**6. Acromegaly and gigantism**

Acromegaly is a rare disorder resulting from exposure to high levels of GH which is associated with significant morbidity and mortality. The most common cause of acromegaly is pituitary adenomas which may be either pure-GH secreting adenoma (60%) or mixed cell adenoma. In children before epiphyseal plate closure, GH secreting adenoma results in gigantism. It has an annual prevalence of 4 new cases per million inhabitants, with male and female being equally affected [19]. Other rare causes of acromegaly include growth hormone releasing hormone (GHRH) secretion from hypothalamus (e.g. hamartoma or glioma) or ectopic GHRH secreting tumors (e.g. primary bronchial carcinoid or pancreatic cancers).

#### **6.1 Clinical presentation**

The majority of acromegaly cases are due to GH-secreting pituitary adenomas. Similar to other subtypes of pituitary adenomas, GH-secreting adenomas may present with mass effect symptoms and/or with signs and symptoms of the endogenous effect of the over secreted hormone (i.e. GH).

Acromegaly dysmorphic features include enlarged hands and feet, facial bone enlargement that results in frontal bossing, prognathism, maxillary widening with the resultant of teeth separation and jaw malocclusion. The pathophysiology of bone changes is due to GH/IGF-1 effects on the periosteum of bones that results in new bone formation and bone remodeling. In the extremities, these effects will result in osteophyte formation over the digits with cartilage hypertrophy. Radiological hand findings include joint spaces widening, enthesopathy, diaphysis broadening and soft tissue hypertrophy. Due to these changes, two-thirds of patients will have degenerative arthropathy with large joints more commonly affected. In fact, arthropathy is the most common symptom referred by patients with acromegaly on presentation and the leading cause of morbidity. The axial skeleton can be affected by the same mechanism resulting in excessive kyphotic angulation of the thoracic spine with a compensatory hyperlordotic angulation of lumber vertebrae. These factors contribute to the fact that approximately half of these patients have low back pain. Neurogenic claudication is not uncommon due to ligamentum flavum hypertrophy with the resultant spinal canal stenosis. Patients with pure somatotroph pituitary adenoma usually have normal bone mineral density, however, acromegaly patients showed a higher incidence of vertebral compression fractures with high IGF-1 being a significant risk factor [20].

Growth Hormone and insulin like growth factor 1 can also affect visceral organs. Up to 50% of acromegaly patients have hypertension [21, 22]. The underlying cause is multifactorial. Endothelial dysfunction can be caused by GH-induced hyper-reactivity of the sympathetic nervous system [23]. In addition, high levels of GH/IGF-1 increase sodium reabsorption in renal distal tubules which results in chronic water retention/hypervolemia and increased plasma volume (up to 40%) when compared with normal individuals. Another important cause is chronic-sleep-apnea-induced hypertension as 80% of acromegaly patients have obstructive-sleep apnea induced by soft tissue hypertrophy. In addition, hypertrophic cardiomyopathy is commonly found in long standing acromegaly with diastolic dysfunction being the most common cardiac manifestation. Moreover, premature ventricular contractions can be detected in up to 50% of patients. The most common cause of mortality in acromegaly patients is due to cardiac arrhythmias or dysfunction [19].

Acromegaly has deleterious effects on both the upper and lower respiratory systems. Costal bone and subsequently chest wall changes (e.g. barrel chest) are common. Intercostal muscles also are affected by segmental degenerative fibrotic changes resulting weak inspiratory and expiratory efforts [24]. In the upper respiratory tract, acromegaly patients develop macroglossia, narrowing of pharyngeal airway space and thickening of vocal cords. These changes contribute largely to the pathogenesis of obstructive sleep apnea. One third of acromegalic patients with sleep apnea have neurogenic causes due to the effect of GH/IGF-1 on the respiratory center in the brain stem. Total lung capacity is increased in the majority of acromegalic patients due to increased alveolar volume. Narrowing of bronchi and bronchioles lead to obstructive patterns found in approximately 30% of patients, but they rarely have hypoxia due to the absence of ventilation-perfusion mismatch.

In the intestine, increased GH results in an incidence of colon polyps and cancer. Delhougne et al. [25] found in a prospective study that 45% of acromegalic patients had colonic polyps, 24% of them were of the adenomatous type. IGF-1 is unique in that it induces cellular growth and proliferation while also possessing an anti-apoptogenic effect. In 2010, The British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) advised to start screening of acromegaly patients at the age of 40 with colonoscopy, 10 years earlier than the general population. Patients who were found to have adenoma at first screening *or* an increased serum IGF1 level above the maximum of

the age-corrected normal range needed to be screened every 3 years. Patients with normal colonoscopy or non-adenomatous polyp, or normal growth hormone/IGF1 level, should be screened every 5–10 years [26].
