acromegaly in a well-characterized cohort of patients with long-term remission of acromegaly. DESIGN: We conducted a cross-sectional study. METHODS: The presence of the d3GHR polymorphism was assessed in 86 acromegalic patients with long-term disease control and related to anthropometric parameters, cardiovascular risk factors, osteoarthritis, bone mineral density, colonic polyps and diverticulae, and dolichocolon. RESULTS: Fifty-one patients had two wild-type alleles (59%), whereas 29 patients (34%) had one allele and six patients (7%) had two alleles encoding for the d3GHR isoform. Carriers of the d3GHR isoform showed increased prevalence of osteoarthritis, especially of the hip [adjusted odds ratio (OR), 5.2; 95% confidence interval (CI), 3.2-7.1], of adenomatous polyps (adjusted OR, 4.1; 95% CI, 2.4-5.6), and dolichocolon (adjusted OR, 3.2; 95% CI, 1.8-4.6). Anthropometric parameters, cardiovascular risk factors, bone mineral density, and (non)vertebral fractures were not significantly different between patients with and without the d3GHR allele. CONCLUSION: In patients with long-term cured acromegaly, the d3GHR polymorphism is associated with an increased prevalence of irreversible comorbidities such as osteoarthritis, dolichocolon, and adenomatous colonic polyps, but not with other comorbidities such as cardiovascular risk factors.

Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: a systematic review and meta-analysis.

CONTEXT: The exon-3 deleted GH receptor (GHR(d3)) polymorphism is associated with an increased growth response to recombinant human GH (rhGH) therapy in some, but not all, studies in GH-deficient (GHD) and non-GHD children with short stature. OBJECTIVE: The aim of the study was to assess the effects of GHR(d3) on baseline height and the first year's growth response to rhGH treatment in prepubertal GHD and non-GHD children with short stature. DESIGN: We conducted a systematic review and meta-analysis. METHODS: Fifteen studies reporting the effect of GHR(d3) on growth parameters were included. Principal outcomes were baseline height sd score (SDS) and the weighted average of change in growth velocity (Delta cm/yr) and height gain (Delta height SDS) after 1 yr of rhGH. RESULTS: In GHD, not in non-GHD, baseline height SDS was 0.159 sd higher [95% confidence interval (CI), 0.020, 0.298] in GHR(d3) compared with GHR(wt-wt). In GHR(d3), rhGH therapy resulted in a higher increase in growth velocity (0.521 cm/yr; 95% CI, 0.196, 1.015) and height gain (0.075 sd; 95% CI, 0.007, 0.143) compared with GHR(wt-wt). Meta-regression demonstrated a larger difference between GHR(d3) and GHR(wt-wt) in studies using lower rhGH doses and carried out at a higher age, independently of the cause of short stature. CONCLUSIONS: This meta-analysis in prepubertal children with short stature indicates that GHR(d3) is associated with increased baseline height in GHD, but not in non-GHD. Furthermore, GHR(d3) stimulates growth velocity by an additional effect of approximately 0.5 cm during the first year of rhGH treatment, and this effect is more pronounced at lower doses of rhGH and higher age.

Pretreatment insulin-like growth factor-I concentrations predict radiographic osteoarthritis in acromegalic patients with long-term cured disease.

OBJECTIVE: The aim of the study was to identify factors influencing the development of osteoarthritis during long-term control of acromegaly, focusing on disease-specific parameters, GH and IGF-I concentrations, and duration of disease, adjusted for the well-known determinants of primary osteoarthritis. DESIGN: We conducted a follow-up study. METHODS: We studied 67 patients with adequate biochemical control of acromegaly for a mean of almost 13 yr. Study parameters were the results of radiological assessment of the spine, hip, knee, and hand. Osteoarthritis was defined as radiological osteoarthritis using the scoring system developed by Kellgren and Lawrence. Correlations between potential factors of influence and osteoarthritis were performed by analysis of covariance and adjusted for age, gender, and body mass index. RESULTS: Patients with pretreatment IGF-I sd scores in the highest tertile had an almost 4-fold increased risk for radiological osteoarthritis of the hip when compared with patients in the lowest tertile. After adjustment for age, gender, BMI, and disease duration, pretreatment IGF-I sd scores predicted radiographic osteoarthritis in all joint sites. Osteoarthritis was not predicted by other factors, including pretreatment GH levels, type of treatment, and duration of follow-up. CONCLUSION: This is the first study to document pretreatment IGF-I concentration as a predictor of radiographic osteoarthritis in acromegalic patients with long-term disease control.

High prevalence of arthropathy, according to the definitions of radiological and clinical osteoarthritis, in patients with long-term cure of acromegaly: a case-control study.

OBJECTIVE: To evaluate the prevalence and rheumatological and radiological characteristics of arthropathy in patients after long-term cure of acromegaly in comparison with age-matched controls. DESIGN: Case-control study. PATIENTS: We compared 89 patients with adequate biochemical control of acromegaly (mean 14 years) and 67 age-matched controls. MEASUREMENTS: Study parameters were the results of symptom questionnaires, structured physical examination and radiographs of the spine, hip, knee and hand. The diagnosis of osteoarthritis was based on a) radiological osteoarthritis determined by Kellgren and Lawrence and b) clinical osteoarthritis determined by the American College of Rheumatology (ACR) criteria. For the radiological comparison with controls, a Dutch reference group was used. RESULTS: Pain/stiffness at > or =1 joint site was reported by 72% of patients, most frequently in the spine and hands. Radiological osteoarthritis at > or =1 joint site was present in 99% of patients, most frequently in the spine and hip, and increased at all joint sites in comparison with controls (odds ratios: 2-20). Despite long-term cure of acromegaly, the characteristic widening of joint spaces was still present. In addition, severe osteophytosis was present. Representative radiographs of these typical features are included in the manuscript. According to the ACR criteria, clinical osteoarthritis at > or =1 joint site was present in 63% of patients, most frequently in the spine and hand. Patients had a higher prevalence of osteoarthritis than controls at all joint sites according to all scoring methods and at a younger age. CONCLUSIONS: Prior GH excess has irreversible, deleterious late effects on the clinical and radiological aspects of joints in patients with long-term cure of acromegaly.