Handbook of Clinical Neurology, Vol. 124 (3rd series) Clinical Neuroendocrinology E. Fliers, M. Korbonits, and J.A. Romijn, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 14
Acromegaly PHILIPPE CHANSON1,2,3,*, SYLVIE SALENAVE1, AND PETER KAMENICKY1,2,3 Department of Endocrinology and Disorders of Reproduction, Hoˆpital Bictre and Reference Center for Rare Endocrine Disorders of Growth, Le Kremlin-Bictre, Paris, France
1
2
Faculty of Medicine, Universit Paris-Sud 11, Le Kremlin-Bictre, Paris, France 3
INSERM U693, Le Kremlin-Bictre, Paris, France
INTRODUCTION
PATHOPHYSIOLOGY
Acromegaly is a rare disease characterized by progressive somatic disfigurement, mainly involving the face and extremities, together with systemic manifestations related to organ overgrowth. Acromegaly is associated with severe comorbidity and premature death if not adequately treated. It is due to excessive secretion of growth hormone (GH), originating from a pituitary adenoma in the vast majority of cases.
Acromegaly related to a pituitary tumor
EPIDEMIOLOGY The prevalence of acromegaly was long estimated to be about 40–70 cases per million inhabitants (Holdaway and Rajasoorya, 1999), but recent studies have suggested that it may be much higher: around 80–130 cases per million in Belgium or the UK, for example (Daly et al., 2006; Fernandez et al., 2010). A prevalence of around 1000 per million inhabitants was found in a German study based on screening with IGF-1 measurement in the general population (Schneider et al., 2008). In a recent Finnish study the adjusted annual incidence of acromegaly was estimated to be 3.4 cases per million (Raappana et al., 2010). These new data need to be confirmed. Owing to the insidious clinical onset, acromegaly is often diagnosed late. Older series, in the 1980s, suggested a mean diagnostic delay of 6–10 years after onset, at an average age of about 40 years (Nabarro, 1987; Ezzat et al., 1994; Melmed, 2002). More recent retrospective studies suggest that this interval has fallen to around 3–5 years on average (Nachtigall et al., 2008; Reid et al., 2010).
In more than 95% of cases, acromegaly is secondary to GH hypersecretion by a benign monoclonal pituitary adenoma which develops from somatotroph cells (Asa et al., 2002; Heaney and Melmed, 2004; Melmed, 2009, 2011; Dworakowska et al., 2011).
SOMATOTROPH PITUITARY ADENOMAS Pure somatotroph pituitary adenomas (60%) contain either cells rich in secretory granules that show diffuse immunostaining or cells poor in secretory granules with scattered immunolabeling (Asa et al., 2002). Some of these pure somatotroph adenomas also express free a subunits shared by several glycoprotein hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and chorionic gonadotropin hormone (CG), co-localized in the same cells or even in the same granules as GH (Beck-Peccoz et al., 1985). Mixed GH- and prolactin (PRL)-secreting adenomas are frequent (25%). Some adenomas contain both cell types, while other develop from a mammosomatotropic stem cell and consist of more mature monomorphic cells that express both GH and PRL (Asa et al., 2002). Mixed GH- and TSH-secreting adenomas are rare and cause acromegaly associated with hyperthyroidism and inappropriate TSH secretion (Beck-Peccoz et al., 1996; Socin et al., 2003). Very rarely, corticotrophin (ACTH) hypersecretion may also be found.
*Correspondence to: Prof. Philippe Chanson, Assistance Publique-Hoˆpitaux de Paris, Hoˆpital BiceˆtreService d’Endocrinologie et des Maladies de la Reproduction, 78 rue du Ge´ne´ral Leclerc, F-94275 Le Kremlin-Biceˆtre, France. Tel: þ33-1-45213708, Fax: þ33-145212212, E-mail: [email protected]
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The pituitary versus hypothalamic origin of pituitary somatotroph adenomas is controversial (Melmed, 2006, 2009). Evidence pointing to a hypothalamic origin suggests that the main actor is growth hormone-releasing hormone (GHRH), which can cause not only hyperplasia of somatotroph cells but also, as demonstrated in animal models, true adenomas (albeit such adenomas have never been observed in humans). In contrast, the monoclonal nature of these tumors and the absence of relapse after total adenoma removal point instead to a pituitary origin (Melmed, 2002). In fact, the initiation and/or progression of neoplastic transformation of normal somatotrophs could be due to a polyclonal hyperplastic response of these cells secondary to hypothalamic dysregulation. The prerequisite for an abnormal response to pathologic GHRH secretion may be the existence of a mutation in somatotroph cells. Most human somatotroph adenomas seem to be associated with clonal expansion (Herman et al., 1990) of cells bearing a somatic mutation. However, as in other types of pituitary adenoma, it has proved difficult to isolate a single causative factor in sporadic pituitary tumorigenesis (Lytras and Tolis, 2006; Horvath and Stratakis, 2008; Melmed, 2009). A mutated Gsa protein has been identified in up to 40% of somatotroph adenomas. Mutations at two critical sites (gsp mutations) inhibit GTPase activity and lead to constitutive adenyl cyclase activation (Vallar et al., 1987). Cell-cycle disruption also seems to play an important role (Melmed, 2009), as demonstrated in MEN1 or in patients with mutations of CDKN1B which encodes the cyclin-dependent kinase inhibitor p27KIP1, an atypical tumor suppressor playing a key role in cell-cycle regulation, cell proliferation, and differentiation. Overexpression of HMGA2, a nuclear architectural protein (De Martino et al., 2009), and an activating gene (PTTG, pituitary tumor transforming gene), also play a role. This latter gene (a securin homolog) is overexpressed in functional pituitary tumors, and this could lead to aneuploidy (Vlotides et al., 2007); the degree of overexpression correlates with tumor size and invasiveness (Filippella et al., 2006). Premature senescence likely explains the persistence of a benign phenotype and the rarity of progression to carcinoma. Epigenetic mechanisms may also contribute to cell proliferation by silencing genes such as CDKN2A, which encodes p16, a CDK inhibitor that inhibits cell proliferation. Finally, even if it is clear that somatotroph cells are altered in somatotroph adenomas, the sequence of events leading to their clonal expansion seems to be multifactorial. An activated oncogene may be necessary to initiate tumorigenesis, while promotion of cell growth may require GHRH or other growth factors such as bFGF (basic fibroblast growth factor) (Asa and Ezzat, 2002; Melmed, 2003).
GROWTH HORMONE-SECRETING CARCINOMAS The large majority of these somatotroph adenomas are benign. Pituitary carcinomas are exceptional (fewer than 20 published cases) and the presence of distant metastases is generally required to support the diagnosis of malignancy (review in Chanson et al., 2009a).
GENETIC SYNDROMES ASSOCIATED WITH ACROMEGALY Syndromes associated with acromegaly have been recently reviewed (see Chanson et al., 2009a; Daly et al., 2009; Dworakowska et al., 2011; Gadelha et al., 2013). McCune–Albright syndrome, which is associated with multiple fibrous bone dysplasia, precocious puberty and cafe´-au-lait spots, can be accompanied by acromegaly. This syndrome is related to a somatic mutation that activates the a subunit of Gs protein (Chanson et al., 2007; Collins et al., 2012). More than 20% of these patients develop acromegaly (Chanson et al., 2007; Collins et al., 2012; Vortmeyer et al., 2012). Acromegaly can also be associated with hyperparathyroidism, neuroendocrine tumors (e.g., gastrinoma, insulinoma, or a nonfunctional pancreatic tumor), adrenal and other endocrine or nonendocrine tumors in patients with multiple endocrine neoplasia (MEN) type 1, which is generally related to a germline mutation of the MEN1 gene encoding menin (Verges et al., 2002; Thakker et al., 2012). Mutations in CDKN1B are responsible for a very rare MEN syndrome, MEN type 4, which combines hyperparathyroidism, pituitary adenomas (including acromegaly), and other endocrine or nonendocrine neoplasia (Pellegata et al., 2006; Georgitsi, 2010). When acromegaly is associated with bilateral pigmented micronodular adrenal hyperplasia (causing ACTHindependent hypercorticism) and with cutaneous lesions or cardiac myxomas, the patient should be screened for the Carney complex, which is often related to a germline mutation of the regulatory 1-a subunit of protein kinase A (PRKAR1A) (Kirschner et al., 2000; Bertherat, 2006). Recently, familial acromegaly related to germline mutations of the AIP (aryl hydrocarbon receptor interacting protein) gene was described (Vierimaa et al., 2006; Chahal et al., 2011; Beckers et al., 2013). These mutations can also, albeit rarely, be found in some apparently sporadic cases of acromegaly, particularly in young patients (Barlier et al., 2007; Cazabat et al., 2007, 2011, 2012; Daly et al., 2007).
Extrapituitary acromegaly This topic has been recently reviewed by Chanson et al. (2009a).
ACROMEGALY Acromegaly can also be due to eutopic hypothalamic GHRH hypersecretion (gangliocytoma, hamartoma, choristoma, glioma, etc.) or, more often, to ectopic, peripheral GHRH hypersecretion (pancreatic or bronchial carcinoid tumor) that stimulates normal somatotrophs to become hyperplastic and to hypersecrete GH (Gola et al., 2006; Biermasz et al., 2007; Garby et al., 2012). The diagnosis is based on plasma GHRH assay (revealing excess secretion) and on identification of the GHRH-secreting endocrine tumor (Thorner et al., 1982). The prognosis is generally good (Garby et al., 2012). GH can also be hypersecreted by an ectopic pituitary adenoma (sphenoidal sinus, petrous temporal bone, nasopharyngeal cavity) or, in exceptional cases, by a peripheral tumor (pancreatic islet tumor or lymphoma) (Melmed et al., 1985; Beuschlein et al., 2000).
SIGNS AND SYMPTOMS Acromegaly is generally suspected on clinical signs and symptoms which are important to recognize (Molitch, 1992; Melmed, 2002; Giustina et al., 2003; Colao et al., 2004; Chanson and Salenave, 2008; Nachtigall et al., 2008; Melmed et al., 2009; Reid et al., 2010; RibeiroOliveira and Barkan, 2012).
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The dysmorphic syndrome The extremities (hands and feet) are broadened, the fingers are widened, thickened and stubby, and the soft tissues are thickened. The patient may have had to enlarge his or her ring in recent years, or to change shoe size. The facial aspect is characteristic, and patients with established acromegaly are generally alike in this respect: the nose is widened and thickened, the cheekbones are prominent, the forehead bulges, the lips are thick and the facial lines are marked (Fig. 14.1). The forehead and overlying skin are thickened, sometimes leading to frontal bossing. There is a tendency towards mandibular overgrowth with prognathism, maxillary widening, teeth separation, and jaw malocclusion. Photographs show a slow, insidious transformation over several years (Fig. 14.1). As a result, the diagnosis is often raised by a doctor who has never seen the patient before. Deformations can also affect the rest of the skeleton, and dorsal kyphosis with distortion of rib cage may be observed in severe chronic forms, leading to the classic “Punchinello” aspect, especially when GH hypersecretion begins prior to closure of the epiphyses. Acral changes are the most common problem leading to diagnosis, which is made by a general practitioner in the
Fig. 14.1. Series of photographs of a patient with acromegaly showing the progressive changes in facial appearance. It is possible to assume that the disease began between 1988 and 1990, 12 years before the diagnosis, made in 2011. In 1990, the patient had to cut the ring that she bought in 1988 because it was too narrow.
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majority of cases (Nachtigall et al., 2008; Reid et al., 2010). However, most patients complain of a delay in diagnosis, despite clear signs and symptoms: this is because many physicians are unaware of this disease, having never encountered such a patient during their training or practice (Danzig, 2007). In our experience it is not uncommon that a patient makes the diagnosis himself by searching the Internet.
TRUNK
Symptoms
LIMBS
Acromegaly can cause a variety of symptoms, such as headache (whether the pituitary adenoma is large or small): this is the second initial complaint leading to diagnosis of acromegaly) (Nachtigall et al., 2008); malodorous sweating (especially at night); acroparesthesia (carpal tunnel syndrome); and joint pain. A gradual deepening of the voice is also observed.
Skin changes Nearly 70% of patients have sweaty, oily skin. Skin thickening is due to glycosaminoglycan deposition and to increased collagen production by connective tissue. Skin tags are frequent and may be a marker of colonic polyps. Raynaud’s disease is present in one-third of cases.
Bone changes CRANIOFACIAL In response to both GH and IGF-1, new periosteal bone formation leads to an increase in skeletal growth, especially at the level of the mandible (prognathism). Jaw thickening, teeth separation, frontal bossing, malocclusion, and nasal bone hypertrophy are the standard facial bony deformities in acromegaly. Radiography shows a thickening of the cranial vault and protuberances, frontal internal hyperostosis, and condensation of the walls of the sella turcica with clinoid hypertrophy. Hypertrophy of the sinuses, especially the frontal sinuses, is also clearly visible. This, along with laryngeal hypertrophy, explains why the voice tends to become deeper and acquires a sonorous resonance.
EXTREMITIES These changes are not only due to soft tissue hypertrophy and excessive growth of bone and cartilage but also to bone deformation. Indeed, radiographic findings are abnormal in half these patients, showing distal tufting of the phalanges, widening of the base of the phalanges with osteophyte formation, enthesopathy (mineralization of ligamentous insertions), widening of the diaphysis in cortical bone, and widening of joint spaces due to cartilage hypertrophy.
Bony deformation also affects the spine, with upper dorsal kyphosis and compensatory lumbar hyperlordosis. Vertebral enlargement, widened intervertebral spaces and osteophyte formation are also observed. The thorax is deformed by protuberance of the lower portion of the sternum, and by elongation and divergence of the ribs, due to overgrowth of the chondrocostal joints.
Imaging studies show diaphyseal cortical thickening of the long bones and widened joint spaces, sometimes with osteophytes.
BONE MINERAL DENSITY Bone remodeling is stimulated in acromegaly (Ueland et al., 2006; Giustina et al., 2008). Cortical bone thickens (as measured by the metacarpal index and histomorphometric parameters) and its porosity is diminished. Trabecular bone mass may be decreased, normal, or increased. Measurement of spinal bone mass can give contradictory results, probably because acromegaly is often associated with other endocrine disorders that interfere with bone mass. In general, bone mass is normal in the lumbar spine in patients with isolated acromegaly but is decreased in patients with associated hypogonadism, as is also generally the case in patients with hypogonadism, whatever its cause. In a recent study (Mazziotti et al., 2008), although bone mineral density (BMD) was not significantly different between acromegalic patients and control subjects, the prevalence of vertebral fractures was higher in acromegalic patients (57.5% versus 22.6%). Fractures were associated with higher serum IGF-1 values, a longer duration of active disease, and a longer history of untreated hypogonadism. This higher prevalence of vertebral fractures persists despite biochemical control of acromegaly (Claessen et al., 2013a).
Rheumatologic complications PERIPHERAL ARTHROPATHY This topic has been reviewed in detail by Liote and Orcel (2000) and Kropf et al. (2013). Peripheral joint symptoms are very frequent. Arthralgia and myalgia occur in 30–70% of patients. All the joints can be affected, especially the large joints (knees, shoulders, hands, wrists, and hips). Acromegalic arthropathy develops within an average of 10 years after diagnosis. The arthralgia is mainly mechanical, degenerative, and noninflammatory in origin, but features of osteoarthritis may develop in some patients. Joint mobility (especially of the shoulders) can be limited in the later
ACROMEGALY stages of the disease. Joint effusion is rare and synovial aspiration shows a generally degenerative picture with no evidence of inflammation; it may also reveal calcium microcrystals (associated chrondrocalcinosis). Physical examination of the joints often provides little information. The abnormalities are generally minor despite subjective functional discomfort. The shoulders and hips may show a loss of mobility and function. In contrast, some patients have joint hyperlaxity. There is no correlation between the presence (or severity) of arthropathy and the age of onset of acromegaly, or the mean GH or IGF-1 concentration at baseline or during follow-up. Arthropathy appears to be more frequent after age 45 years. Radiologic studies show a widening of the joint spaces, reflecting hypertrophy of the hyaline cartilage, as well as the presence of osteophytes, bone proliferation at the attachment sites of tendons and ligaments, periarticular calcium deposition, and exostosis of the bone surface (Fig. 14.2). The joint space subsequently diminishes due to destructive arthropathy. Sonography shows a thickening of the cartilage in the shoulder, wrist and knee joints, which improves during treatment for acromegaly. The arthropathy progresses inexorably in advanced stages and unpredictably in minor forms. It is not influenced by successful treatment of acromegaly, with the exception of diffuse articular symptoms and some sites of pain (Wassenaar et al., 2009). It considerably impairs patients’ quality of life (Miller et al., 2008; Claessen et al., 2013b).
SPINAL INVOLVEMENT The estimated prevalence of spinal involvement is about 40–50% (Scarpa et al., 2004). Backache is more frequent at the level of the lumbar spine than the cervical or dorsal spine. The pain is mainly mechanical in nature, but inflammatory features can occur (16%). Spinal
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involvement may be accompanied by nerve compression. Occasionally, bilateral intermittent claudication reveals lumbar spinal stenosis. Pain may also be related to increased prevalence of vertebral fractures despite normal BMD (Mazziotti et al., 2008; Wassenaar et al., 2011). Radiologic examination shows typical features, including ossification of the anterior and lateral surfaces of the vertebral bodies, contributing to enlargement of their anteroposterior diameter, as well as a biconcave vertebral aspect and scalloping of the vertebral bodies (exaggerated concavity of the posterior vertebral wall). The mechanism is poorly understood but may involve hypertrophy of the intraspinal soft tissues (ligamentous hypertrophy, epidural lipomatosis) or bone. In more severe cases, ossification of the anterior surface of the vertebral bodies can bridge the disc space and give an aspect of diffuse idiopathic skeletal hyperostosis.
Neuropathies Symptomatic carpal tunnel syndrome is frequent. Nerve conduction studies have shown that the vast majority of acromegalic patients have subclinical abnormalities of nerve conduction. Magnetic resonance imaging (MRI) shows a higher amplitude and intensity of the median nerve signal in patients with symptomatic carpal tunnel syndrome compared to asymptomatic patients (Jenkins et al., 2000). The mechanism appears to involve median nerve edema more than extrinsic compression due to an excess of connective tissue, bone, or synovial hypertrophy, or an increase in extracellular fluid within the carpal tunnel itself with Schwann cell demyelination. The nerve edema, which can easily be evaluated with ultrasonography (Tagliafico et al., 2008a), improves when GH and IGF-1 levels fall, suggesting that hormonal control is a key prerequisite for improving these patients’ neurologic status. Sometimes, however, the carpal tunnel syndrome persists.
Fig. 14.2. Osteoarticular consequences of acromegaly at the level of shoulder, knee and foot. Radiographs show thickening of the interarticular spaces (white stars), osteophytes (black arrows), bone proliferation at the attachment sites of tendons and ligaments (black stars), periarticular calcium deposition (white diamond), and exostosis of the bone surface (white arrow).
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Ulnar nerve neuropathy at the cubital tunnel is also frequent in patients with acromegaly (Tagliafico et al., 2008b) and improves with treatment of acromegaly.
Cardiovascular manifestations ARTERIAL HYPERTENSION Hypertension occurs in 20–50% of patients. Its prevalence increases with time after the onset of acromegaly, as well as with the GH level and age. It is at least partly due to chronic hypervolemia (the plasma volume is 10–40% above normal, owing to increased renal sodium reabsorption at the distal tubule level) (Chanson et al., 1990). Body fluid expansion is related to enhanced epithelial sodium channel (ENaC) activity (Kamenicky et al., 2008, 2011, 2014). Hypertension can also result from endothelial dysfunction (Maison et al., 2000). Neither renin–angiotensin–aldosterone nor sympathetic systems seem to be involved in the pathogenesis of hypertension in this setting. Insulin resistance and diabetes may also play a role in the onset of hypertension (Colao et al., 2000; Jaffrain-Rea et al., 2001). Sleep apnea syndrome is likely to contribute to the pathogenesis of hypertension.
SPECIFIC CARDIOMYOPATHY Cardiac disorders are a consistent feature. Many lines of evidence, especially from experimental studies, point to the existence of specific cardiac disorders in acromegaly, independently of coronary involvement (found in only a minority of patients nowadays) and valve disorders (Sacca et al., 1994; Clayton, 2003; Colao et al., 2004). Initially the cardiac involvement is asymptomatic (at least at rest), and consists mainly of myocardial hypertrophy (of the interventricular septum and left ventricular posterior wall), as assessed by echocardiography or magnetic resonance imaging (MRI) (Fig. 14.3), but the dimensions of the left ventricle are normal (concentric hypertrophy). Myocardial hypertrophy can occur in the absence of hypertension and even in young patients (
Chapter 14
Acromegaly PHILIPPE CHANSON1,2,3,*, SYLVIE SALENAVE1, AND PETER KAMENICKY1,2,3 Department of Endocrinology and Disorders of Reproduction, Hoˆpital Bictre and Reference Center for Rare Endocrine Disorders of Growth, Le Kremlin-Bictre, Paris, France
1
2
Faculty of Medicine, Universit Paris-Sud 11, Le Kremlin-Bictre, Paris, France 3
INSERM U693, Le Kremlin-Bictre, Paris, France
INTRODUCTION
PATHOPHYSIOLOGY
Acromegaly is a rare disease characterized by progressive somatic disfigurement, mainly involving the face and extremities, together with systemic manifestations related to organ overgrowth. Acromegaly is associated with severe comorbidity and premature death if not adequately treated. It is due to excessive secretion of growth hormone (GH), originating from a pituitary adenoma in the vast majority of cases.
Acromegaly related to a pituitary tumor
EPIDEMIOLOGY The prevalence of acromegaly was long estimated to be about 40–70 cases per million inhabitants (Holdaway and Rajasoorya, 1999), but recent studies have suggested that it may be much higher: around 80–130 cases per million in Belgium or the UK, for example (Daly et al., 2006; Fernandez et al., 2010). A prevalence of around 1000 per million inhabitants was found in a German study based on screening with IGF-1 measurement in the general population (Schneider et al., 2008). In a recent Finnish study the adjusted annual incidence of acromegaly was estimated to be 3.4 cases per million (Raappana et al., 2010). These new data need to be confirmed. Owing to the insidious clinical onset, acromegaly is often diagnosed late. Older series, in the 1980s, suggested a mean diagnostic delay of 6–10 years after onset, at an average age of about 40 years (Nabarro, 1987; Ezzat et al., 1994; Melmed, 2002). More recent retrospective studies suggest that this interval has fallen to around 3–5 years on average (Nachtigall et al., 2008; Reid et al., 2010).
In more than 95% of cases, acromegaly is secondary to GH hypersecretion by a benign monoclonal pituitary adenoma which develops from somatotroph cells (Asa et al., 2002; Heaney and Melmed, 2004; Melmed, 2009, 2011; Dworakowska et al., 2011).
SOMATOTROPH PITUITARY ADENOMAS Pure somatotroph pituitary adenomas (60%) contain either cells rich in secretory granules that show diffuse immunostaining or cells poor in secretory granules with scattered immunolabeling (Asa et al., 2002). Some of these pure somatotroph adenomas also express free a subunits shared by several glycoprotein hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and chorionic gonadotropin hormone (CG), co-localized in the same cells or even in the same granules as GH (Beck-Peccoz et al., 1985). Mixed GH- and prolactin (PRL)-secreting adenomas are frequent (25%). Some adenomas contain both cell types, while other develop from a mammosomatotropic stem cell and consist of more mature monomorphic cells that express both GH and PRL (Asa et al., 2002). Mixed GH- and TSH-secreting adenomas are rare and cause acromegaly associated with hyperthyroidism and inappropriate TSH secretion (Beck-Peccoz et al., 1996; Socin et al., 2003). Very rarely, corticotrophin (ACTH) hypersecretion may also be found.
*Correspondence to: Prof. Philippe Chanson, Assistance Publique-Hoˆpitaux de Paris, Hoˆpital BiceˆtreService d’Endocrinologie et des Maladies de la Reproduction, 78 rue du Ge´ne´ral Leclerc, F-94275 Le Kremlin-Biceˆtre, France. Tel: þ33-1-45213708, Fax: þ33-145212212, E-mail: [email protected]
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The pituitary versus hypothalamic origin of pituitary somatotroph adenomas is controversial (Melmed, 2006, 2009). Evidence pointing to a hypothalamic origin suggests that the main actor is growth hormone-releasing hormone (GHRH), which can cause not only hyperplasia of somatotroph cells but also, as demonstrated in animal models, true adenomas (albeit such adenomas have never been observed in humans). In contrast, the monoclonal nature of these tumors and the absence of relapse after total adenoma removal point instead to a pituitary origin (Melmed, 2002). In fact, the initiation and/or progression of neoplastic transformation of normal somatotrophs could be due to a polyclonal hyperplastic response of these cells secondary to hypothalamic dysregulation. The prerequisite for an abnormal response to pathologic GHRH secretion may be the existence of a mutation in somatotroph cells. Most human somatotroph adenomas seem to be associated with clonal expansion (Herman et al., 1990) of cells bearing a somatic mutation. However, as in other types of pituitary adenoma, it has proved difficult to isolate a single causative factor in sporadic pituitary tumorigenesis (Lytras and Tolis, 2006; Horvath and Stratakis, 2008; Melmed, 2009). A mutated Gsa protein has been identified in up to 40% of somatotroph adenomas. Mutations at two critical sites (gsp mutations) inhibit GTPase activity and lead to constitutive adenyl cyclase activation (Vallar et al., 1987). Cell-cycle disruption also seems to play an important role (Melmed, 2009), as demonstrated in MEN1 or in patients with mutations of CDKN1B which encodes the cyclin-dependent kinase inhibitor p27KIP1, an atypical tumor suppressor playing a key role in cell-cycle regulation, cell proliferation, and differentiation. Overexpression of HMGA2, a nuclear architectural protein (De Martino et al., 2009), and an activating gene (PTTG, pituitary tumor transforming gene), also play a role. This latter gene (a securin homolog) is overexpressed in functional pituitary tumors, and this could lead to aneuploidy (Vlotides et al., 2007); the degree of overexpression correlates with tumor size and invasiveness (Filippella et al., 2006). Premature senescence likely explains the persistence of a benign phenotype and the rarity of progression to carcinoma. Epigenetic mechanisms may also contribute to cell proliferation by silencing genes such as CDKN2A, which encodes p16, a CDK inhibitor that inhibits cell proliferation. Finally, even if it is clear that somatotroph cells are altered in somatotroph adenomas, the sequence of events leading to their clonal expansion seems to be multifactorial. An activated oncogene may be necessary to initiate tumorigenesis, while promotion of cell growth may require GHRH or other growth factors such as bFGF (basic fibroblast growth factor) (Asa and Ezzat, 2002; Melmed, 2003).
GROWTH HORMONE-SECRETING CARCINOMAS The large majority of these somatotroph adenomas are benign. Pituitary carcinomas are exceptional (fewer than 20 published cases) and the presence of distant metastases is generally required to support the diagnosis of malignancy (review in Chanson et al., 2009a).
GENETIC SYNDROMES ASSOCIATED WITH ACROMEGALY Syndromes associated with acromegaly have been recently reviewed (see Chanson et al., 2009a; Daly et al., 2009; Dworakowska et al., 2011; Gadelha et al., 2013). McCune–Albright syndrome, which is associated with multiple fibrous bone dysplasia, precocious puberty and cafe´-au-lait spots, can be accompanied by acromegaly. This syndrome is related to a somatic mutation that activates the a subunit of Gs protein (Chanson et al., 2007; Collins et al., 2012). More than 20% of these patients develop acromegaly (Chanson et al., 2007; Collins et al., 2012; Vortmeyer et al., 2012). Acromegaly can also be associated with hyperparathyroidism, neuroendocrine tumors (e.g., gastrinoma, insulinoma, or a nonfunctional pancreatic tumor), adrenal and other endocrine or nonendocrine tumors in patients with multiple endocrine neoplasia (MEN) type 1, which is generally related to a germline mutation of the MEN1 gene encoding menin (Verges et al., 2002; Thakker et al., 2012). Mutations in CDKN1B are responsible for a very rare MEN syndrome, MEN type 4, which combines hyperparathyroidism, pituitary adenomas (including acromegaly), and other endocrine or nonendocrine neoplasia (Pellegata et al., 2006; Georgitsi, 2010). When acromegaly is associated with bilateral pigmented micronodular adrenal hyperplasia (causing ACTHindependent hypercorticism) and with cutaneous lesions or cardiac myxomas, the patient should be screened for the Carney complex, which is often related to a germline mutation of the regulatory 1-a subunit of protein kinase A (PRKAR1A) (Kirschner et al., 2000; Bertherat, 2006). Recently, familial acromegaly related to germline mutations of the AIP (aryl hydrocarbon receptor interacting protein) gene was described (Vierimaa et al., 2006; Chahal et al., 2011; Beckers et al., 2013). These mutations can also, albeit rarely, be found in some apparently sporadic cases of acromegaly, particularly in young patients (Barlier et al., 2007; Cazabat et al., 2007, 2011, 2012; Daly et al., 2007).
Extrapituitary acromegaly This topic has been recently reviewed by Chanson et al. (2009a).
ACROMEGALY Acromegaly can also be due to eutopic hypothalamic GHRH hypersecretion (gangliocytoma, hamartoma, choristoma, glioma, etc.) or, more often, to ectopic, peripheral GHRH hypersecretion (pancreatic or bronchial carcinoid tumor) that stimulates normal somatotrophs to become hyperplastic and to hypersecrete GH (Gola et al., 2006; Biermasz et al., 2007; Garby et al., 2012). The diagnosis is based on plasma GHRH assay (revealing excess secretion) and on identification of the GHRH-secreting endocrine tumor (Thorner et al., 1982). The prognosis is generally good (Garby et al., 2012). GH can also be hypersecreted by an ectopic pituitary adenoma (sphenoidal sinus, petrous temporal bone, nasopharyngeal cavity) or, in exceptional cases, by a peripheral tumor (pancreatic islet tumor or lymphoma) (Melmed et al., 1985; Beuschlein et al., 2000).
SIGNS AND SYMPTOMS Acromegaly is generally suspected on clinical signs and symptoms which are important to recognize (Molitch, 1992; Melmed, 2002; Giustina et al., 2003; Colao et al., 2004; Chanson and Salenave, 2008; Nachtigall et al., 2008; Melmed et al., 2009; Reid et al., 2010; RibeiroOliveira and Barkan, 2012).
199
The dysmorphic syndrome The extremities (hands and feet) are broadened, the fingers are widened, thickened and stubby, and the soft tissues are thickened. The patient may have had to enlarge his or her ring in recent years, or to change shoe size. The facial aspect is characteristic, and patients with established acromegaly are generally alike in this respect: the nose is widened and thickened, the cheekbones are prominent, the forehead bulges, the lips are thick and the facial lines are marked (Fig. 14.1). The forehead and overlying skin are thickened, sometimes leading to frontal bossing. There is a tendency towards mandibular overgrowth with prognathism, maxillary widening, teeth separation, and jaw malocclusion. Photographs show a slow, insidious transformation over several years (Fig. 14.1). As a result, the diagnosis is often raised by a doctor who has never seen the patient before. Deformations can also affect the rest of the skeleton, and dorsal kyphosis with distortion of rib cage may be observed in severe chronic forms, leading to the classic “Punchinello” aspect, especially when GH hypersecretion begins prior to closure of the epiphyses. Acral changes are the most common problem leading to diagnosis, which is made by a general practitioner in the
Fig. 14.1. Series of photographs of a patient with acromegaly showing the progressive changes in facial appearance. It is possible to assume that the disease began between 1988 and 1990, 12 years before the diagnosis, made in 2011. In 1990, the patient had to cut the ring that she bought in 1988 because it was too narrow.
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majority of cases (Nachtigall et al., 2008; Reid et al., 2010). However, most patients complain of a delay in diagnosis, despite clear signs and symptoms: this is because many physicians are unaware of this disease, having never encountered such a patient during their training or practice (Danzig, 2007). In our experience it is not uncommon that a patient makes the diagnosis himself by searching the Internet.
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Symptoms
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Acromegaly can cause a variety of symptoms, such as headache (whether the pituitary adenoma is large or small): this is the second initial complaint leading to diagnosis of acromegaly) (Nachtigall et al., 2008); malodorous sweating (especially at night); acroparesthesia (carpal tunnel syndrome); and joint pain. A gradual deepening of the voice is also observed.
Skin changes Nearly 70% of patients have sweaty, oily skin. Skin thickening is due to glycosaminoglycan deposition and to increased collagen production by connective tissue. Skin tags are frequent and may be a marker of colonic polyps. Raynaud’s disease is present in one-third of cases.
Bone changes CRANIOFACIAL In response to both GH and IGF-1, new periosteal bone formation leads to an increase in skeletal growth, especially at the level of the mandible (prognathism). Jaw thickening, teeth separation, frontal bossing, malocclusion, and nasal bone hypertrophy are the standard facial bony deformities in acromegaly. Radiography shows a thickening of the cranial vault and protuberances, frontal internal hyperostosis, and condensation of the walls of the sella turcica with clinoid hypertrophy. Hypertrophy of the sinuses, especially the frontal sinuses, is also clearly visible. This, along with laryngeal hypertrophy, explains why the voice tends to become deeper and acquires a sonorous resonance.
EXTREMITIES These changes are not only due to soft tissue hypertrophy and excessive growth of bone and cartilage but also to bone deformation. Indeed, radiographic findings are abnormal in half these patients, showing distal tufting of the phalanges, widening of the base of the phalanges with osteophyte formation, enthesopathy (mineralization of ligamentous insertions), widening of the diaphysis in cortical bone, and widening of joint spaces due to cartilage hypertrophy.
Bony deformation also affects the spine, with upper dorsal kyphosis and compensatory lumbar hyperlordosis. Vertebral enlargement, widened intervertebral spaces and osteophyte formation are also observed. The thorax is deformed by protuberance of the lower portion of the sternum, and by elongation and divergence of the ribs, due to overgrowth of the chondrocostal joints.
Imaging studies show diaphyseal cortical thickening of the long bones and widened joint spaces, sometimes with osteophytes.
BONE MINERAL DENSITY Bone remodeling is stimulated in acromegaly (Ueland et al., 2006; Giustina et al., 2008). Cortical bone thickens (as measured by the metacarpal index and histomorphometric parameters) and its porosity is diminished. Trabecular bone mass may be decreased, normal, or increased. Measurement of spinal bone mass can give contradictory results, probably because acromegaly is often associated with other endocrine disorders that interfere with bone mass. In general, bone mass is normal in the lumbar spine in patients with isolated acromegaly but is decreased in patients with associated hypogonadism, as is also generally the case in patients with hypogonadism, whatever its cause. In a recent study (Mazziotti et al., 2008), although bone mineral density (BMD) was not significantly different between acromegalic patients and control subjects, the prevalence of vertebral fractures was higher in acromegalic patients (57.5% versus 22.6%). Fractures were associated with higher serum IGF-1 values, a longer duration of active disease, and a longer history of untreated hypogonadism. This higher prevalence of vertebral fractures persists despite biochemical control of acromegaly (Claessen et al., 2013a).
Rheumatologic complications PERIPHERAL ARTHROPATHY This topic has been reviewed in detail by Liote and Orcel (2000) and Kropf et al. (2013). Peripheral joint symptoms are very frequent. Arthralgia and myalgia occur in 30–70% of patients. All the joints can be affected, especially the large joints (knees, shoulders, hands, wrists, and hips). Acromegalic arthropathy develops within an average of 10 years after diagnosis. The arthralgia is mainly mechanical, degenerative, and noninflammatory in origin, but features of osteoarthritis may develop in some patients. Joint mobility (especially of the shoulders) can be limited in the later
ACROMEGALY stages of the disease. Joint effusion is rare and synovial aspiration shows a generally degenerative picture with no evidence of inflammation; it may also reveal calcium microcrystals (associated chrondrocalcinosis). Physical examination of the joints often provides little information. The abnormalities are generally minor despite subjective functional discomfort. The shoulders and hips may show a loss of mobility and function. In contrast, some patients have joint hyperlaxity. There is no correlation between the presence (or severity) of arthropathy and the age of onset of acromegaly, or the mean GH or IGF-1 concentration at baseline or during follow-up. Arthropathy appears to be more frequent after age 45 years. Radiologic studies show a widening of the joint spaces, reflecting hypertrophy of the hyaline cartilage, as well as the presence of osteophytes, bone proliferation at the attachment sites of tendons and ligaments, periarticular calcium deposition, and exostosis of the bone surface (Fig. 14.2). The joint space subsequently diminishes due to destructive arthropathy. Sonography shows a thickening of the cartilage in the shoulder, wrist and knee joints, which improves during treatment for acromegaly. The arthropathy progresses inexorably in advanced stages and unpredictably in minor forms. It is not influenced by successful treatment of acromegaly, with the exception of diffuse articular symptoms and some sites of pain (Wassenaar et al., 2009). It considerably impairs patients’ quality of life (Miller et al., 2008; Claessen et al., 2013b).
SPINAL INVOLVEMENT The estimated prevalence of spinal involvement is about 40–50% (Scarpa et al., 2004). Backache is more frequent at the level of the lumbar spine than the cervical or dorsal spine. The pain is mainly mechanical in nature, but inflammatory features can occur (16%). Spinal
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involvement may be accompanied by nerve compression. Occasionally, bilateral intermittent claudication reveals lumbar spinal stenosis. Pain may also be related to increased prevalence of vertebral fractures despite normal BMD (Mazziotti et al., 2008; Wassenaar et al., 2011). Radiologic examination shows typical features, including ossification of the anterior and lateral surfaces of the vertebral bodies, contributing to enlargement of their anteroposterior diameter, as well as a biconcave vertebral aspect and scalloping of the vertebral bodies (exaggerated concavity of the posterior vertebral wall). The mechanism is poorly understood but may involve hypertrophy of the intraspinal soft tissues (ligamentous hypertrophy, epidural lipomatosis) or bone. In more severe cases, ossification of the anterior surface of the vertebral bodies can bridge the disc space and give an aspect of diffuse idiopathic skeletal hyperostosis.
Neuropathies Symptomatic carpal tunnel syndrome is frequent. Nerve conduction studies have shown that the vast majority of acromegalic patients have subclinical abnormalities of nerve conduction. Magnetic resonance imaging (MRI) shows a higher amplitude and intensity of the median nerve signal in patients with symptomatic carpal tunnel syndrome compared to asymptomatic patients (Jenkins et al., 2000). The mechanism appears to involve median nerve edema more than extrinsic compression due to an excess of connective tissue, bone, or synovial hypertrophy, or an increase in extracellular fluid within the carpal tunnel itself with Schwann cell demyelination. The nerve edema, which can easily be evaluated with ultrasonography (Tagliafico et al., 2008a), improves when GH and IGF-1 levels fall, suggesting that hormonal control is a key prerequisite for improving these patients’ neurologic status. Sometimes, however, the carpal tunnel syndrome persists.
Fig. 14.2. Osteoarticular consequences of acromegaly at the level of shoulder, knee and foot. Radiographs show thickening of the interarticular spaces (white stars), osteophytes (black arrows), bone proliferation at the attachment sites of tendons and ligaments (black stars), periarticular calcium deposition (white diamond), and exostosis of the bone surface (white arrow).
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Ulnar nerve neuropathy at the cubital tunnel is also frequent in patients with acromegaly (Tagliafico et al., 2008b) and improves with treatment of acromegaly.
Cardiovascular manifestations ARTERIAL HYPERTENSION Hypertension occurs in 20–50% of patients. Its prevalence increases with time after the onset of acromegaly, as well as with the GH level and age. It is at least partly due to chronic hypervolemia (the plasma volume is 10–40% above normal, owing to increased renal sodium reabsorption at the distal tubule level) (Chanson et al., 1990). Body fluid expansion is related to enhanced epithelial sodium channel (ENaC) activity (Kamenicky et al., 2008, 2011, 2014). Hypertension can also result from endothelial dysfunction (Maison et al., 2000). Neither renin–angiotensin–aldosterone nor sympathetic systems seem to be involved in the pathogenesis of hypertension in this setting. Insulin resistance and diabetes may also play a role in the onset of hypertension (Colao et al., 2000; Jaffrain-Rea et al., 2001). Sleep apnea syndrome is likely to contribute to the pathogenesis of hypertension.
SPECIFIC CARDIOMYOPATHY Cardiac disorders are a consistent feature. Many lines of evidence, especially from experimental studies, point to the existence of specific cardiac disorders in acromegaly, independently of coronary involvement (found in only a minority of patients nowadays) and valve disorders (Sacca et al., 1994; Clayton, 2003; Colao et al., 2004). Initially the cardiac involvement is asymptomatic (at least at rest), and consists mainly of myocardial hypertrophy (of the interventricular septum and left ventricular posterior wall), as assessed by echocardiography or magnetic resonance imaging (MRI) (Fig. 14.3), but the dimensions of the left ventricle are normal (concentric hypertrophy). Myocardial hypertrophy can occur in the absence of hypertension and even in young patients (
