Endocrinology and metabolism

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12 Endocrinology and metabolism

Nandu Thalange, Richard Beach

Introduction

The body maintains stability of its many functions by means of a complex network of control systems. Such controls are present in every system controlling e.g. heart rate, respiration and body temperature. This chapter is concerned with the systems that regulate the body’s endocrine and metabolic functions, and how they are affected by disease.

Regulating blood glucose

Glucose is a key energy-providing substrate for the body’s metabolism – especially the brain. Insulin produced by the pancreatic beta cells controls the flow of glucose into cells and is produced in response to hyperglycaemia.

Hypoglycaemia results in release of glucagon, cortisol and adrenaline (epinephrine) with resultant gluconeogenesis and release of glucose from glycogen stores.

Glucose measurement is conveniently performed at the bedside on a capillary blood sample using a blood glucose meter. These meters greatly simplify assessment of children with suspected hypo- or hyperglycaemia.

Hypoglycaemia

Significant hypoglycaemia – defined as blood glucose <2.6 mmol/L (as in Case 12.1) – is rare outside the neonatal period. The symptoms of altered consciousness, pallor and sweatiness are secondary to impaired cerebral metabolism (neuroglycopenia) and adrenaline (epinephrine) release. After a period of fasting, blood glucose levels fall, insulin secretion is suppressed and lipolysis leads to ketone body production. Thus, ketosis during fasting is a normal physiological response. This response is exaggerated in ketotic hypoglycaemia, and ketones rise to toxic levels causing severe acidosis, in addition to the presence of hypoglycaemia, as in Case 12.1. Affected children may have recurrent episodes during illness or after exercise. Treatment is with additional high-energy snacks and carbohydrate-containing drinks at bedtimes and during illness.

Case 12.1

A boy with hypoglycaemia

A 4-year-old boy presented with a 12-hour history of drowsiness, vomiting and sighing respiration. He was pale, sweaty and confused but circulation was normal with no evidence of shock or dehydration. His blood glucose was 1.0 mmol/L and blood ketones (beta-hydroxybutyrate) 5.6 mmol/L (normal <1.0). After treatment with 5 mL/kg of 10% dextrose he recovered to an alert, albeit irritable, state. The vomiting and ketosis resolved over a few hours of intravenous dextrose therapy. His parents recalled repeated episodes of vomiting and lethargy in the past.

Hypoglycaemia with ketosis also occurs with hypopituitarism and primary and secondary adrenal insufficiency secondary to growth hormone and/or cortisol deficiency. Metabolic causes include glycogen storage diseases, fatty acid disorders, galactosaemia and fructose intolerance. Absence of ketones with hypoglycaemia implies the presence of insulin; this occurs with dysregulated insulin secretion as occurs in persistent hyperinsulinaemic hypoglycaemia of infancy, or insulinoma, or exogenous insulin administration as in diabetes.

Diabetes

Type 1 diabetes mellitus results from progressive immune-mediated destruction of insulin-producing pancreatic beta cells, as in Case 12.2. It is increasingly common in children (0.2% of children under 16 years), and the mean age of diagnosis is falling. Insulin deficiency results in progressive hyperglycaemia, weight loss, polydipsia and polyuria (as in Case 12.2). Rapid lipolysis results in production of acidic ketone bodies (ketosis), and ultimately diabetic ketoacidosis, if the symptoms of diabetes are not recognized. For management of diabetic ketoacidosis, see Appendix I, p. 290.

When diabetes is suspected, it is imperative to measure blood glucose. If diabetes is confirmed (random glucose >11.1 mmol/L), then prompt referral to the local diabetes team is indicated, even if the child seems well, as deterioration may be rapid.

Case 12.2

A girl with hyperglycaemia

A 7-year-old girl had been lacking in energy for a month or so and losing weight. For a week she seemed thirsty all the time and was awake at night, drinking and passing large amounts of urine. On the day of admission she had abdominal pain and had vomited once. On examination she had clearly lost some weight but there was no circulatory compromise. Her blood glucose was 19.6 mmol/L with blood ketones of 0.5 mmol/L, thus excluding diabetic ketoacidosis. Islet cell antibodies were found on investigation, confirming type 1 diabetes.

In hospital, it is now routine to assess blood ketones (beta-hydroxybutyrate) using a rapid bedside test. This is very helpful in identifying the child with ketoacidosis and gives a result within minutes. Blood ketones above 3.0 mmol/L indicate the potential for ketoacidosis, which is confirmed by blood gas testing. Particularly in the very young, symptoms of diabetes may be difficult to spot. Ketosis may induce abdominal pain and vomiting which may be mistaken for gastroenteritis, and hyperventilation secondary to metabolic acidosis (‘Kussmaul respiration’) may be mistaken for asthma or pneumonia.

After diagnosis, the key goals are to teach the child and parents to administer insulin and to perform blood glucose testing. Insulin administration is facilitated by modern insulin pens and, in the younger child, pens which can administer insulin in ½ unit increments. Blood glucose monitoring should be made integral to insulin therapy, and parents and children should be encouraged to adjust insulin doses from the outset. With conventional ‘human’ insulins, it is necessary to wait 20–30 minutes before eating, but with newer rapid-acting insulin analogues this is unnecessary. Modern intensive insulin regimes use a once-daily injection of long-acting ‘basal’ insulin and mealtime boluses of quick-acting insulin (‘basal-bolus’). This allows flexible mealtimes and insulin dosing adjusted to carbohydrate intake, and is particularly suitable for older children and teenagers with diabetes. Insulin infusion pumps are a refinement of the basal-bolus technique, and are increasingly being used in the UK.

Diet

Dietary management of diabetes boils down to a healthy diet, with low sugar choices, comprising regular meals and appropriate snacks before exercise. Ideally, carbohydrate should contribute 45–60% of energy needs, primarily as unrefined complex carbohydrate. Fat intake should be moderated to a maximum of 35% of energy intake. Dietetic help is vital in managing the child at diagnosis.

Control

The management of diabetes requires a team approach using the skills of the paediatrician, diabetes specialist nurse, dietitian, psychologist, and of course the parents and child, to achieve the best results. The quality of diabetes control may be judged from home blood glucose measurements and measurement of glycated haemoglobin A₁ (HbA_1C). HbA_1C provides an integrated measure of glycaemic control over 2 to 3 months. Above the target of 48–58 mmol/mol (6.5–7.5%) for each 10–15 mmol/mol rise in HbA_1C complication risk increases by 30%. Good glycaemic control reduces the long-term risk of microvascular complications of diabetes: nephropathy, retinopathy and neuropathy, and macrovascular disease – ischaemic heart disease, strokes and peripheral vascular disease. Management is geared to attaining the lowest practicable HbA_1C for each individual, taking into account what is realistic and achievable for them.

Complications and co-morbidity

Hypoglycaemia is part of life for children with diabetes. Mild hypoglycaemia in which the patient feels ‘low’ occurs commonly in a well-controlled diabetic, but moderate and severe hypoglycaemia should be avoided if possible. Moderate hypoglycaemia induces irritability and autonomic symptoms: sweating, pallor, tachycardia. Recurrent episodes of hypoglycaemia cause loss of hypoglycaemic awareness and greatly increase the risk of severe hypoglycaemia. Severe hypoglycaemia, characterized by collapse, coma or seizures secondary to neuroglycopenia, requires third-party assistance. Treatment of mild and moderate hypoglycaemia is with glucose in the form of food, drink or dextrose tablets or oral glucose gel. Severe hypoglycaemia requires prompt administration of oral glucose gel (not in unconscious or fitting patients), intramuscular glucagon, or, if practicable, intravenous glucose.

Screening for microalbuminuria and elevated blood pressure should be undertaken at least annually from diagnosis. Microalbuminuria is an early marker of diabetic nephropathy. Screening for diabetic retinopathy should commence annually from 12 years of age, ideally with retinal photography. In adults, it is recognized that blood pressure and lipid levels also contribute to complication risk. Trials of therapy are under way to determine whether adolescents may benefit from antihypertensive and lipid-lowering therapies.

Growth may be impaired, particularly if there is marked non-compliance with therapy, and height and weight should be plotted at each visit to the clinic.

Annual thyroid function testing is recommended for all children with diabetes, due to the high incidence of autoimmune thyroid disease. Coeliac screening is recommended at diagnosis. Some centres continue to screen for coeliac disease 3-yearly, but this falls outside current NICE guidance on screening for coeliac disease. The value of lipid screening in children with type 1 diabetes is unclear. Elevated cholesterol and/or triglycerides are commonly seen with poor glycaemic control.

Diabetes in adolescence

Teenage years are challenging – especially so for the teenager with diabetes. It is essential to have a non-judgemental approach that focuses on realistic shared goals. Threats of future complications are counterproductive and should be avoided. There needs to be effective preparation for adult life, including advice on sexual health, pregnancy and contraception, driving, employment, living away from home, alcohol and drugs. Eating disorders and depression are very common in older teenagers and require specialist input.

Good hand-over arrangements to the adult diabetes service are also essential, as many young people fall by the wayside at this stage.

Type 2 diabetes and MODY

Type 2 diabetes is increasingly evident in obese adolescents, particularly those from ethnic minorities. Management is aimed at weight control through healthy eating, exercise and the use of metformin to maximum tolerated doses. Other oral hypoglycaemic agents are added as necessary. Ultimately, all individuals with type 2 diabetes will required insulin therapy (on average after about 6–7 years).

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes due to specific genetic defects of beta cell function, the commonest being mutations affecting hepatic nuclear factor 1α. MODY may present similarly to type 1 diabetes. It is dominantly inherited, therefore a parent is usually affected. Specific genetic tests are available. Treatment with a sulfonylurea such as glibenclamide is effective.

Secondary diabetes

Diabetes or glucose intolerance may occur secondarily to steroid excess, as in Cushing’s syndrome, or from high-dose steroid therapy.

The hypothalamus and pituitary

The hypothalamus and pituitary gland are together the principal command centre of the endocrine system. Pituitary hormones regulate metabolism (TSH), growth (growth hormone) and sexual development (follicle-stimulating hormone and luteinizing hormone – see ‘Sexual development’ later in the chapter), the adrenal gland (ACTH), water balance (antidiuretic hormone; see Chapter 11, p. 131) and lactation (prolactin and oxytocin). Structural lesions of the hypothalamus and pituitary include congenital malformations and tumours, e.g. craniopharyngioma (see Chapter 7, p. 74), and result in deficiency of some or all of the pituitary hormones – known as hypopituitarism.

The pituitary gland may be congenitally absent or hypoplastic. This may be associated with other midline congenital anomalies such as cleft palate. Congenital hypopituitarism of hypothalamic or pituitary origin may be associated with the development of neonatal hypoglycaemia and, less commonly, cholestatic jaundice secondary to neonatal hepatitis (see also Chapter 13, p. 175).

Cushing’s syndrome

Cushing’s syndrome in children is almost always iatrogenic. The principal clinical features are growth impairment, central obesity, moon face, buffalo hump, hypertension and glucose intolerance or frank diabetes. After iatrogenic steroid exposure, ACTH-secreting pituitary adenomas (Cushing’s disease) are the commonest cause of Cushing’s syndrome in childhood, albeit still very rare. Adrenocortical tumours may also cause Cushing’s syndrome. Investigation is aimed at confirming glucocorticoid excess and determining if it is ACTH-dependent. Imaging is then used to localize the lesion, preparatory to surgery.

Adrenal insufficiency

The adrenal glands, named for their position at the superior pole of each kidney, comprise an inner medulla and an outer cortex. The medulla secretes the vasoactive catecholamines adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The adrenal cortex secretes the steroids cortisol and aldosterone and a modest quantity of androgens. Cortisol production is stimulated by the pituitary hormone, adrenocorticotrophic hormone (ACTH).

Cortisol is essential for survival and has diverse effects on metabolism, immunity and cardiovascular and renal function. These effects are most apparent as mediators of the body’s response to stress, such as illness, through its ability to mobilize glucose stores, improve myocardial and skeletal muscle contractility, and to enhance the pressor action of catecholamines.

Aldosterone has a key role in maintaining electrolyte balance and blood pressure by causing sodium retention and potassium excretion by the kidney. Retention of sodium leads to elevation of blood pressure.

Adrenal insufficiency most often occurs due to congenital adrenal hyperplasia (see p. 152) or secondary to hypopituitarism (as in Case 12.3). Primary adrenal insufficiency is extremely rare. It may be congenital, but it most commonly arises from autoimmune destruction of the adrenal gland, often in association with other autoimmune diseases, notably mucocutaneous candidiasis, hypoparathyroidism, hypothyroidism and diabetes mellitus (polyglandular endocrinopathy), in which case there is often a positive family history. It manifests with insidious malaise, weakness and weight loss and orthostatic hypotension. Hyperpigmentation may occur, classically affecting the buccal mucosa, scars and skin creases.

Case 12.3

A boy with adrenal insufficiency

Freddie, aged 7 years, was admitted with gastroenteritis. He had congenital hypopituitarism requiring multiple pituitary hormone replacement therapy. His oral hydrocortisone treatment was doubled, but the following morning he was found to be hypotensive and drowsy. His blood glucose was 2.9 mmol/L, and his serum sodium was 128 mmol/L. A diagnosis of adrenal crisis was made, and he was promptly treated with parenteral glucose, intravenous hydrocortisone and 20 mL/kg of normal saline. Within a few hours, he was much better.

Physiological steroid replacement with hydrocortisone is essential. This must be doubled or trebled with intercurrent illness, and in severe illness the parenteral route must be used. Failure to give adequate steroid therapy results in adrenal crisis, as in case 12.3, when the patient presents with refractory hypotension, hypoglycaemia, hyponatraemia and variable hyperkalaemia. Prompt treatment with intravenous fluids, glucose and hydrocortisone is essential.

Adrenal crisis may also occur with surgery or intercurrent illness in patients on chronic steroid therapy, or following abrupt cessation of high-dose steroid therapy. Patients at particular risk include those with asthma on high-dose inhaled steroids, notably fluticasone preparations, or those who have recently completed high-dose steroid therapy, such as children with leukaemia or inflammatory bowel disease.