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The number of international acromegaly related registries is increasing; however, heterogeneity of acromegaly symptoms and signs across countries is not well described. We compared clinical disease manifestations at diagnosis between two large University referral centers from two continents. Retrospective, comparative epidemiological study of acromegaly patients at two centers: (i) C. I. Parhon National Institute of Endocrinology, 'Carol Davila' University of Medicine and Pharmacy Bucharest, Romania (Parhon), and (ii) Pituitary Center, Oregon Health & Science University, Portland, Oregon, United States (OHSU) from approved data repositories was undertaken. Data were extracted from medical charts and questionnaires. Binary logistic regression analysis was undertaken for the most frequently noted symptoms and clinical signs. ResultsThe study included 216 patients (87 Parhon, 129 OHSU). Age, sex, and median delay in diagnosis were similar between centers. IGF-1 index was higher in patients at Parhon (3.3 vs 2.1, P < 0.001). The top five symptoms at both centers were enlarged hands/feet, headache, arthralgia, fatigue, and irregular menses in women. A significant difference was noted for multiple signs and symptoms frequency, often > 20 percentage points between centers. Center was a predictor of many signs and symptoms, independent of acromegaly biochemical severity or disease duration. ConclusionWe show in the first comparative study that differences in medical practice, documentation, and likely cultural differences can influence patients’ symptom(s) reporting and screening patterns in geographically different populations. Pooling data into large multicenter international registry databases may lead to loss of regional characteristics and thus a mixed overall picture of combined cohorts. The number of international acromegaly related registries is increasing; however, heterogeneity of acromegaly symptoms and signs across countries is not well described. We compared clinical disease manifestations at diagnosis between two large University referral centers from two continents. Retrospective, comparative epidemiological study of acromegaly patients at two centers: (i) C. I. Parhon National Institute of Endocrinology, 'Carol Davila' University of Medicine and Pharmacy Bucharest, Romania (Parhon), and (ii) Pituitary Center, Oregon Health & Science University, Portland, Oregon, United States (OHSU) from approved data repositories was undertaken. Data were extracted from medical charts and questionnaires. Binary logistic regression analysis was undertaken for the most frequently noted symptoms and clinical signs. The study included 216 patients (87 Parhon, 129 OHSU). Age, sex, and median delay in diagnosis were similar between centers. IGF-1 index was higher in patients at Parhon (3.3 vs 2.1, P < 0.001). The top five symptoms at both centers were enlarged hands/feet, headache, arthralgia, fatigue, and irregular menses in women. A significant difference was noted for multiple signs and symptoms frequency, often > 20 percentage points between centers. Center was a predictor of many signs and symptoms, independent of acromegaly biochemical severity or disease duration. We show in the first comparative study that differences in medical practice, documentation, and likely cultural differences can influence patients’ symptom(s) reporting and screening patterns in geographically different populations. Pooling data into large multicenter international registry databases may lead to loss of regional characteristics and thus a mixed overall picture of combined cohorts. Keywords: acromegaly; growth hormone excess; diagnosis; symptoms; signs; complications IntroductionAcromegaly is a rare disease that is caused by excessive growth hormone (GH) secretion by a pituitary adenoma (1, 2, 3). The clinical picture of active acromegaly is characterized by a combination of symptoms, signs, and comorbidities related to the tumor itself (e.g. headache, oculomotor never palsy or hypopituitarism) or to GH and insulin-like growth factor-1 (IGF-1) excess (arthralgia, morphologic changes, or obstructive sleep apnea (OSA), cardiovascular disease, and secondary diabetes mellitus (DM)) (2, 3, 4). Long-standing acromegaly is relatively easy to diagnose due to multiple pathognomonic signs and symptoms. However, milder disease cases pose a great challenge, and an acromegaly diagnosis is eventually considered after numerous non-endocrine evaluations. Clinical manifestations are insidious and a diagnosis is usually delayed by 6–10 years (5, 6, 7, 8); although a few publications reported a shorter time to diagnosis, 2.5–5.5 years (9, 10, 11) and a decline of the diagnostic delay overtime (5). Interestingly, in most cases, an evaluation is initiated by primary care providers (PCP) (10). Several studies have identified a clinical profile that accompanies active acromegaly along with the severity and frequency of various signs, symptoms, and complications, often with vast differences between studies (4, 5, 12, 13, 14, 15). Many investigators, because acromegaly is a rare disease, have attempted to increase the subject number and statistical accuracy by aggregating data from national or international acromegaly data registries (5, 12, 16). Although the importance of these studies is without question, some have uncovered significant differences between countries and/or centers in the diagnosis and treatment of acromegaly and disease-related complications (5, 16, 17). This might be one reason for the relative lack of success of studies that have attempted to determine a specific combination of signs and symptoms most indicative of acromegaly (12, 14). While differences in clinical presentation in patients from different countries and centers could be due to genetic variation, other important socio-economic factors such as access to medical care, trust in medical care providers, imaging modalities used, type of IGF-1 assays, local practice of medicine, provider bias, and cultural factors such as family influence on decision-making, and misconceptions and/or misinterpretations regarding symptoms likely also play a role (18, 19, 20, 21). If these differences are inherent to the studied populations, data pooling into national and international registries might lead to inappropriate result generalization (22), and local relevance could be lost. We aimed to compare the acromegaly clinical picture, at diagnosis, between two university referral centers: (i) Department of Pituitary and Neuroendocrine Disorders, C. I. Parhon National Institute of Endocrinology, 'Carol Davila' University of Medicine and Pharmacy Bucharest, Romania (Parhon), and (ii) Pituitary Center, Oregon Health & Science University, Portland, Oregon, United States (OHSU). We also aimed to assess any differences, and if any such differences were disease-related per se or due to factors such as specific medical practice(s), medical record chart documentation, or culture. MethodsStudy design and patientsThis is a retrospective, comparative epidemiological study of newly diagnosed and previously untreated acromegaly patients who presented to two university referral centers; Parhon (years; 2012–2020) and OHSU (years; 2006–2018). Parhon maintains an approved repository of all patients with pituitary adenomas followed by the institution since 1990. The present cohort includes patients with acromegaly (n = 87) assessed before any treatment (years; 2012–2020). Patients presenting prior to 2012 were excluded as IGF-1 measurements were performed with various assays that are no longer in use. Patients assessed after 2012 had serum IGF-1 measured with the same IGF-1 assay. OHSU maintains an institutional review board approved repository of all patients with pituitary adenomas; those prior to 2006 were not included here due to the transition to electronic medical records (EMR) in 2006. Clinical evaluationAt Parhon, patients were clinically assessed by history and clinical examinations; there were no pre-printed questionnaires or checklists. All medical staff working at Parhon have large experience treating acromegaly patients as it is the largest Pituitary Center in Romania serving most of the country’s population (23). At OHSU, the majority of patients were assessed by the same neuroendocrinologist (MF) using a standard acromegaly documentation template in the EMR. A pituitary symptoms questionnaire written in lay terms was completed by patients. Quality of life (QoL) questionnaires were not routinely evaluated at diagnosis and thus, not included. Data on symptoms and physical exam findings were extracted from clinic chart notes and questionnaires. Age, sex, and delay in diagnosis (determined as time between the first symptom and official diagnosis) were also recorded. Biochemical evaluationBiochemical diagnosis of acromegaly was made based on elevated IGF-1 and/or non-suppressible growth hormone (GH) on oral glucose tolerance test when applicable. In Parhon patients, GH and IGF-1 were measured with an automated chemiluminescent analyzer (Liaison XL, Diasorin). Measuring ranges were 3–1500 ng/mL for IGF-1, and 0.05–80 ng/mL for GH, respectively. At OHSU, the majority of GH and IGF-1 were measured as previously published (24). Growth hormone values that were below the detection limit were reported as the lower limit of normal, and the values that were above the assay reading capacity were reported as the maximum reading capacity (e.g. GH > 100 ng/mL was reported as 100 ng/mL). Some patients had IGF-1 performed at an outside laboratory and the reference range differed between laboratories. To normalize the values across the IGF-1assays and adjust for the age- and sex-related differences, IGF-1 values were expressed as IGF-1 index (IGF-1/upper limit of normal (ULN) for each patient).This is a common approach undertaken in most multicenter acromegaly studies, both prospective and retrospective in the absence of a central lab (5, 12). Imaging evaluationIn both OHSU and Parhon patients, MRI was performed at various facilities, and the data on tumor size at diagnosis were extracted from imaging reports. Maximum tumor diameter was recorded. Comorbidity evaluationAt Parhon, patients’ medical history was obtained at presentation, and the following comorbidities were routinely recorded: hypertension, DM, dyslipidemia, arrhythmia, and thyroid nodules. Data on obstructive sleep apnea (OSA), coronary artery disease (CAD), heart failure, colonic polyps, bone mass (by dual-energy X-ray absorptiometry), and spinal fractures were not routinely collected as screening information but were performed as clinically indicated and recorded if a patient mentioned it at the visit. At OHSU, patients’ medical history was obtained at presentation and the following comorbidities were recorded: OSA, hypertension, coronary artery disease, heart failure, arrhythmia, DM, dyslipidemia, colonic polyps, thyroid nodules, and spinal fractures. Patients without a history of these comorbidities were referred for sleep study evaluation, echocardiogram (ECHO), colonoscopy, thyroid ultrasound – if a palpable thyroid abnormality was present, and spinal x-rays, and bone mass (by dual-energy X-ray absorptiometry) since 2011. Hemoglobin A1c and lipid panel were either measured or requested to be obtained by a PCP. Prevalence of comorbidities was calculated as the number of patients with identified comorbidity divided by the total number of patients in the cohort. Statistical analysisStatistical analysis was performed using SPSS 25. Mann–Whitney test was used to evaluate continuous variables (age, delay in diagnosis, IGF-1 index, GH, maximum tumor diameter). Chi-square test was used to evaluate categorical variables (sex, symptoms, and physical exam findings at presentation). Binary logistic regression analysis was performed for symptoms and physical exam findings with the occurrence of >20% using center (institution), age, sex, delay in diagnosis, IGF-1 index, and GH as independent predictors. Forward LR stepwise method was utilized. ResultsEighty-seven acromegaly patients from Parhon and 129 from OHSU were included. There was no significant difference in age, sex, and median delay in diagnosis between the two centers. Interestingly, the median age in males (45 years) at Parhon was 9 years younger than females (54 years) at diagnosis, while males and females at OHSU were diagnosed around the same age (51.5 vs 51 years, respectively). Patients at Parhon presented with significantly higher IGF-1 index (3.3 × ULN) and nadir GH (5.3 ng/mL) compared with OHSU patients (2.1 × ULN and 2.1 ng/mL, respectively). There was no difference in random GH levels and tumor diameters (Table 1). Table 1 Patient baseline characteristics. All data are presented as median (25, 75 percentile) except females (percent). GH, growth hormone; IGF-1, insulin-like growth factor-1; NS, not significant; ULN, upper limit of normal. The descending order of the aggregate (Parhon plus OHSU) percentages for reported symptoms were large extremities (66.7%), headache (59.7%), arthralgia (52.8%), fatigue (52.3%), weight gain (35.6%), snoring (32.9%), memory loss (29.2%), frontal bossing (25%), hirsutism (25%), jaw changes (24.5%), excessive sweating (23.6%), coarse facies (21.8%), skin tags (21.3%), carpal tunnel syndrome (20.4%), round face (19.4%), back neck pain (19%), spread teeth (18.1%), oily skin (18.1%), increased nose (17.6%), and enlarged lips (15.3%). Loss of libido, peripheral neuropathy, depression, macroglossia, visual defects, acne, constipation, shortness of breath, hyperpigmentation, increased head, galactorrhea, thick skin, and gigantism had an aggregate frequency of < 15% each. The descending order of the aggregate (Parhon plus OHSU) percentages for physical exam findings were hand enlargement (68.5%), frontal bossing (67.6%), protruding jaw (58.8%), coarse facies (38.4%), sweaty or oily skin (37.5%), skin tags (33.8%), gaps between teeth (32.4%), macroglossia (31.9%), facial rounding (26.4%), truncal obesity (25.5%), skin thickening (23.6%), hand edema (20.8%), and goiter (17.1%). Dental articulation problems, abnormal visual field, hirsutism, galactorrhea, arthropathy, husky voice, acne, plethora, acanthosis nigricans, hyperpigmentation, leg edema, and gynecomastia had an aggregate frequency of < 15% each. Figure 1 compares the frequencies of symptoms and the corresponding physical exam findings at Parhon vs OHSU (with an aggregate frequency of at least 20%). Figure 1 Reported symptoms (gray bars) and corresponding physical exam findings (white bars) in Parhon (clear bars) and OHSU patients (shaded bars). *P < 0.05 between Parhon and OHSU patients. Citation: Endocrine Connections 10, 7; 10.1530/EC-21-0035
Figure 1 Reported symptoms (gray bars) and corresponding physical exam findings (white bars) in Parhon (clear bars) and OHSU patients (shaded bars). *P < 0.05 between Parhon and OHSU patients. Citation: Endocrine Connections 10, 7; 10.1530/EC-21-0035
Figure 1 Reported symptoms (gray bars) and corresponding physical exam findings (white bars) in Parhon (clear bars) and OHSU patients (shaded bars). *P < 0.05 between Parhon and OHSU patients. Citation: Endocrine Connections 10, 7; 10.1530/EC-21-0035
A significant difference was found in multiple symptoms at presentation between the two centers (Fig. 1). Symptoms that were more commonly documented in OHSU patients included headache, arthralgia, fatigue, weight gain, snoring, memory and concentration problems, coarse facies, frontal bossing, jaw changes, spreading of the teeth, macroglossia, hirsutism, acne, oily skin, skin tags, hyperpigmentation, irregular menses, carpal tunnel syndrome (CTS), back and neck pain, loss of libido, depression, constipation, and galactorrhea. Nose enlargement, lip enlargement, and increased head size were more commonly documented in Parhon patients. There was no difference in documented frequency of enlarged extremities, excessive sweating, rounding of the face, peripheral neuropathy, thickening of the skin, visual defects, shortness of breath, and gigantism. With regards to physical exam findings, hand enlargement, frontal bossing, coarse facies, gaps between the teeth, facial rounding, truncal obesity, skin thickening, hand edema, abnormal thyroid exam, and dental articulation problems were more frequently documented in Parhon patients, whereas skin tags were more frequently documented in OHSU patients (Fig. 1). There was no difference in documented protruding jaw, oily/sweaty skin, macroglossia, abnormal visual field, hirsutism, acne, galactorrhea, arthropathy, husky voice, facial plethora, acanthosis, hyperpigmentation, leg edema, and gynecomastia. Logistic regression analysis was performed to determine which independent variables (center, age, sex, delay in diagnosis, IGF-1 index, and GH) could serve as predictors of reported symptoms and physical exam findings with an aggregate prevalence of at least 20% (Table 2). Patients at OHSU were more likely than patients at Parhon to report headache, arthralgia, fatigue, weight gain, snoring, memory/concentration problems, hirsutism, jaw changes, and carpal tunnel syndrome. Endocrinologists at OHSU were more likely to document skin tags, macroglossia, and hirsutism and less likely to document hand enlargement, coarse facies, gaps between the teeth, truncal obesity, skin thickening, and hand edema. Higher IGF-1 index predicted symptoms of enlarged extremities and protruding jaw and several physical exam findings (hand enlargement, frontal bossing, protruding jaw, sweaty/oily skin, and macroglossia). Longer delay in diagnosis was the independent predictor only for symptom of hand enlargement and for physical findings of hand enlargement, protruding jaw, and truncal obesity; however, the odds ratio (OR) for this predictor was essentially 1. When multiple predictors were retained in the regression model, the center had the highest impact based on the OR (Table 2). Table 2 Predictors of symptoms and physical exam findings in acromegaly patients – results of binary logistic regression analysis. dx, diagnosis; GH, growth hormone; IGF-1, insulin-like growth factor-1; OR, odds radio; OHSU; Oregon Health and Science University; NS, not significant. Frequency of comorbidities before the diagnosis of acromegaly and total (at any time up until last follow-up) are presented in Fig. 2. We found the variable prevalence of comorbidities in patients at Parhon and OHSU; hypertension, hyperlipidemia, and DM/impaired glucose tolerance being most common at both centers. Numerically, hypertension, myocardial hypertrophy, and thyroid nodules were more prevalent at Parhon, while diabetes, sleep apnea, colonic polyps, and vertebral fractures were more prevalent at OHSU. Of note, the percent of patients screened with a sleep study, ECHO, x-rays, colonoscopy, and thyroid ultrasound differed considerably between the centers, contributing to the difference in the prevalence of comorbidities. Figure 2 Frequency of comorbidities at diagnosis (black bars) and at final assessment (white bars) in OHSU (left side) or Parhon (right side) patients. DM, diabetes mellitus; IGT, impaired glucose tolerance. What is the most common presenting symptom in patients with acromegaly?The most frequent manifestations were morphologic (enlarged hands, enlarged feet), facial modifications (frontal bump, enlargement of the nose), snoring syndrome, and asthenia. The manifestations that were more common in women than men were headache, carpal or cubital tunnel syndrome, constipation, and thyroid nodules.
What is acromegaly and its signs?Acromegaly is a rare but serious medical condition that happens when you have too much growth hormone in your body. Acromegaly affects your body's bones and tissues and causes them to grow in irregular ways. The most common treatments for acromegaly include surgery, medication and radiation therapy.
Which of the following is characteristic of acromegaly?Adult patients with acromegaly have the characteristic facial features of a large lower jaw, prominent forehead, and large hands and feet. This occurs after the growth plates are fused, distinguishing acromegaly from gigantism, which occurs before the fusion of growth plates.
Which is a possible complication of acromegaly?The most common acromegaly complications involve joint problems, pituitary hormone deficiency, and respiratory problems. It's also possible to develop complications if acromegaly is undertreated, which is why it's so important to work closely with your doctor to monitor hormone levels.
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