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acromegaly

Acromegaly

Acromegaly is characterized by GH and IGF-1 hypersecretion, and GH and IGF-1 play important roles in regulating body composition and glucose homeostasis.

History

Pierre Marie coined the term 'acromegaly' in 1886 and linked this to a distinct clinical disease with a characteristic clinical picture. However, Pierre Marie was not the first physician to give a full record of the clinical picture of acromegaly, but others had preceded him, like the Dutch physician Johannes Wier.

After Marie, pituitary enlargement was noted in almost all patients with acromegaly. Subsequently it was discovered that pituitary hyperfunction caused by a pituitary tumour was indeed the cause of acromegaly.

Epidemiology

An increased rate of acromegaly was reported in industrialized areas, suggesting an involvement of environmental pollutants in the pathogenesis and behavior of GH secreting pituitary adenomas 1).

Etiology

The cause of acromegaly could be determined after the discovery of growth hormone (GH) and insulin-like growth factor I (IGF-I) and demonstrating an association with GH hypersecretion and elevated circulating IGF-I. Usually caused by pituitary adenomas.

In > 95 % of cases GH secreting pituitary adenoma.

In >75 % macroadenomas with cavernous sinus invasion and/or suprasellar extension.

A duplication event in GPR101 is implicated in cases of gigantism and acromegaly.

AHR gene rs2066853 polymorphism is significantly more frequent in acromegalic patients than in healthy subjects, regardless of gender, pituitary tumor size, age at diagnosis and prevalence of colonic tumours and is associated with increased disease aggresivity. Moreover, the rs4986826 variant was detected in few patients with rs2066853 polymorphism, but its role is to be cleared 2).

Pituitary carcinomas are exceedingly rare. Extremely infrequently acromegaly occurs as a result of ectopic secretion of growth hormone releasing hormone (GHRH) from a peripheral neuroendocrine tumour, or from excessive hypothalamic GHRH secretio. Approximately 5% of cases are associated with familial syndromes, most commonly multiple endocrine neoplasia type 1 (MEN1) syndrome, but also McCune Albright syndrome, familial acromegaly, Carney’s syndrome and Familial Isolated Pituitary Adenoma (FIPA) 3).


Co-secretion of growth hormone (GH) and prolactin (PRL) from a single pituitary adenoma is common. In fact, up to 25% of patients with acromegaly may have PRL co-secretion. The prevalence of acromegaly among patients with a newly diagnosed prolactinoma is unknown. Given the possibility of mixed GH and PRL co-secretion, the current recommendation is to obtain an insulin-like growth factor-1 (IGF-1) in patients with prolactinoma at the initial diagnosis. Long-term follow-up of IGF-1 is not routinely done 4).

Clinics

Patients with acromegaly often complain of headaches and fatigue.

Hypertension

Is present in approximately 30% of cases, presumably attributable to volume overload and structural changes in the vascular system.

Because hypertension often persists after successful treatment of acromegaly, other mechanisms, such as essential hypertension, may be present in such patients.

Hypertension may lead to cardiac hypertrophy, although there are characteristic cardiac changes that are the result of a more specific form of acromegalic cardiomyopathy 5).

Cardiac disease

Usually begins with a hyperkinetic syndrome characterized by increased heart rate. Left ventricular (LV) function is usually preserved in young patients with a brief duration of disease, although LV mass may be increased and LV function in response to exercise may be reduced. Diastolic dysfunction is prevalent in patients with acromegaly. The degree of cardiomyopathy correlates with the duration of disease. Overt heart failure may occur in advanced disease if hormone excess is left untreated. Successful reduction in serum GH and IGF-I concentrations can lead to reduction in cardiac mass and improvement in LV function 6).

The high prevalence of hypertension and diabetes mellitus in association with acromegaly contributes to progression of coronary artery disease.

Sleep apnea

Sleep apnea syndrome is present in most patients with acromegaly; it is detected in up to 90% of patients with symptoms such as snoring.

Musculoskeletal complications

Include enlargement of the synovial tissue and cartilage, causing hypertrophic arthropathy, primarily of the weight-bearing joints, can lead to degenerative changes and the need for surgical replacement of joints. Recently, investigators showed that joint improvement may be achieved after 12 months of medical therapy, although joint thickening was not completely reversed 7).

Acromegaly may produce the following signs and symptoms, which can vary from one person to another:

Enlarged hands and feet

Coarsened, enlarged facial features

Coarse, oily, thickened skin

Excessive sweating and body odor

Small outgrowths of skin tissue (skin tags)

Fatigue and muscle weakness

A deepened, husky voice due to enlarged vocal cords and sinuses

Severe snoring due to obstruction of the upper airway

Impaired vision

Headaches

Enlarged tongue

Pain and limited joint mobility

Menstrual cycle irregularities in women

Erectile dysfunction in men

Enlarged liver, heart, kidneys, spleen and other organs

Increased chest size (barrel chest)

Treatment

From the beginning of the 20th century, acromegaly could be treated by pituitary surgery and/or radiotherapy. After 1970, medical therapies were introduced that could control acromegaly. First, dopamine agonists were introduced, followed by somatostatin analogues and GH-receptor blockers.

Now surgery is the first-line therapy for patients with surgically accessible lesions. Surgery provides the greatest value for management of patients with acromegaly. However, in accordance with the Acromegaly Consensus Group's recent recommendations, somatostatin analogs provide the greatest value and should be used as first-line therapy for patients who cannot be managed surgically. At present, the substantial cost is the most significant negative factor in the value of medical therapies for acromegaly 8).

Conservative

Asymptomatic elderly patients.

Surgery

Surgical removal of as much tumor mass as possible is usually considered the first step of treatment in acromegaly, unless the patients are unfit for surgery or refuse an operation. To date, in almost all cases, minimally invasive, transsphenoidal microscopic or endoscopic approaches are used. Whether a curative approach is feasible or a debulking procedure is planned, can be anticipated on the basis of preoperative magnetic resonance imaging. It mostly depends on localization, size, and the invasive character of the lesion. The surgical results depend on tumor-related factors such as size, extension, the presence or absence of invasion, and the magnitude of IGF-1 and growth hormone oversecretion, respectively. However, even surgeon-related factors such as experience and case load of the centers have been shown to strongly affect surgical results and complication rates. A reoperation can be considered at various stages in the treatment algorithm. There are several new technical gadgets which might aid in the surgical procedure: navigation, the Doppler probe, and variants of intraoperative imaging 9).

see transsphenoidal approach.

Endoscopic endonasal approach

Acromegaly patients present a particular challenge to the endoscopic skull base surgeon. Despite preoperative anesthesia and otolaryngology evaluation, many of these patients will experience an unanticipated airway challenge during intubation. Preoperative preparation and perioperative awareness of anatomic and physiologic abnormalities of acromegalic patients is essential for successful endoscopic surgery in this unique population 10).

The endoscopic endonasal approach in 214 cases was achieved in 134 (62.6%) of 214 patients. One hundred sixty-nine patients were primary cases, and of these 109 (64.5%) were cured, whereas 61 patients were previously operated cases and of these 25 (41%) were cured. With a 51.1% decrease in the 1st month postoperatively, IGF-I levels were found to be predictive of cure (74.4% sensitivity and 73.7% specificity). Cut-off values for GH levels in predicting cure for the 1st day, 1st week, and 1st month postoperatively were 2.33, 2.05, and 2.25 μg/L, respectively. The cut-off value for surgical experience was 57 for primary surgeries (58.5% cure rate before this cut-off value compared with 72.6% after it; p = 0.025) and 108 for all operations (45.8% vs. 79.4%, p = 0.037). Although 28 patients were found to be in remission according to the criteria in 2000, they were not in remission according to the new consensus criteria. Nine of these cases (32.1%) had random GH levels < 1 μg/L at the 1-year follow-up. The 1-year IGF-I and GH levels in these 28 patients showed no significant difference when compared with the cases defined as cured according to the current criteria.

In acromegaly treatment, transsphenoidal endoscopic surgery performed by an expert senior surgeon and increased surgical experience are important for higher cure rates. Random GH levels < 2.33 μg/L after the 1st day postoperatively and a > 50% decrease in IGF-I levels after the 1st month postoperatively are predictive of cure. Moreover, there is no urgency for additional therapy in patients with GH levels of 0.4-1 μg/L and MRI sequences showing no tumor at the 3-month follow-up, because for these cases remission can be achieved at the 1-year follow-up 11).

Radiotherapy

Variable efficacy of pituitary radiotherapy in acromegaly is reported.

High precision CONFORMAL FRACTIONATED RADIOTHERAPY (CRT) is an effective modality to achieve remission in patients with acromegaly after failed TRANSSPHENOIDAL SURGERY (TSS) 12)

Medical therapy

Patients not cured by surgery

Who cannot tolerate surgery

Recurrence after surgery or radiotherapy

Current pharmacotherapy includes:

Somatostatin analogs

GH receptor antagonist: pegvisomant.

More satisfactory surgical outcomes for noninvasive macroadenomas treated with presurgical SA may be achieved, although controversy of such adjuvant therapy exists. Combination of SA and pegvisomant or cabergoline shows advantages in some specific cases. Thus, an individual treatment program should be established for each patient under a full evaluation of the risks and benefits 13).

Outcome

The clinical complications involving cardiovascular, respiratory, and metabolic systems lead to elevated morbidity in acromegaly.

Control of serum growth hormone GH and insulin like growth factor (IGF) 1 hypersecretion by surgery or pharmacotherapy can decrease morbidity 14).

Medical therapy for acromegaly may lead to decreased symptoms of sleep apnea 15).

Outcomes of transsphenoidal surgery for acromegaly by experienced pituitary surgeons do not differ between endoscopic and microscopic techniques. Regardless of the mode of resection, patients with high preoperative GH levels and Knosp classification scores are less likely to achieve remission. An immediate postoperative GH level of less than 1.15 ng/mL provides the best immediate predictor of remission, but long-term outcomes are indicated 16).


Even if treated, acromegaly has a considerable impact on patient quality of life (QoL); despite this, the exact clinical determinants of QoL in acromegaly are unknown. A study retrospectively examines a cohort of treated patients with acromegaly, with the aim of identifying these determinants.

Diagnostic delay and lack of diagnostic acumen in medical care provision are strong predictors of poor QoL in patients with acromegaly. Other identified parameters are radiotherapy, age, BMI and employment status. An efficient acromegaly service should address these aspects when devising disease management plans 17).

Books

MRI of the Pituitary Gland By Jean-François Bonneville, Fabrice Bonneville, Françoise Cattin, Sonia Nagi

This clinically oriented book will familiarize the reader with all aspects of the diagnosis of tumors and other disorders of the pituitary gland by means of magnetic resonance imaging (MRI). The coverage includes acromegaly, Cushing’s disease, Rathke cleft cysts, prolactinomas, incidentalomas, Clinically nonfunctioning pituitary adenomas, other lesions of the sellar region, hypophysitis, and central diabetes insipidus. Normal radiologic anatomy and the numerous normal variants are described, and guidance is also provided on difficulties, artifacts, and other pitfalls. The book combines concise text and high-quality images with a question and answer format geared toward the needs of the practitioner. MRI is today considered the cornerstone in the diagnosis of diseases of the hypophyseal-hypothalamic region but the relatively small size of the pituitary gland, its deep location, the many normal anatomic variants, and the often tiny size of lesions can hinder precise evaluation of the anatomic structures and particularly the pituitary gland itself. Radiologists and endocrinologists will find MRI of the Pituitary Gland to be full of helpful information on this essential examination, and the book will also be of interest to internists and neurosurgeons.

Case series

2017

The purpose of a study was to investigate body composition, including ectopic lipids, measures of glucose homeostasis, and gonadal steroids in patients with active acromegaly compared to age-, BMI-, and sex-matched controls and to determine changes in those parameters following biochemical control of acromegaly. Design:

Cross-sectional study of 20 patients with active acromegaly matched controls. Prospective study of 16 patients before and after biochemical control of acromegaly. Main outcome measures:

Body composition including ectopic lipids by MRI/1H-MRS; measures of glucose homeostasis by an OGTT; gonadal steroids.

Patients with active acromegaly had lower mean intrahepatic lipids (IHL) and higher mean fasting insulin and insulin AUC compared to controls. Men with acromegaly had lower mean total testosterone, SHBG, and estradiol compared to male controls. Following therapy, HOMA-IR, fasting insulin and insulin AUC decreased despite an increase in IHL, abdominal and thigh adipose tissue and a decrease in muscle mass. Conclusions:

Acromegaly is characterized by insulin resistance and hyperinsulinemia but lower IHL, compared to age-, BMI- and sex-matched healthy controls. Biochemical control of acromegaly improves insulin resistance but leads to a less favorable anthropometric phenotype with increased IHL, abdominal adiposity and decreased muscle mass 18).


Retrospective study of 55 consecutive patients [29 men; median age 47years (interquartile range 38-68)] diagnosed with acromegaly between 2003 and 2014. After treatment serum IGF-I and/or GH was measured according to a standardized protocol. The biochemical remission status was defined according to the clinical guidelines from 2010 and 2014.

Out of 55 patients, 44 patients were primarily operated. Of these, 33 (75%) were evaluated 3-12 months postoperatively by measuring serum IGF-I and GH during an oral glucose tolerance test. According to the 2010 guidelines, 11 patients (33%) were in biochemical remission, 15 patients (46%) were not and 7 patients (21%) had discordant results (normal IGF-I and high GH or vice versa). Applying the 2014 guidelines in the same group, 16 patients (49%) were in biochemical remission, 7 patients (21%) were not and 10 patients (30%) had discordant results. Thus, by using the most recent criteria for biochemical control, more patients were considered to be in remission, or with discordant results, and fewer patients not in remission (P<0.05).

An apparently minor adjustment of the criteria for biochemical control has a significant impact on remission status in patients treated for acromegaly, eventually affecting follow-up and treatment strategies 19).


Babu et al. report all patients undergoing endoscopic transsphenoidal surgery for acromegaly from 2005 to 2013 at Cedars-Sinai Pituitary Center. Hormonal remission was established by normal insulin-like growth factor (IGF)-1, basal serum growth hormone <2.5 ng/mL, and growth hormone suppression to <1 ng/mL following oral glucose tolerance test. Oral glucose tolerance test was performed at 3 months after surgery, and then as indicated. IGF-1 was measured at 3 months and then at least annually. We evaluated tumor granularity, nuclear expression of p21, Ki67 index, and extent of cavernous sinus invasion, and correlated these with remission status.

Fifty-eight patients that underwent surgery had follow-up from 38 to 98 months (mean 64 ± 32.2 months). There were 21 microadenomas and 37 macroadenomas. Three months after surgery 40 of 58 patients (69%) were in biochemical remission. Four additional patients were in remission at 6 months after surgery, and 1 patient had recurrence within the first year after surgery. At last follow-up, 43 of 44 (74.1%) of patients remained in remission. Cavernous sinus invasion by tumor predicted failure to achieve remission.

Prognostic markers of disease aggressiveness other than cavernous sinus invasion did not correlate with surgical outcome. Long-term remission after surgery alone was achieved in 74% of patients, indicating long-term efficacy of endoscopic surgery 20).

1)
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6)
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11)
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12)
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14)
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15)
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16)
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18)
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19)
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20)
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acromegaly.txt · Last modified: 2018/02/02 18:46 by administrador