Endocrine and Metabolic Disorders

25 Endocrine and Metabolic Disorders



Endocrine and metabolic disorders affect a large number of children and may be rare (e.g., nephropathic cystinosis) or relatively common (e.g., type 1 and type 2 diabetes mellitus). This chapter begins with an overview of anatomy, physiology, and pathophysiology of the endocrine and metabolic systems and general issues related to assessment and management of these disorders. Following are two sections covering endocrine and metabolic disorders as they are managed by primary care providers in collaboration with specialists. Although there is a great degree of overlap in these disorders, distinctive processes occur in each, and as such, specific conditions may involve different approaches to assessment and management.



image Anatomy and Physiology


The endocrine system regulates growth, pubertal development and reproduction; homeostasis of the individual; and the production, storage, and use of energy. Classically the endocrine system was understood to function via hormones produced in glands with action at a distant site. Now the understanding is that hormones may also act in a paracrine fashion affecting cells adjacent to the hormone-secreting cell or in an autocrine fashion in which the hormone affects the secreting cell by diffusion. Many endocrine glands are controlled by the hypothalamic-pituitary axis. Many of the hormones of the hypothalamic-pituitary axis (or molecules that are structurally similar to such hormones) are also made in the gut and other tissues.


Hormones are often activated by a feedback loop; for example, thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates pituitary thyrotropin (TSH) secretion, which in turn stimulates thyroid hormone production (T3 [triiodothyronine] and T4 [thyroxine]). Thyroid hormone levels provide feedback to the hypothalamus and pituitary thereby suppressing TRH and TSH secretion so that a balance is reached. In similar fashion, the adrenal glands secrete corticosteroids and the gonads produce progesterone, androgens, and estradiol, all of which influence hypothalamic and pituitary hormone production. For some systems, the set-point changes as individuals develop. Hormone secretion can be regulated by nerve cells and by factors important in the immune system (e.g., cytokines interact with hormones that influence weight homeostasis).


Metabolic function in the body involves complex biochemical processes to transform essential amino acids, carbohydrates, and lipids to substances or energy that can be used at the cellular level; to produce molecules; and to perform cell functions. These biochemical processes or metabolic pathways are driven by enzyme activity.




image Assessment


Endocrine and metabolic disorders disrupt organs throughout the body and can alter various body functions. Assessment requires a thorough family history, physical examination, and specific diagnostic testing for the suspected disorder.




Physical Examination


A detailed examination should include the following:



Measure stature. Supine length is preferred for children younger than 2 years old. Use a stadiometer for children older than 2 or 3 years. Plot height, weight, and head circumference on a standardized growth chart appropriate to the child’s age and gender. In addition, growth charts are available for children with certain genetic conditions, such as Down and Turner syndromes, and should be used to assess growth patterns of children with these conditions (see Appendix B). Serial measurements are critical to assess growth patterns over time.


Check for proportionate appearance. Measure sitting and standing heights for upper to lower segment ratio (see Chapter 32).


Assess height age (the age corresponding to the child’s height when plotted at the 50th percentile on a growth chart) and growth velocity (linear growth in centimeters or inches over the past year).


Inspect the child’s genitalia for signs of either normal or ambiguous genitalia.


Identify the stage of sexual development using Tanner staging (see Chapter 8).


Note facial, axillary, and pubic hair for presence, distribution, and texture.


Examine the skin for presence of striae and acanthosis nigricans (see Color Plate) of the neck, axilla, breast, knuckles, and skinfolds.


Palpate the neck for thyroid gland symmetry and size, noting enlargement or presence of nodules.


Examine for presence of dysmorphic features.


Examine the abdomen noting any organomegaly.


Complete general neurologic examination.


Acquired endocrine disorders are often due to either hyposecretion or hypersecretion of a specific hormone or combination of hormones, and the child may or may not appear ill. Signs of dehydration, exophthalmos, and tachycardia are physical findings associated with endocrine pathology. Newborns with metabolic disorders may initially appear well, but physical signs develop with metabolic activity. Characteristic physical findings associated with specific disease entities are presented later in this chapter.




image Management Strategies









image Growth Disorders


Children grow in a predictable way, and deviation from a normal growth pattern can be the first sign of an endocrine disorder. Every effort should be made to collect serial growth data so that a pattern of growth can be assessed and current growth velocity determined. Care must be taken to obtain accurate supine (for children under 2 or 3 years old) or standing measurements and to plot the child’s length or height on the appropriate growth chart (see Appendix B). A child’s predicted growth potential is based in large part on genetic potential and may change with altered nutritional status and illness patterns. An estimate of the expected stature (±2 standard deviations where 1 standard deviation equals 2 inches [4.5 cm]) for a particular child can be made by calculating a midparental target height:



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Growth disorders may be classified as primary or secondary. Primary growth disorders include skeletal dysplasias, chromosomal abnormalities (e.g., Turner syndrome), and genetic short stature. Secondary growth disorders may result from undernutrition, chronic disease, endocrine disorder, and idiopathic (constitutional) growth delay [CGD]) (Box 25-1). The following discussion focuses on growth hormone deficiency (GHD) and CGD (Table 25-1).





Growth Hormone Deficiency





Clinical Findings


Findings that suggest a GHD include hypoglycemia, deficiencies of other pituitary hormones, presence of midline defects, history of treatment with cranial radiation, and low serum levels of insulin-like growth factor 1 (IGF-1) or insulin-like growth factor binding protein 3 (IGFBP-3).







Management


Children should be referred to a pediatric endocrinologist if hypothyroidism, low IGF-1 and IGFBP-3 or other hormone deficiency is confirmed, or for unexplained persistent slow growth without evidence of chronic illness. The U.S. Food and Drug Administration (FDA) has approved a number of indications for GH therapy (Box 25-3) (Schwenk, 2006). GH dosing is based on a child’s body weight with doses ranging from 0.15 to 0.30 mg/kg/wk. Response to GH therapy is greater for children receiving daily injections compared with those receiving three injections per week. During the first year of therapy, growth velocity may exceed normal growth rates as much as fourfold. Reported side effects of GH include glucose intolerance, pseudotumor cerebri, edema, growth of nevi, slipped capital femoral epiphyses, and scoliosis (Schwenk, 2006). The cost of GH therapy may present an economic burden to the family and referral to a social worker to assist in finding financial support may be appropriate.






image Pubertal Disorders


The physical changes of puberty occur in response to production of sex steroids by the ovaries or testes (see Chapter 8). Hypothalamic gonadotropin-releasing hormone (GnRH) regulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn stimulates gonadal hormone secretion.


By midgestation the fetal hypothalamic-pituitary-gonadal axis is intact; at term, the production of GnRH, LH, and FSH in this system is low. When placental and maternal hormones are removed at delivery, unrestrained production of these hormones occurs in the newborn, and the infant experiences a “mini puberty” between 2 weeks and 3 months of postnatal life. After infancy the hypothalamic GnRH pulse generator is more sensitive to feedback inhibition from the brain, and by 1 year of age, LH and FSH decrease to the prepubertal range, and the child enters a “latency” period that continues until puberty. Puberty occurs when the feedback inhibition is released and GnRH is again produced (Greiner and Kerrigan, 2006; Nathan and Palmert, 2005). The timing of the release correlates better with bone age than chronologic age.


The initiation of puberty in girls is earlier now compared with past decades and varies by race and ethnicity. A large epidemiologic study using data from 1300 girls who participated in the third National Health and Nutrition Examination Survey (NHANES) demonstrated that Tanner stage 2 breast development was present in less than 5% of non-Hispanic Caucasian girls with normal body mass index (BMI) by the age of 8 years; however, thelarche (breast bud development) is a normal finding in non-Hispanic black and Mexican-American girls before 8 years of age. Although girls are starting puberty at a younger age than in past generations, the timing of menarche and reaching Tanner stage 5 have not changed dramatically (Rosenfield et al, 2009). Menarche typically occurs within 3 years from the start of breast development; 95% of girls will have signs of puberty by the age of 12 years and achieve menarche by the age of 14 years. Boys normally begin puberty from age 9 to 14 years. The first sign of puberty is increased testicular volume in 85% of boys. Clinicians should be concerned when puberty presents early or is delayed.




Precocious Puberty





Clinical Findings


Children who present with features of puberty at a younger age than normal should have an evaluation as to the etiology. Children who start to develop signs of puberty at the early end of the normal range should be evaluated if they have rapid progression of pubertal signs resulting in a bone age more than 2 years ahead of chronologic age, or new CNS-related findings (e.g., headaches, seizures, focal neurologic defects) (Kaplowitz, 2009).







Delayed Puberty







image Adrenal Disorders



Anatomy and Physiology


Adrenal gland steroid production is under the control of the hypothalamic-pituitary axis. The hypothalamus secretes corticotropin-releasing hormone (CRH) in a pulsatile fashion, which stimulates production and secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland. ACTH regulates adrenal glucocorticoid (cortisol) and androgen production. Cortisol is produced in a series of enzymatic steps (Fig. 25-1) and is highest in the morning, low in the afternoon and evening, and lowest at midnight. Secreted in response to hypoglycemia, hypotension, pain, or other stressful events, cortisol has negative feedback on the synthesis and secretion of CRH, vasopressin, and ACTH.



The adrenal gland also produces mineralocorticoid hormones (aldosterone), regulated by renal production of renin interacting with angiotensinogen to create angiotensin. The renin-angiotensin system is involved in regulation of salts, especially sodium; blood pressure; and renal blood flow. Aldosterone production also occurs in enzymatic steps, many of which are common to the cortisol production pathway.



Adrenal Insufficiency




Epidemiology


Primary adrenal insufficiency may be due to an inability to produce cortisol secondary to an enzyme defect in the adrenal steroid pathway (CAH), hypoplasia of the adrenal gland, or an acquired defect (Box 25-7). Lesions of the hypothalamus or pituitary lead to secondary adrenal insufficiency. Suppression of the hypothalamic-pituitary-adrenal axis secondary to steroid use can also lead to adrenal insufficiency. Infants born extremely prematurely (24 to 28 weeks’ gestation) sometimes demonstrate symptoms of adrenal insufficiency because of immaturity of the hypothalamic-pituitary-adrenal axis.



Secondary adrenal insufficiency can occur as a result of ACTH deficiency, as one of multiple hypothalamic-pituitary deficiencies, or rarely as an isolated problem. Most often the infant or child has a syndrome known to be associated with hypopituitarism (for example septo-optic dysplasia), has also been discovered to have GHD, or has a destructive lesion (e.g., tumor or radiation to the brain) or prior CNS trauma.


CAH is caused by a deficiency of any of the enzymes in the cortisol pathway. In addition to interrupting normal cortisol production, the most common enzymatic abnormality, 21-hydroxylase (21-OH) deficiency, causes shunting of cortisol precursors to the androgen pathway resulting in production of elevated levels of adrenal androgens in utero. Female infants born with classic CAH typically have ambiguous genitalia (e.g., enlarged clitoris and/or posterior fusion of the labia) from this excessive androgen exposure in utero. However, male infants have no signs of CAH at birth with the exception of subtle hyperpigmentation and possible mild enlargement of the penis (Antal and Zhou, 2009). About 75% of children with CAH caused by 21-OH deficiency also have aldosterone deficiency. Newborn screening programs now routinely test for the presence of CAH caused by 21-OH deficiency to detect CAH early to avoid a potentially life-threatening salt-wasting crisis in affected infants.




Management


Treatment of adrenal insufficiency includes hormone replacement and is best managed by a pediatric endocrinologist. An adrenal crisis is a medical emergency requiring immediate and vigorous administration of intravenous dextrose, normal saline, and stress doses of hydrocortisone. Intravenous stress doses of hydrocortisone succinate vary with age: 25 mg in children younger than 3 years; 50 mg in children ages 3 to 12 years; and 100 mg in children older than age 12, administered every 6 hours. Parents should be instructed regarding the need for stress doses of hydrocortisone when their child has a febrile illness, surgery, or trauma; they should also be taught how to administer hydrocortisone via intramuscular injection in case the child is vomiting or otherwise unable to swallow or retain oral medication. This injection allows parents extended time to seek further medical advice or intervention.


Long-term therapy of CAH includes oral hydrocortisone in replacement doses of 8 to 10 mg/m2 (8 to 10 mg per square meter of body surface) in children with ACTH deficiency or primary adrenal insufficiency. Children with CAH tend to have higher hydrocortisone needs. If present, aldosterone deficiency must be treated with fludrocortisone acetate. Treatment of CAH requires a fine balancing act to replace steroids, thereby preventing androgen overproduction. Excess steroid intake can lead to delayed growth; not enough steroids contribute to rapid bone age growth and ultimate short stature. Individual treatment plans are essential to meet the specific needs of individual children. The primary care provider should be familiar with the medical endocrinology treatment plan and reinforce it at routine well- and sick-child visits.

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Jul 24, 2016 | Posted by in PEDIATRICS | Comments Off on Endocrine and Metabolic Disorders

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