Chapter 11 Julia Petty The aim of this chapter is to offer a brief overview of the anatomy and physiology of the endocrine system. Altered pathophysiology is outlined and how this can impact on a person’s development, health and wellbeing. The endocrine system is a complex system that controls many vital functions of the body (Hinson, Raven & Chew, 2010; Jameson & De Groot, 2010). This chapter offers an outline of the endocrine system, the glands and hormones that make up this system and the associated pathophysiology when there is disease, injury or malfunction, for whatever reason. A number of endocrine‐related conditions and their allied diagnosis, treatments and care are discussed. The endocrine and nervous systems are responsible for the transmission of vital messages and the regulation of bodily functions. Whereas the nervous system works by transmission of electrical impulses, the endocrine system comprises a collection of ductless, highly vascular glands (Fig. 11.1) that secrete a range of different types of hormone directly into the blood stream. Hormones are then transported to distant target organs or tissues (Molina, 2013) where they take effect. Endocrine glands are controlled directly by stimulation from the nervous system, and by chemical receptors in the blood and hormones produced by other glands (Waugh & Grant, 2010). By regulating the functions of organs in the body, these glands help to maintain the body’s homeostasis. Growth and development, sexual development and control of many internal body functions, such as glucose and mineral regulation, and the stress response, are among the many essential physiological processes regulated by the actions of hormones (Rogers, 2012; Petty, 2015). The anatomy of the endocrine system can be seen in Fig. 11.1. Figure 11.1 The endocrine system. Source: http://commons.wikimedia.org/wiki/File:Illu_endocrine_system.jpg The integrity and health of the endocrine system are essential to maintaining healthy body weight, growth, and physical and emotional development. Damage or disease to the endocrine system therefore can lead to significant consequences for the child or young person. A summary of the endocrine organs, their functions and associated disorders can be seen in Table 11.1. Table 11.1 Overview of the endocrine system, its associated functions and disorders. (For full details of endocrine system function and specific hormones as relevant to children, see Petty, 2015) ACTH, adrenocorticotrophic hormone; ADH, anti‐diuretic hormone; DSD, disorder of sex development; PG, pineal gland; TSH, thyroid‐stimulating hormone. Referring to the systems in Table 11.1, this chapter will now discuss each associated disorder in turn, outlining the pathophysiology, diagnosis and presenting signs along with a brief overview of care and management. For all conditions involving the endocrine system, referral to a paediatric endocrinology team and/or other health professionals, as appropriate, is necessary, for ongoing follow‐up and management. This is a disorder of the hypothalamus caused by damage from malnutrition, including anorexia and other eating disorders, genetic disorders, radiation, surgery, head trauma, lesion, tumour or other physical injury. Damage to the hypothalamus may impact any of the hormones outlined in Table 11.1 and the related endocrine systems. As many of these hypothalamic hormones act on the pituitary gland, hypothalamic disease in turn affects it’s function as well as the target organs controlled by the pituitary, including the adrenal glands, ovaries and testes, and the thyroid gland. Damage to the hypothalamus may cause disruptions in body temperature regulation, growth, weight, sodium and water balance, milk production, emotions, and sleep cycles. Hypopituitarism, neurogenic diabetes insipidus, hypothyroidism and problems with development of puberty are examples of conditions caused by hypothalamic disease. The signs and symptoms exhibited by these conditions, and the associated care will be covered in the sections that follow. As for hypothalamic disease, because of the widespread functions of the pituitary gland (Dorton, 2000), there are many diseases associated with hypopituitarism. The term refers to an inability of the pituitary gland to provide sufficient hormones due to inadequate production or an insufficient supply of hypothalamic‐releasing hormones. When pituitary hormone production is impaired, target gland hormone production is reduced because of a lack of trophic stimulus. Normally, sub‐physiologic target hormone levels stimulate the pituitary gland to increase trophic hormone production; however, in hypopituitarism, the pituitary gland response is absent, suboptimal, or inappropriate. This results in progressive secondary failure of the target glands (Kim, 2015). It is usually a mixture of several hormonal deficiencies and can be chronic and lifelong, unless successful surgery or medical treatment of the underlying disorder can restore pituitary function (Schneider et al., 2007). Children with hypopituitarism typically present with low target hormone levels accompanied by low or inappropriately normal levels of the corresponding trophic hormone (Coremblum, 2016). Thus, pituitary function is assessed by the target gland function, not by measuring the pituitary hormone as an isolated event. Symptoms depend on the degree and type of hormone depletion, the rapidity of onset and the specific condition that manifests as a result of reduced pituitary function. Specific conditions caused by hypopituitarism are now described, namely: growth disorder, diabetes insipidus, and tumours of the pituitary gland. Growth disorders can be due to a number of constitutional and genetic causes such as achondroplasia, hypothyroidism, Cushing syndrome, Silver‐Russell syndrome, nutritional short stature, intrauterine growth restriction and bone disorders. The causation relevant to this chapter is short stature due to hormone deficiency in hypopituitarism. This type of growth disorder is characterised by growth that is very slow or delayed early in childhood before the ossification of bone cartilages (Dattani & Preece, 2004) and is caused by insufficient secretion of pituitary growth hormone. The condition begins in childhood, and poor growth and/or shortness becomes more evident during puberty. It usually starts to show from late in the first year until mid‐teens. The most obvious sign is a noticeable slowing of growth. Children may also possess signs of low blood sugar or obesity but they display average body proportions and average intelligence (Human Growth Foundation, 2015). Through the use of injections of synthetic human growth hormone (HGH) over a period of several years, these children can achieve average height. Conversely, acromegaly is due to an over‐production of growth hormone during childhood characterised by excessive growth and height well above the average. Rarely, it affects children. If it develops in a child, usually between the ages of 15 and 17 years, it causes the condition known as gigantism and promotes growth of bones in the body. Diabetes insipidus (DI) can be classified according to the primary cause. Neurogenic or cranial DI is of interest for this chapter, caused by a reduced amount of anti‐diuretic hormone (ADH) being produced and released by the pituitary gland. Other forms of DI are nephrogenic DI, which originates in the kidney where the renal tubules are unresponsive to ADH, and idiopathic DI where the cells in the hypothalamus become damaged by an autoimmune response and stop producing ADH. ADH, also called arginine vasopressin, is a hormone that constantly regulates and balances the amount of water in the blood. Osmoreceptors in the hypothalamus cells detect changes in the osmotic pressure in blood capillaries. A nerve message is sent to the pituitary to release ADH, which then travels in the blood to the kidneys. ADH increases the permeability of the distal tubule and collecting duct, so more water is reabsorbed. This causes the urine to be more concentrated. Osmoreceptors also regulate the body’s sense of thirst. However, if less ADH is released, an increased volume of dilute urine will be passed (Roth & Kemp, 2015) and the child will become more thirsty leading to neurogenic DI. Signs and symptoms therefore include excessive thirst and excessive urination (Khardori & Ulla, 2012). Signs of dehydration may ensue if this condition continues without recognition or diagnosis. Neurogenic DI may just be a problem on its own but it can also occur with other problems because the production of other hormones that are released by the pituitary gland is also affected. For an example of the presenting signs of diabetes insipidus, refer to Case Study 1 at the end of this chapter. For neurogenic DI, the treatment of choice is the synthetic ADH analogue desmopressin (1‐deamino‐8‐D‐arginine vasopressin [DDAVP]) (Mishra & Chandrashekhar, 2011). Parents must be educated regarding water replacement in infants and young children who cannot express thirst or access fluids without assistance. Gastrointestinal illnesses that cause decreased intake, increased stool losses, or both, must receive early and serious attention to prevent life‐threatening electrolyte and fluid balance abnormalities (Roth & Kemp, 2015). Tumours can also be a cause of pituitary dysfunction. They are usually benign and can cause problems either due to local effects of the tumour, or because of excessive hormone production or inadequate hormone production by the remaining, unaffected pituitary gland. Pituitary tumours include: Tumours can potentially cause symptoms in the following ways: In craniopharyngioma, increased pressure on the brain causes headache, nausea, vomiting and difficulty with balance. Damage to the pituitary gland causes hormone imbalances that can lead to various problems with the associated functions of those hormones, such as DI and stunted growth. When the optic nerve is damaged by the tumour, visual problems can develop. These defects are often permanent and may get worse after surgery to remove the tumour. Children will show evidence of decreased hormone production at the time of diagnosis. Investigations for diagnosis include: In pituitary adenoma, the onset of the signs of Cushing disease may be insidious. Growth failure or deceleration associated with weight gain is a hallmark of Cushing syndrome in children. Other signs and symptoms often seen in children and adolescents with this condition include facial plethora, increased fine downy hair on the face, body and extremities, a temporal fat pad, round face, and diabetes. In prolactinoma, this can cause various symptoms including reduced fertility, breast changes, and headaches. In children there may be reduced growth or delayed puberty. The management of the condition depends on the tumour. Traditionally, surgery has been the main treatment for craniopharyngioma but radiation treatment instead of surgery may be the best choice for some patients. In tumours that cannot be removed completely with surgery, radiation therapy is usually necessary. A biopsy may not be necessary if treatment with radiation alone is planned. In general, the prognosis for patients with craniopharyngioma is good, with an 80–90% chance of permanent cure if the tumour can be completely removed with surgery or treated with high doses of radiation. Recurrences may occur within the first 2 years after surgery. The prognosis for an individual child depends on whether the tumour is completely removed and the neurological deficits and hormonal imbalances caused by the tumour and the treatment. A significant percentage of patients have long‐term hormonal, visual, and neurological problems following the treatment of craniopharyngioma. In patients where the tumour is not completely removed, the condition may recur (Maity et al., 2008). For a pituitary adenoma, the first‐line treatment in childhood is surgical in the form of an adenomectomy or radiation for children in whom surgical intervention has failed (Keil & Stratakis, 2008). Prolactinomas can be treated successfully usually with medication using dopamine agonists to shrink the mass (Colao & Loche, 2009). The pineal gland is the centre for production of the hormone melatonin, which is implicated in a wide range of human activities. It regulates daily body rhythms, most notably the day/night cycle (circadian rhythms). Melatonin is released in the dark, during sleep. Benign pineal cysts are a common finding in children and do not usually cause any serious consequences (Lacroix‐Boudhrioua et al., 2011). Generally, pineal dysfunction is rare. Disruption of the circadian system can occur as a result of external factors such as crossing meridian time zones (jet lag), but it can also be related to a genetic predisposition or abnormalities that affect the functioning of the retinohypothalamic system, the production of melatonin, physical damage or tumours of the pineal gland. Sleep problems can manifest in children with these conditions but these are, of course, also a common finding in children (Carr et al., 2007); it is reported that problems of sleep initiation and maintenance occur in 15–25% of children and adolescents (Cummings, 2012). Studies of the benefits of melatonin for sleep disorders have been published for children and adolescents with chronic insomnia, attention deficit hyperactivity disorder, neurological injury, visual problems and for children with autism. These studies demonstrate short‐term benefit with minimal side effects although data concerning the safety and efficacy of long‐term melatonin use is limited (Buck, 2003; Phillips & Appleton, 2004). The pituitary gland secretes a hormone called thyroid‐stimulating hormone (TSH), which tightly controls the amount of thyroid hormone produced. The system is designed as a feedback loop where the pituitary senses how much thyroid hormone is being released by the thyroid and adjusts the amount by making more or less TSH. An elevated TSH with a low or low‐normal thyroid hormone level is called hypothyroidism, and a low or suppressed TSH with an elevated thyroid hormone level is called hyperthyroidism. Congenital hypothyroidism (CH) can be defined as a lack of thyroid hormones present from birth, which, unless detected and treated early, is associated with irreversible neurological problems and poor growth (BSPED, 2013). Hypothalamic or pituitary dysfunction accounts also for some cases of hypothyroidism (Willacy, 2011). Pituitary hypothyroidism usually occurs with other disorders of pituitary dysfunction, for example, lack of growth. Some infants may develop a lack of thyroid hormones after birth and this may represent primary hypothyroidism rather than CH. Children with primary hypothyroidism do not experience the irreversible neurological problems that are seen with untreated CH. There may be thyroid aplasia, hypoplasia or ectopic thyroid tissue. It is not inherited, so the chances of another sibling being affected are low. There may also be disorders of thyroid hormone metabolism, such as TSH unresponsiveness and defects in thyroglobulin. This is usually inherited and therefore there is a risk that further children may also be affected. Transient hypothyroidism may also occur, although rarely in children, and is usually related to either maternal medications, for example, carbimazole, or to maternal antibodies. In maternal thyroid disease, IgG auto‐antibodies can cross the placenta and block thyroid function in utero; this improves after delivery. A number of genetic defects have been associated with CH (Wassner & Brown, 2013). Infants are usually clinically normal at birth due to the presence of maternal thyroid hormones. Symptoms that develop in due course include feeding difficulties, drowsiness, lethargy, constipation and clinical signs include large fontanelles, myxoedema with coarse features, large head, oedema of the genitalia and extremities, nasal obstruction, macroglossia, low temperature (often <35 °C) with cold and mottled skin on the extremities, prolonged jaundice, umbilical hernia, hypotonia, cardiomegaly, bradycardia, failure of fusion of distal femoral epiphyses. The growing child may exhibit short stature, hypertelorism, depressed bridge of nose, narrow palpebral fissures and oedema of the eyelids. A goitre (enlarged thyroid gland) may also be present. A blood test can diagnose hypothyroidism or may also rule it out if symptoms suggest that it could be a possible diagnosis. One or both of the following may be measured in a blood sample: thyroid‐stimulating hormone (TSH) and thyroxine (T4). If the level of thyroxine in the blood is low, then the pituitary releases more TSH. Therefore, a high level of TSH means that the thyroid gland is underactive and is making too little thyroxine. A low level of T4 confirms hypothyroidism. For an example of the presenting signs of hypothyroidism, refer to Case Study 2 at the end of this chapter. In congenital hypothyroidism, treatment with thyroxine replacement should be initiated as soon as the diagnosis is suggested, immediately after obtaining blood for confirmatory tests. Delaying treatment after 6 weeks of life is associated with a substantial risk of delayed cognitive development. Newborns with elevated TSH should be treated with thyroid hormone replacement until they are aged 2 years to eliminate any possibility of permanent cognitive deficits caused by hypothyroidism. Once treatment is initiated for congenital hypothyroidism, serum total T4 and TSH concentrations should be assessed monthly until the total or free T4 levels normalize, then every 3 months until the patient is aged 3 years. Thereafter, total T4 and TSH should be measured every 6 months (Sinha & Kemp, 2014). Therapeutic goals are normalization of thyroid function test results and elimination of all signs and symptoms of hypothyroidism (Monzani et al., 2012). Hyperthyroidism means a raised level of thyroid hormone. Thyrotoxicosis is an alternative term, and the two terms mean much the same. There are various causes, which include the following: Graves’ disease, an autoimmune disease, which is the most common cause; and autoimmune thyroiditis (Cappa, Bizzarri & Crea, 2011). Hyperthyroidism is most common in women aged 20–50 years but can affect children and young people; there is often a family history of the condition as well as other autoimmune diseases, such as diabetes, rheumatoid arthritis and myasthenia gravis. Symptoms of hyperthyroidism include: being restless, nervous, emotional, irritable, sleeping poorly, tremor, weight loss, palpitations, sweating, diarrhoea or increased frequency of bowel movements, shortness of breath, skin problems, such as hair thinning and itch, menstrual changes, tiredness and muscle weakness. In Graves’ disease, the thyroid gland usually enlarges causing a goitre in the neck. The eyes may also be affected in some cases and are pushed forwards looking more prominent (proptosis) causing discomfort and watering eyes. Problems with eye muscles may also occur and lead to double vision. For an example of presenting vital signs in a 12‐year‐old child with hyperthyroidism, see the following Vital signs box. As for hypothyroidism, a blood test can diagnose hyperthyroidism and again, a normal blood test will also rule it out if symptoms suggest that it may be a possible diagnosis. If the level of thyroxine in the blood is high, then the pituitary releases less TSH. Therefore, a low level of TSH means that the thyroid gland is overactive and is making too much thyroxine. A high level of T4 confirms hyperthyroidism. Sometimes the results of the tests are borderline and so the tests may be repeated a few weeks later, as borderline tests can be due to another illness. Treatment options to reduce the thyroxine level include: medication, such as carbimazole, radio‐iodine and surgery. Beta‐blockers can ease some symptoms. Long‐term follow‐up is important, even after successful treatment. With treatment, the outlook is good, and if this is successful, most of the symptoms and risks of complications will go. The main aim of treatment is to reduce thyroxine levels to normal. Other problems, such as a large goitre or associated eye problems, may also need treatment. It can be difficult to judge the correct dose of carbimazole, or just the right amount of radio‐iodine in each case. Too much treatment may make T4 levels drop too low and insufficient treatment means levels remain higher than normal. Regular blood tests are needed to check T4. One option is to take a high dose of carbimazole each day or to receive a one‐off high dose of radio‐iodine. This stops the thyroid gland making any thyroxine. The child or young person needs to take a daily dose of thyroxine to keep their blood level within the normal range. Some young people are given a beta‐blocker drug (e.g., propranolol, and atenolol) for a few weeks while the level of thyroxine is reduced gradually by one of the treatments mentioned earlier. Beta‐blockers can help to reduce symptoms of tremor, palpitations, sweating, agitation and anxiety. Surgery involves removing part of the thyroid gland; however, if too much thyroid tissue is removed then thyroxine medication may be required to keep the T4 level normal. Regular follow‐up is recommended, even after successful treatment is completed. It is very important to have a regular blood test to check T4 levels as some people can become hyperthyroid again in the future. Others who have been treated successfully later develop an underactive thyroid. If this occurs, it can usually be treated easily with thyroxine tablets.
Disorders of the endocrine system
Aim
Introduction
Endocrine anatomy and function
Endocrine organ
Function
Associated disorders
Hypothalamus
Serves as a central endocrine control centre by communication with the pituitary gland and has many different functions such as growth, thermoregulation, control of hunger and thirst, sexual development and regulation of stress defences
Hypothalamic disease, which in turn can cause the disorders below
Pituitary gland
Controlled by the releasing and inhibiting hormones from the hypothalamus, many endocrine functions are regulated by this gland. The hormones either released or inhibited are: anti‐diuretic hormone (ADH) and oxytocin from the posterior pituitary gland (PG) and growth hormone (somatotropin), thyroid‐stimulating hormone (TSH), adreno‐cortico trophic hormone (ACTH) follicle‐stimulating hormone, luteinising hormone, prolactin, melanocyte‐stimulating hormone, beta‐endorphin from the anterior PG
Pineal gland
Produces the hormone melatonin that helps to regulate the human sleep–wake cycle known as the circadian rhythm
Thyroid gland
Releases thyroxine that regulates metabolism, stimulates body oxygen and energy consumption, plays a part in growth by promoting protein synthesis and influences the activity of the nervous system. Calcitonin lowers calcium levels of calcium
Parathyroid gland
Releases parathyroid hormone that raises blood calcium level and decreases phosphate level by increasing the rate of calcium absorption from the intestine into the blood
Thymus gland
Releases thymosin and other related hormones that play an integral role in the maturation of T cells as part of the immune system
Adrenal gland
Produces mineralocorticoids that stimulate sodium reabsorption in the kidneys increasing blood levels of sodium and water, corticosteroids that stimulate gluconeogenesis and fat breakdown in adipose tissue so increasing glucose availability in the blood, promote metabolism and resistance to stress and gonadocorticoids, which influence masculinisation (virilisation) in both males and females. Adrenaline and noradrenaline from the adrenal medulla are an integral part of the body’s flight–fight responses to stress
Pancreas
Produces and releases insulin which results in targets cells taking up free glucose so lowering blood levels. Conversely, glucagon is also released that targets the liver to break down glycogen into glucose which increases blood glucose levels
Testes and ovaries
Release sex hormones testosterone or oestrogen from either the testes or ovaries
Endocrine disorders
Disorders of the hypothalamus and pituitary gland
Hypothalamic disease
Hypopituitarism
Growth disorders
Diabetes insipidus
Tumours of the pituitary gland
Disorders of the pineal gland
Disorders of the thyroid gland
Hypothyroidism
Hyperthyroidism
Vital sign
Observation
Normal
Temperature
37.8 °C
36.5–37.5 °C
Pulse
140 beats per minute
60–100
Respiration
25 breaths per minute
15–20
Blood pressure
130/85 mmHg
100–120 mmHg (systolic)
PEWS
3
0–1
Other
Low thyroid‐stimulating hormone (TSH) and high T4 (thyroxine), calcium low
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