Porth's Essentials of Pathophysiology, 4e

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Disorders of Endocrine Control of Growth and Metabolism

C h a p t e r 3 2

In addition to its effects on growth, GH increases the rate of protein synthesis by all of the cells of the body, enhances fatty acid mobilization and increases the use of fatty acids for fuel, and maintains or increases blood glucose levels by decreasing the use of glucose for fuel. Growth hormone has an initial effect of increasing insu- lin levels. However, the predominant effect of prolonged GH excess is to increase blood glucose levels despite an insulin increase. This is because GH induces a resistance to insulin in the peripheral tissues, inhibiting the uptake of glucose by muscle and adipose tissues. 2 Many of the effects of GH are mediated by insulin-like growth factors (IGFs), which are produced mainly by the liver. 9 Growth hormone cannot directly produce bone growth; instead, it acts indirectly by causing the liver to produce IGFs. These peptides act on cartilage and bone to promote their growth. Several IGFs have been identified; of these, IGF-1 (previously known as somatomedin C) appears to be the more important in terms of growth, and it is the one that usually is measured in laboratory tests. The IGFs have been sequenced and found to have struc- tures that are similar to those of proinsulin. This undoubt- edly explains the insulin-like activity of the IGFs and the weak action of insulin on growth. Insulin-like growth fac- tor levels are themselves influenced by a family of at least six binding factors called IGF-binding proteins (IGFBPs). Growth hormone is carried unbound in the plasma and has a half-life of approximately 20 to 50 minutes. The secretion of GH is regulated by two hypothalamic hormones: GH-releasing hormone (GHRH), which increases GH release, and somatostatin, which inhib- its GH release. A third hormone, the recently identified ghrelin, also may be important (see Chapter 28). The hypothalamic influences of GHRH and somatostatin are tightly regulated by neural and metabolic influences. The secretion of GH fluctuates over a 24-hour period, with peak levels occurring 1 to 4 hours after onset of sleep. The nocturnal sleep bursts, which account for 70% of daily GH secretion, are greater in children than in adults. Growth hormone secretion is stimulated by hypo- glycemia, fasting, starvation, increased blood levels of amino acids (particularly arginine), and stress conditions such as excitement, emotional stress, heavy exercise, and trauma. Growth hormone is inhibited by increased glu- cose levels, free fatty acid release, cortisol, and obesity. Short Stature in Children Short stature is a condition in which the attained height is well below the third percentile or linear growth is below normal for age and gender. Short stature, or growth retardation, has a variety of causes, includ- ing chromosomal abnormalities such as Turner syn- drome (see Chapter 6), GH deficiency, hypothyroidism, and panhypopituitarism. 9 Other conditions known to cause short stature include protein-calorie malnutri- tion, chronic diseases such as chronic kidney disease and poorly controlled diabetes mellitus, malabsorption syndromes such as celiac disease, and certain thera- pies such as excessive glucocorticoid administration.

Emotional disturbances can lead to functional endocrine disorders, causing psychosocial dwarfism. The causes of short stature are summarized in Chart 32-1. Accurate measurement of height is an extremely important part of the physical examination of children. Completion of the developmental history and growth charts is essential. 10,11 Growth curves and growth velocity studies also are needed. The Centers for Disease Control and Prevention (CDC) growth charts are available at http://www.cdc.gov/growthcharts. Diagnosis of short stature is not made on a single measurement, but is based on sequential height measurements and on veloc- ity of growth and parental height. 9 The diagnostic procedures for short stature include tests to exclude nonendocrine causes. If the cause is hormonal, extensive hormonal testing procedures are initiated. Usually, GH and IGF-1 levels are determined (IGFBP-3 levels also are useful). Tests can be performed using insulin (to inducehypoglycemia),GHRH, levodopa, and arginine, all of which stimulate GH secretion so that GH reserve can be evaluated. 9 Because administra- tion of pharmacologic agents can result in false-negative responses, two or more tests usually are performed. If a prompt rise in GH is realized, the child is considered nor- mal. Physiologic tests of GH reserve (e.g., GH response to exercise) also can be performed. Levels of IGF-1 usu- ally reflect those of GH and may be used to indicate GH deficiency. Radiologic films are used to assess bone age, which most often is delayed. Magnetic resonance imaging of the hypothalamic-pituitary area is recommended if a CHART 32-1  Causes of Short Stature Variants of normal Genetic or “familial” short stature Constitutional growth delay Low birth weight (e.g., intrauterine growth retardation) Functional endocrine disorders (psychosocial dwarfism) Growth hormone (GH) deficiency Primary GH deficiency (idiopathic GH deficiency, pituitary agenesis) Secondary GH deficiency (panhypopituitarism) Biologically inactive GH production Deficient IGF-1 production in response to normal or elevated GH (Laron-type dwarfism) Hypothyroidism Glucocorticoid excess Endogenous (Cushing syndrome) Exogenous (glucocorticoid drug treatment) Abnormal mineral metabolism (e.g., pseudohypoparathyroidism) Diabetes mellitus in poor control Chronic illness and malnutrition (e.g., asthma, especially when treated with glucocorticoids; heart or renal disease)

Malabsorption syndrome (e.g., celiac sprue) Chromosomal disorders (e.g.,Turner syndrome) Skeletal abnormalities (e.g., achondroplasia)