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GHRH/GH/IGF-1 axis controls somatic growth. Regulation is complex, and nutrition status and feeding pattern have a recognized role. Like systemic inflammation or chronic liver disease, fasting and malnutrition decrease the expression of hepatic GH receptors, with consequent reduction of IGF-1 levels, through resistance to GH. This clinical report shows that caloric restriction may represent a pitfall in acromegaly follow-up.
Acromegaly is a rare systemic disease caused by pathologic secretion of growth hormone (GH) and Insulin-like growth factor (IGF1). Recent population studies, mainly from Europe, estimate a prevalence of acromegaly between 2.8 and 13.7 cases per 100 000 people, similar between males and females in the majority of the studies. The annual incidence was estimated of 0.2 to 1.1 cases per 100 000/year [1, 2]. Patients were diagnosed in the median age that varied between 40.5 and 47 years [1].
In 2014 the Endocrine Society published evidence-based guidelines focusing diagnosis, treatment and follow up of acromegaly [3]. These guidelines focus the determination of serum IGF-1 to rule out acromegaly in patients with suspicious clinical features, coexistence of several associated conditions/complications of acromegaly and/or in the diagnosis of a pituitary mass [3]. A cornerstone role is also posed in IGF-1 serum levels to monitor response to therapy and to define persistent vs controlled or cured acromegaly. However several conditions may interfere with IGF-1 determination, conditioning false positive and false negative results.
Three and a half months later her IGF-1 levels were normal (0.57 times the ULRR), in June 2011. Four months later she got pregnant. During pregnancy IGF-1 determinations were in the reference range, however, two months after labor, acromegaly recurred (IGF-1 1.5 times the ULRR), while breastfeeding. Sellar MNR suggested the presence of small residual tissue of the previous macroadenoma. Radiosurgery was proposed, however, patient expressed the desire of get pregnant again, what occurred 3 years later.
Although biggest country registries mainly from Europe show that medical therapies have gained space over the last years in the treatment of acromegaly (mainly for macroadenomas and invasive adenomas), even as first line therapy [2, 6,7,8,9], surgery still represents the best chance for cure. Concordantly, international guidelines and recommendations emphasize transsphenoidal surgery as the first line treatment of acromegaly [3, 10,11,12].
More recently, Caputo M. et al. [22], reviewed dietary nutrients and patterns impact on regulation of GH and IGF-I. Regarding acromegaly, they conclude that a) eucaloric very-low-carbohydrate ketogenic diet, b) periodical or prolonged regimens of caloric restriction, c) Okinawa diet (poor in proteins and rich in carbohydrates) and d) modified diets poor in leucine, valine and isoleucine, may favor acromegaly control. In the clinical setting, Coopmans et al. [23] published in 2020 a pivotal study focusing the impact of an eucaloric very-low-carbohydrate ketogenic diet (35 g of carbohydrate per day) as adjuvant to medical treatment in acromegaly. 11 patients with active disease under first-generation somatostatin receptor ligands were followed for 2-weeks. The authors aimed to reduce IGF-I synthesis following the down-regulation of hepatic growth hormone receptors through induction of ketosis and reduction of portal insulin concentrations. During the diet IGF-I concentration significantly decreased from 1.10 to 0.83 times the upper limit of the normal range, normalizing in all but one patient. Growth hormone did not increase during the two weeks. In half of the patients who maintained this diet after the study, dose reduction of somatostatin receptor ligand was possible [23].
Similarly, in the clinical case we describe, reduced IGF1 values and increased GH were observed during extreme caloric restriction. Then, when an eucaloric diet was introduced, IGF1 values increased above the reference range, while GH values remained elevated, albeit to a lesser extent. Relevant is the fact that, although the IGF1 values decreased during the relatively long period of caloric restriction (intermittent fasting and periods of severe restriction), no improvement was observed in relation to the clinical and phenotypic characteristics of acromegaly.
The extremities (hands and feet) are broadened, the fingers are widened, thickened and stubby, and the soft tissue is thickened (Figure 1). 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 obvious, the forehead bulges, the lips are thick and the facial lines are marked (Figure 2). The forehead and overlying skin is 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. The diagnosis is often raised by a doctor who has never seen the patient before. The deformations can also affect the rest of the skeleton and, in severe chronic forms, dorsal kyphosis with deformation of rib cage may be observed, leading to the classical \"punchinello\" aspect, especially when GH hypersecretion begins prior to closure of the epiphyses.
Facial aspect of a patient with acromegaly. The nose is widened and thickened, the cheekbones are obvious, the forehead bulges, the lips are thick and the facial lines are marked. The forehead and overlying skin is thickened, sometimes leading to frontal bossing.
In response to both GH and IGF-I, periosteal new 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 usual facial bony deformities seen in acromegaly (Figure 3).
Radiography shows a thickening of the cranial vault and protuberances, frontal internal hyperostosis, 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 in acromegaly tends to become deeper and has a sonorous resonance.
Bone remodeling is stimulated in acromegaly. Cortical bone thickens (as measured by the metacarpal index and histomorphometric parameters) and its porosity is diminished. The 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 [12], as it is generally the case for hypogonadism whatever its cause. Vertebral compression is rare and is usually due to other causes.
Physical examination of joints often provides little information. The abnormalities are generally minor as compared to the 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-I concentration at baseline or during follow-up. Arthropathy appears to be more frequent after age of 45 years.
Radiological studies show a widening of the joint spaces, reflecting hypertrophy of the hyaline cartilage, the presence of osteophytes, bone proliferation at the attachment sites of tendons and ligaments, periarticular calcium deposit and exostosis of the bone surface. 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 [15].
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.
Hypertension occurs in 20% to 50% of patients. Its prevalence increases with time after the onset of acromegaly, the GH level, and age. It is at least partly due to chronic hypervolemia (the plasma volume is 10% to 40% above normal due to increased renal sodium reabsorption at the distal tubule level) [17, 18]. Hypertension can also result from endothelial dysfunction [19]. Neither renin angiotensin aldosterone nor sympathetic systems seem to be involved in the pathogenesis of hypertension. Insulin resistance and diabetes may also play a role in the onset of hypertension [20, 21]. Sleep apnea syndrome is likely to contribute also to the pathogenesis of hypertension.
Cardiac involvement is a consistent feature of acromegaly. Many lines of evidence, especially from experimental studies, point to the existence of specific cardiac disorders in acromegaly, independently of coronary involvement (found in a minority of patients nowadays) and valve disorders [8, 22, 23].
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, but the dimensions of the left ventricle are normal (concentric hypertrophy). It can occur in the absence of hypertension, and even in young patients (< 30 years), reflecting the role of GH itself on the myocardium. Hypertension further aggravates cardiac hypertrophy. Echocardiography and isotope studies show altered diastolic function (abnormal left and right ventricle filling) related to ab