11_McClure_11.indd 388 11/14/2012 3:25:32 PM RENAL CALCULI 389 Blood \200 \200 \200 \200 U&E, bicarbonate, creatinine. Calcium, phosphate, PTH. Liver function tests. Uric acid. Renal tract ultrasound Other investigations \200 AXR: \200 \200 IV pyleogram or CT scan. Renal stone analysis: composition. radio-opaque stones: calcium/cysteine/infective; radiolucent stones: uric acid/xanthine. \200 Treatment The acute treatment of renal colic secondary to renal stones is based on the prov ision of adequate analgesia and hydration. Treat any under- lying UTI with antibiotics. If severe renal impairment and urinary tract obstruction is evident refer to the pediatric uro logy team for considera- tion for extracorporeal shock-wave lithotripsy. Surgery (e.g. perc utaneous nephrolithotomy or open surgery) is now seldom indicated. Long-term management is aimed at preventing further obstruction and bouts of renal colic. The simplest and most eff ective measures to achieve this are to ensure adequate hydration and diuresis to maintain a good urinary \202 ow and dilute urine. Treatment of any underlying urinary tract infecti on and metabolic disorder is also required. Primary hyperoxaluria type 1 This is an autosomal recessive condition. Three forms are reco gnized. \200 Infantile form: stage renal failure (ESRF/Stage 5 CKD). Child/adolescent form: Adult form: early nephrocalcinosis and progression to CKD and end- \200 recurrent urolithiasis and progression to ESRF. urolithiasis only. 11_McClure_11.indd 389 11/14/2012 3:25:32 PM CHAPTER 11 Nephrology 390 Hypertension: de \201 nition De \201 ned by reference to sex, height centile charts (see Fig. 11.1). \200 \200 \200 \200 Normal: High normal: Hypertension: Severe hypertension: systolic and diastolic <90th centile. systolic or diastolic between 90th and 95th centile. systolic or diastolic >95th centile. systolic or diastolic >99th centile. BP measurement should be part of routine examination. Measurement technique \200 Cuff size. \200 \200 \200 \200 After 5min rest (ideally!). Sitting position with ar m at level of heart (children). Supine position in infants. On auscultation: systolic and d iastolic values, respectively. bladder width mid-arm circumference; bladder length Note: \200\22470% of acromion olecranon distance or 40% \200\224should completely encircle arm. small cuff area is a common cause of false positive high BP! \200 \200 \200 1st and 5th (disappearance) Korotkoff sounds used for Measurement devices \200 \200 \200 \200 Manual oscillometric sphygmomanometer (mercury now withdrawn). Doppler: not all devices sui table. Automatic oscillometry: Ambulatory blood pressure monitoring (ABPM) for 24-hr pro \201 les: \200 \200 Intra-arterial (in intensive therapy unit (ITU) setting). infants (for systolic pressure). little normative data in pediatrics; signi \201 cant hypertension \211 30% readings above 95th centile. 11_McClure_11.indd 390 11/14/2012 3:25:32 PM HYPERTENSION: DEFINITION 391 Fig. 11.1 Blood pressure centile \201 gures for girls and boys. Copyright Lisa Jackson an d Nandu Thalange. 11_McClure_11.indd 391 11/14/2012 3:25:32 PM CHAPTER 11 Nephrology 392 Fig. 11.1 (Contd.) 11_McClure_11.indd 392 11/14/2012 3:25:34 PM HYPERTENSION: DEFINITION 393 11_McClure_11.indd 393 11/14/2012 3:25:35 PM CHAPTER 11 Nephrology 394 Hypertension: causes and features Causes of hypertension Primary (essential) hypertension This is a diagnosis of exclusion. High body mass index, ex cessive salt intake, lack of exercise, and family history may be underlying predispos- ing factors Secondary hypertension \200 Renal (commonest cause in hospital referral practice): \200 \200 \200 \200 \200 V ascular: \200 umbilical arterial/venous catheters \200 renal artery stenosis \200 ren al vein thrombosis \200 coarctation of aorta \200 vasculitis Endocrine: \200 \200 \200 \200 \200 Trauma Neurological: \200 2 to pain \200 raised intracranial hype rtension Tumors: \200 neuroblastoma \200 Wilms Medication: \200 steroids \200 amino phylline/caffeine \200 oral contraceptive pill \200 erythropoietin \200 calcineurin i nhibitors; decongestants \200 amphetamines; cocaine Others: \200 \200 \200 chronic renal parenchymal disease (re \202 ux/scarring) polycystic kidney disease obstruct ive uropathy acute nephritis chronic renal failure congenital adrenal hyperplasia hyperthyroidism increased steroids (iatrogenic or endogenous ) phaeochromocytoma (BP intermittently raised) hyperaldosteronism \200 bronchopulmonary dysplasia ECMO \200\230white-coat \200\231 hypertension 11_McClure_11.indd 394 11/14/2012 3:25:35 PM HYPERTENSION: CAUSES AND FEATURES 395 Clinical features Most are asymptomatic. Infants \200 \200 \200 Vomiting. Failure to thrive (rare). Congestive cardiac failure/respiratory distress (in new borns). Children \200 \200 \200 \200 \200 \200 \200 \200 Headache/nausea and vomiting. Visual symptoms. Irritable/tired. Bell \200\231s palsy. Epist axis. Growth failure. Fits. Altered consciousness. Examination \200 Check fundi. \200 Feel abdomen for abdominal masses. \200 Listen for renal bruits. \200 Feel femoral pulses and compare to radial/brachial pulses (to exclude \200 coarctation) and check BP in all 4 limbs. \200 Examination of the heart. Investigations A s cause is more likely with severe hypertension. Treatment and inves- tiga tions may need to proceed together. \200 Urine: \200 \200 \200 Blood tests: \200 FBC; \200 U&E and creatinine; \200 bica rbonate, calcium, phosphate, albumin; \200 plasma renin and aldosterone. CXR and ECG. ECG . US of urinary tract + Doppler if renal artery stenosis suspected. Further imaging will de pend upon suspected cause and ultrasound \201 ndings, e.g. DMSA, CT scan, arteriogram. Sp ecialized tests, e.g. for phaeochromocytoma (see urinalysis, microscopy, and culture; vanillylmandelic acid (VMA):creatinine ratio; steroid pro \201 le and toxicology. \200 \200 \200 \200 \200 b p.675). 11_McClure_11.indd 395 11/14/2012 3:25:35 PM CHAPTER 11 Nephrology 396 Hypertension: management Hypertensive crises Acute, severe hypertension will require carefu l monitoring in a pediatric ICU and treatment with drugs shown in Table 11.8. Maintenance antihypertensive therapy Dosing schedules of many hypertensive drugs have not b een evaluated in children. The favored combination is a beta-adrenergic blocker with a vaso dilator. A diuretic can be used if BP is still not controlled. ACE inhibi- tors should be a voided if renal artery stenosis is suspected but are useful for renin-mediated hypertension . Phentolamine is used if catecholamine- induced hypertension is suspected, e.g. phaeochrom ocytoma. Table 11.9 gives dosing schedules for various hypertensive drugs. Table 11.8 Emergency treatment of hypertensive crisis (see also b pp.58, 397)* Drug Administration Onset of effect Side-effects Nifedipine Sublingual hourly prn 200 \200\223500micrograms/kg Minutes Headaches, tachycardia Sodium nitroprusside 0.5 \200\22310micrograms/kg/ min as infusion Seconds to minutes Very rapid effect; titrate dose; cyanide accumulates after 48hr of use Labetalol 1 \200\2233mg/kg/hr 10 \200\22330min Postural hypotension Hydralazine Slow IV 100 \200\223500 - micrograms/kg 10 \200\22330min Tachycardia, \202 ushes, headache Phentolamine 10 \200\223100micrograms/kg Minutes Use in catecholamine excess states The aim is to reduce systolic and diastolic BP to <95th centile for age and sex but, if sev erely hypertensive, only one-third of desired BP reduction should occur in the \201 rst 6 hr. Aim for controlled reduction in BP over 72hr. 11_McClure_11.indd 396 11/14/2012 3:25:35 PM HYPERTENSION: MANAGEMENT 397 Table 11.9 Maintenance oral therapy for treatment of hypertension Drug Administration Dose Vasodilators Nifedipine 0.25 \200\2232mg/kg/24hr 2 divided doses Hydralazine 1 \200\2237.5mg/kg/24hr 2 \200\2233 divided doses Prazosin 50 \200\223500micrograms/kg/24hr 2 \200\2233 divided doses Minoxidil 200 \200\2231000micrograms/kg/24hr Single dose Beta-blockers Propranolol 1 \200\2236mg/kg/24hr 2 \200\2233 divided doses Atenolol 1 \200\2234mg/kg/24hr Once a day if adequate renal function Diuretics Furosemide 1 \200\2235mg/kg/24hr 1 \200\2232 divided doses Spironolactone 1 \200\2233mg/kg/24hr 1 \200\2232 divided doses ACE inhibitors Captopril 0. 3 \200\2236mg/kg/24hr 2 \200\2233 divided doses Enalapril 0.1 \200\2231mg/kg/24hr Single dose 11_McClure_11.indd 397 11/14/2012 3:25:35 PM This page intentionally left blank 399 Chapter 12 Endocrinology and diabetes Obesity 400 Obesity: management 404 Type 1 diabetes mellitus 406 Type 1 diabetes mellitus: management 408 Type 1 diabetes mellitus: insulin therapy 410 Acute complications of Type 1 diabetes mellitus 412 Type 1 diabetes mellitus: long-term complications 414 Type 1 diabetes mellitus: associated illnesses 415 Type 2 diabetes mellitus 416 Other forms of diabetes me llitus 418 Goiter 420 Solitary thyroid nodule 421 Thyroid carcinoma 421 Medullary thyroid c ancer 421 Congenital hypothyroidism 422 Acquired hypothyroidism 424 Hyperthyroidism (thyrot oxicosis) 425 Graves \200\231s disease 426 Thyroiditis 428 Adrenal insuf \201 ciency 430 A drenal insuf \201 ciency: treatment 432 Adrenal excess 434 Congenital adrenal hyperplasia 436 Mineralocorticoid excess 438 Mineralocorticoid de \201 ciency 439 Inherited endocrine syndromes 440 Hypocalcaemia 442 Rickets 444 Hypercalcaemia 446 Posterior pituitary: syndrom e of inappropriate antidiuretic hormone secretion 448 Hypopituitarism 449 Posterior pituitary: diabetes insipidus 450 Polycystic ovarian syndrome 452 12_McClure_12.indd 399 11/14/2012 3:27:00 PM CHAPTER 12 Endocrinology and diabetes 400 Obesity This has become an important public health problem, which has achieved epidemic lev els in the developed world. In the UK approximately 20% of children and adolescents are eit her overweight or obese. Obesity in childhood strongly predicts obesity in adulthood. Obesi ty is an impor- tant risk factor for the development of life-threatening disease in later l ife, including type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, and c ancer. De \201 nition and diagnosis Obesity implies increased central (abdominal) fat mass, and c an be quanti- \201 ed using a number of clinical surrogate markers. BMI is the most conve n- ient indicator of body fat mass (see Fig. 12.1). BMI = weight (kg)/[height (m)]2 Overweight: Obese: \200 BMI >91st centile, wt <98th centile BMI >98th centile Other measures of obesity include: \200 \200 waist circumference; waist:hip ratio. Epidemiology The worldwide increase in incidence in obesity has been mainly observed in Wes tern countries and in other developed societies. Risk factors for the development of obesit y include the following: \200 \200 \200 Parental/family history of obesity. Afro-Caribbean/Indian \200\223Asian ethnic origins. Cat ch-up growth (weight) in early childhood (0 \200\2232yrs): for gestational age who demonstr ate signi \201 cant weight catch up (>2SDs) in \201 rst 2yrs of life. infants born small Causes So-called idiopathic (or \200\230simple \200\231) obesity is by far the commonest c ause of obesity accounting for up to 95% of cases. It is multifactorial in origin and repre sents an imbalance in normal nutritional \200\223environmental \200\223gene interaction, wh ereby daily calorie (energy) intake exceeds the amount of calories (energy) expended: \200 \200 \200 genetic predisposition (energy conservation); increasingly sedentary lifestyle (energy expe nditure); increasing consumption and availability of high energy foods. Obesity may be associated with other identi \201 able underlying pathological conditions. 12_McClure_12.indd 400 11/14/2012 3:27:01 PM OBESITY 401 Endocrine (rare) \200 \200 \200 \200 \200 \200 b p.424). Hypothyroidism (see Cushing \200\231s syndrome/disease (see Growth hormone de \201 ciency (see Pseudohypoparathyroidism (see Polycystic ovarian syndrome. b p.430), i.e. CNS tumors and/ Acquired hypothalamic injury (see or surgery resulting in disruption to the neuroendocrine pathways regulating appetite and satiety. b p.434). b pp.470 \200\223473). b p.443). Genetic Obesity is a recognized feature characterizing the phenotype of a number of genetic syndromes. \200 \200 \200 b p.949). Prader \200\223Willi syndrome (see b p.949). Bardet \200\223Biedl syndrome (see M onogenic causes: leptin de \201 ciency (rare); melanocortin 4 receptor gene (5 \200\2236% of all causes). 12_McClure_12.indd 401 11/14/2012 3:27:01 PM CHAPTER 12 Endocrinology and diabetes 402 Fig. 12.1 BMI Centile Charts. Child Growth Foundation. 12_McClure_12.indd 402 11/14/2012 3:27:01 PM OBESITY 403 Fig. 12.1 (Contd.) 12_McClure_12.indd 403 11/14/2012 3:27:01 PM CHAPTER 12 Endocrinology and diabetes 404 Obesity: management Evaluation and investigations This includes taking a detailed clinical and family history. \200 \200 Birth weight (note: small for gestational age). Feeding habits and behavior: particularly i nfancy/early childhood. Hyperphagia: may suggest genetic cause. Weight gain/growth pattern (check previous health records). Physical activity. Neurodevelopment and school performance . Screen for comorbid factors (see Complications and comorbid conditions). Family history: obesity; T2DM; cardiovascular disease. \200 \200 \200 Laboratory investigations are directed at excluding secondary causes of obesity: \200 Blood biochemistry: test; fasting lipid pro \201 le. Genetic studies (e.g. Prader \200\223 Willi syndrome). Oral glucose tolerance test (OGTT; see Box 12.1). thyroid function test; serum cortisol; liver function \200 Complications and comorbid conditions Severe obesity is associated with the following comor bid conditions, which should be screened for at the time of assessment. \200 \200 Pyschological: ENT/respiratory: syndrome; pulmonary hypertension. Orthopedic: Metabolic: dy slipidaemia; polycystic ovarian syndrome. Hepatic: low self-esteem; depression. obstructive sleep apnoea; obesity \200\223hypoventilation \200 bowing of legs; slipped femoral epiphysis; osteoarthritis. impaired glucose tolerance/type 2 diabetes; hypertension; non-alcoholic steatohepatitis. Obesity and oral glucose tolerance testing In children and adolescents with obesity the pre valences of impaired glu- cose tolerance (IGT) and T2DM have been estimated to be in the re gion of 20 \200\22325% and 4%, respectively. An oral glucose tolerance test should be considered when one or more of the following risk factors are present. \200 \200 \200 \200 \200 \200 Severe obesity: nigricans. Acanthosis Positive family history of T2DM. Ethnic origin: Polyc ystic ovarian syndrome. Hypertension. BMI >98th centile Asian/Afro-Caribbean/African-American. 12_McClure_12.indd 404 11/14/2012 3:27:02 PM OBESITY: MANAGEMENT 405 Box 12.1 Oral glucose tolerance testing Conditions Performed in the morning after 8 \200\22310hr fast Dose Glucose 1.75g/kg to a maximum of 75g, drunk within 5 \200\22310min Sampling Blood glucose at 0 min and at 30min intervals thereafter for 120min Interpretation See table below Blood glucose (mmol/L) At 0 min At 120 min Normal <6.0 <7.8 IGT 6.0 \200\2237.0 7.8 \200\22311.1 DM >7.0 >11.1 Management There is currently no consensus on the best approach to treating child- hood obe sity. Treatment requires a multidisciplinary approach. \200 Nutrition and lifestyle educa tion/counseling: important. \200 Decreasing calorie intake/increasing exercise. \200 Be havior modi \201 cation and family therapy strategies. \200 Drug therapies (currently li mited, not licensed for children). \200 Obesity (bariatric) surgery (rarely). Population-based intervention and prevention strategies may be more effective than approach es targeted at the obese individual. 12_McClure_12.indd 405 11/14/2012 3:27:02 PM CHAPTER 12 Endocrinology and diabetes 406 Type 1 diabetes mellitus This is the most common form of diabetes mellitus in children and adoles- cents (90% of cases). It is an autoimmune disorder characterized by T-cell mediated destruction and progressive loss of pancreatic B-cells leading to eventual insulin de \201 ciency and hyperglycaemia. Epidemiology The incidence of Type 1 diabetes mellitus (T1D M) has been increasing, but shows marked geographical variation. In Europe the highest inci dence rates are seen in the Nordic countries (Finland, Sweden). During childhood there are two peaks in presentation, one between ages 5 and 7yrs and the other, larger peak, just bef ore or at the onset of puberty. Seasonal variation in presentation of T1DM is also observed with a peak seen in the winter months. Etiology The cause of T1DM involves both genetic and environmental factors. Over 20 differe nt T1DM susceptibility genes have been identi \201 ed. The insulin-dependent diabetes mell itus (IDDM1) gene locus, which represents the human leukocyte antigen (HLA) DR/DQ locus on the major histocom- patibility complex, accounts for the greatest susceptibility. The role of various environmental interactions and triggers is controversial. Pathophysiology T1DM is a chronic autoimmune condition. \200 B-cell Immune tolerance is broken and antibodies against speci \201 c autoantigens are generated (e.g. anti-islet cell; anti-insulin; anti-GluAD; anti-IA2 antibodies). T-cell activation le ads to subsequent cell loss through apotosis. The rate of presentation of symptomatic diabe tes may depend on factors that increase insulin requirements (e.g. puberty). B-cell in \202 ammation ( \200\230insulitis \200\231) and to B-cell loss varies (months \200\223years) and the timing and Clinical presentation The onset of symptoms evolves over a period of weeks. Symptoms are a re \202 ection of insulin de \201 ciency resulting in increased catabolism and hyper- gly caemia. In the majority, \201 rst presentation is usually made in the early symptomatic p hase with: \200 \200 \200 weight loss; polyuria/polydipsia; nocturia/nocturnal enuresis. Other less common symptoms include: \200 \200 candida infection (e.g. oral thrush, balanitis, vulovaginitis); skin infections. 12_McClure_12.indd 406 11/14/2012 3:27:02 PM TYPE 1 DIABETES MELLITUS 407 Failure to recognize these symptoms will result in delayed or late diagnosis of T1DM and po ssible presentation with DKA (see b pp.98 \200\223101, 413). The risk of \201 rst present ation of T1DM with DKA is increased when non- speci \201 c symptoms of diabetes may go unr ecognized: \200 \200 intercurrent/febrile illness; infants and preschool age child. Assessment of new patient Emphasis should be put on: \200 \200 \200 History: Family history: Examination: duration of symptoms. of diabetes/other autoimmune disease. weight/BMI; signs of DKA (see b pp.98 \200\223101, 41 3). Diagnosis and investigations The diagnosis is readily established in a symptomatic child wi th a random blood glucose level >11.1mmol/L. Other investigations: \200 \200 \200 U&E. Blood pH (to exclude DKA). Diabetes-related autoantibodies: islet cell antibody (ICA)/ anti-insulin antibody (IAA)/anti-GluAD antibody (GluAD)/anti-IA-2. Other autoimmune disease screen: thyroid function test/thyroid antibodies; coeliac disease antibody screen. 12_McClure_12.indd 407 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 408 Type 1 diabetes mellitus: management The initial care and subsequent long-term management o f patients with T1DM should be delivered by a specialist pediatric diabetes team. All newly diagnosed patients must start insulin therapy as soon as possible. An intensive program of education and support is needed for the child and parents. The aims of management of T1DM are: \200 \200 \200 \200 \200 \200 \200 \200 \200 education of child and family about diabetes; insulin therapy; nutritional management; moni toring of glycaemic control; avoidance and management of hypoglycaemia; management of acute illness and avoidance of DKA; screening for development of associated illness; screening f or diabetes-related microvascular complications; prevention and treatment of microvascular complications. Education, counseling, and support An intensive program of education and counseling is need ed in the \201 rst few days/weeks to cover the fundamental principles about T1DM and its management. \200 \200 Basic pathophyisology of T1DM. Insulin therapy: \200 \200 \200 actions of insulin; SC injection techniques; dose adjustment principles, including carbohyd rate counting techniques. \200 Home/self blood glucose monitoring. Acute complications: \200 avoidance, symptom recognition, and treatment of hypoglycaemia and diabetic ketoacidosis (s ee b pp.412 \200\223413). \200\230sick day rules \200\231 during illness to prevent DKA (s ee b p.412). Diet: \200 \200 Long-term complications: Psychological issues. healthy, low-fat; high complex carbohydrate. \200 risk factors and avoidance. A considerable amount of time and need for repetition is required to deliver this informati on. The process of education and support is a con- tinual one with a need for regular revie w and updates of knowledge. Nutritional management Diet and insulin regimen need to be matched to optimize glycaemic co n- trol. Instruction on and application of carbohydrate counting techniques are required. A healthy diet is recommended with a high complex carbo- hydrate and relatively low fat cont ent. 12_McClure_12.indd 408 11/14/2012 3:27:03 PM TYPE 1 DIABETES MELLITUS: MANAGEMENT 409 Daily dietary balance for a healthy diet \200 \200 \200 \200 50 \200\22360% carbohydrate (complex/high \201 bre) <30% fat (<10% in form of saturated f at) 15 \200\22320% protein Re \201 ned sugars limited to <25g/day Blood glucose monitoring \200 Regular daily blood glucose monitoring and testing when blood levels are suspected to be lo w or high is recommended. Home blood glucose monitoring is normally carried out using a por table glucose meter and \201 nger-pricking device. Regular testing is required to assist with insulin dose-adjustment decisions, and to learn and predict how changes in lifestyle, food, and exercise affect glycaemic control. A minimal testing frequency of 4 times per day should be encouraged. SC continuous glucose monitoring (CGM) devices are also now availabl e and in certain select situations may offer some advantages and bene \201 ts to patients. \200 12_McClure_12.indd 409 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 410 Type 1 diabetes mellitus: insulin therapy Table 12.1 describes the various insulin analog p reparations (created by minor amino acid substitutions to the \200\230native \200\231 huma n insulin molecule). Table 12.1 Characteristics of various insulin analog preparations Type Example Onset Peak Duration Short-acting Regular/soluble 30 \200\22360min 1.5 \200\2233hr 4 \200\2236hr Rapid (analog) Insulin lispro 5 \200\22330min 30 \200\22390min 3 \200\2235hr Insulin aspart 15 \200\22330min 1 \200\2233hr 3 \200\2235hr Intermediate acti g NPH 1 \200\2234hr \200\22310hr 10 \200\22316hr Lente 3 \200\2234hr 6 \200\22312hr 12 \200\22318hr Long-acting Ultralente 1 \200\2234hr 8 \200\22316hr 18 \200\22322hr Insulin detemir 2 \200\2234hr None 12 \200\22320hr Long-acting (analog) Insulin glargine \200\2232hr None 20 \200\22324hr The daily requirement for insulin varies with age: \200 \200 \200 \200 at diagnosis, 0.5U/kg/day; childhood/prepubertal, 0.5 \200\2231.0U/kg/day; puberty, 1.2 \200\2232.0U/kg/day; post-puberty, 0.7 \200\2231.2U/kg/day. Insulin is administered SC, usually as a bolus injection. A number of patients receive insu lin in the form of a continuous SC insulin infusion (CSII) deliv- ered by a pump device. In sulin injection sites include the SC tissues of the upper arm, the anterior and lateral thi gh, the abdomen, and buttocks. There is a variety of different daily insulin injection therapy regimens. The choice of reg ime is a compromise between achieving optimal therapy and minimizing psychosocial developme nt. The patient and family must have input into the choice. Insulin regimens Two dose regimen The simplest regimen. Two injections per day. Each inject ion is a mix of short/rapid-acting insulin plus an intermediate-acting insulin. Traditional ly 2/3 of the total daily dose is given at breakfast and 1/3 given before/at the evening me al. Disadvantages \200 \200 \200 \200 Need to mix insulins. Peak action of insulin does not correspond with timing of main meals. Increased frequency of between meal and nocturnal hypoglycaemia. Between meal snacks requi red to minimize hypoglycaemia. Note: Less hypoglycaemia with rapid analog insulin use. 12_McClure_12.indd 410 11/14/2012 3:27:03 PM TYPE 1 DIABETES MELLITUS: INSULIN THERAPY 411 Three-dose regimen Improvement and intensi \201 cation of the two-dose regimen: \200 At breakfast: acting insulin. Before/at evening meal: At bedtime: mix of short or rapid acting insulin plus an intermediate- \200 short- or rapid-acting insulin only. intermediate-acting insulin only. Advantages Delayed evening intermediate-acting insulin results in reduced frequency of noct urnal hypoglycaemia. Basal bolus regimen This regimen attempts to mimic physiological secre- tion. Low level, ba ckground, basal insulin provides for fasting and between meal insulin requirements and larg er acute doses of fast-acting insulin are given to provide for prandial requirements. \200 Basal insulin: (traditionally at bedtime). Fast-acting insulin: meal snacks. once a day intermediate- or long-acting insulin At meal times (i.e. 3 per day) and with between Advantages \200 \200 Increased \202 exibility with meal times/exercise planning. Insulin dose adjustment \200 \224 carbohydrate (CHO) counting. Disadvantages \200 \200 Need for more injections. Need more frequent blood glucose monitoring. CSII Current insulin infusion pumps are reliable and portable. CSII therapy can be used in children of all ages. Short/rapid-acting insulin is adminis- tered as a continuous insulin infusion. Meal time boluses and \200\230blood glu- cose correction \200\231 boluses are ad ministered when required. Advantages \200 \200 \200 \200 No bolus injections/reduced injection frequency. Increased \202 exibility meal times/exer cise planning. Insulin dose adjustment \200\224CHO counting. Reduced frequency hypoglycaemi a. Disadvantages \200 \200 \200 No long-acting insulin. Infusion interruption: risk of rapid DKA. Need more frequent blood glucose monitoring. Greater management expertise required. Insulin requirements and dose adjustment Insulin doses are adjusted based on home blood glu cose monitoring. Generally it is best not to alter the basic insulin regimen every time the blood glucose levels are outside the target range (4 \200\22310mmol/L). Rather, recorded b lood glucose levels should be reviewed and insulin adjustments should be made to correct re current pro \201 les that are either too low or high. Insulin doses are adjusted by 5 \200 \22310% at a time. CHO counting: insulin dose adjustment system Applies the principle that the amounts of fast ing/rapid acting insulin given at mealtimes are adjusted and matched according to the amoun t of CHO consumed. 12_McClure_12.indd 411 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 412 Acute complications of Type 1 diabetes mellitus Hypoglycaemia All children with T1DM will e xperience an episode of hypoglycaemia. Symptoms develop when blood glucose <3.5mmol/L. The frequency of hypoglycaemia is higher with more intensive insulin regimens and in young chil dren. Symptoms and signs include: \200 \200 \200 \200 \200 \200 feeling of hunger; sweatiness; feeling faint/dizzy; \200\230wobbly feeling \200\231; irrit ability/confusion/misbehavior; pallor. Hypoglycaemia unawareness Occasionally, sudden onset of hypoglycaemia may result in unconsc ious- ness and seizures. Children experiencing frequent episodes of hypogly- caemia may fai l to develop the typical (i.e. counter-regulatory/adrenergic) symptoms of hypoglycaemia. Av oidance of hypoglycaemia usually results in restoration of warning symptoms. Nocturnal hypoglycaemia The frequency is thought to be high in T1DM (up to 50%). Nocturnal hy- poglycaemia should be suspected when fasting early morning blood sugars are repeatedly high, despite seemingly adequate overnight insulin cover (secondary to hypoglycaemia counte r-regulation). Detection and con \201 r- mation of nocturnal hypoglycaemia can be achieved by utilizing a SC con- tinuous glucose monitoring system (CGMS) device. Hypoglycaemia: management Acute episodes of mild to moderate symptomatic hypoglycaemia can be managed with oral glucose (glucose tablets or sugary drink). Oral glucose gels applied t o the buccal mucosa can be used in the child who is unwilling or unable to cooperate to eat . Severe hypoglycaemia can be managed in the home with an intramuscular injection of glucag on (1.0mg). This is avail- able as a speci \201 c injection kit. Sick day management During illness and other physiological stresses (e.g. following injury) insulin requirements dramatically increase in response to the body \200\231s increased cat abolic state. Blood glucose should be monitored more frequently than usual and insulin dose s may need to be increased. Insulin must be con- tinued at all times, even though oral inta ke of food and \202 uids may be decreased. Urine or plasma ketones must be monitored and, if elevated, are a sign of increased insulin needs and possible impending DKA. \200 In the presence of moderate to high ketone levels doses of soluble/ regular insulin must be increased (by 25 \200\22350%) and supplemental doses may need to be given. 12_McClure_12.indd 412 11/14/2012 3:27:03 PM ACUTE COMPLICATIONS OF TYPE 1 DIABETES MELLITUS 413 Carbohydrate and \202 uid intake should be maintained as much possible to avoid hypoglyca emia and dehydration. If the child is unable to maintain hydration (e.g. due to excessive vomiting) or cannot tak e in adequate carbohydrate to avoid hypoglycaemia then the child should be evaluated by the diabetes or other medical team and consideration given to treatment with IV \202 uids an d insulin infusions (see DKA). Diabetic ketoacidosis See also b pp.98 \200\223101. DKA is caused by a decrease in effectiv e circu- lating insulin associated with elevations in counter-regulatory hormones (glucagon , catecholamines, cortisol, GH). This leads to increased glucose production by the liver an d kidney and impaired peripheral glucose utiliza- tion with resultant hyperglycaemia and hy perosmolality. Increased lipoly- sis, with ketone body (beta-hydroxybutyrate, acetoacetate) production causes ketonaemia and metabolic acidosis. Hyperglycaemia and acidosis result in osmotic diuresis, dehydration, and obligate loss of electrolytes. Ketoacid accumulation al so induces an ileus, resulting in nausea and vomit- ing and an exacerbation of the dehydrat ion. DKA frequency The frequency of DKA occurring at T1DM onset, or diagnosis, is 10/100 000 chi ldren and is more common in children <4yrs of age. In established T1DM the frequency of DKA is approximately 1 \200\22310% per patient per year. The risk of DKA is increased in child ren with: poor metabolic control; previous episodes of DKA; peripubertal and adolescent gir ls; children with psychiatric disorders, including those with eating disorders; and those w ith dif \201 cult family circumstances. DKA mortality and morbidity Mortality rates for DKA are 0.15 \200\2230.31%. Cerebral oedema (CeO) accounts for 57 \200\22387% of all DKA-related deaths. The incidence of DKA-associat ed CeO is 0.46 \200\2230.87%. Reported mortality from CeO is high (21 \200\22325%) and sign i \201 cant morbidity is evident in 10 \200\22326% of all CeO survivors. 12_McClure_12.indd 413 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 414 Type 1 diabetes mellitus: long-term complications The risk of developing microvascular or m acrovascular complications is related to the duration of diabetes and to the degree of glyc aemic con- trol achieved over time. Patients who achieve and maintain good glycae- mic cont rol (i.e. HbA1c 7.0% or less) have a lower risk. Genetic factors may also in \202 uence th e risk of complications. The conditions outlined in Box 12.2 require screening. Box 12.2 Long-term complications of T1DM (see b p.415) Microvascular complications \200 \200 \200 Renal: Eyes: Nervous: microalbuminuria, diabetic nephropathy retinopathy peripheral neuropathy, autonomic neuropathy Macrovascular \200 Hypertension \200 CHD Macrovascular adolescents. Microvascular adolescent years of T1DM. The incidence and freque ncy is low before puberty. Risk factors for the development of early microvasular disease a re duration of diabetes, glycaemic control (long-term), and the onset of puberty. complications are almost never seen in children and complications may be seen during the childhood and Microalbuminuria (MA) \200 \200 \200 \200 Rare before puberty. May be intermittent and transient. May be associated with increased BP . May require treatment with ACE inhibitor if MA persists (+/ \200\223 hypertension). Retinopathy Signi \201 cant changes are rare before onset of puberty. Background retinopa- thy (microaneurysms, retinal hemorrhages, soft and hard exudates) may be seen. Pre-prolife rative/pro \201 lerative retinopathy rare (b p.920). Both the conditions should be screened for annually from age 11yrs (or from 9yrs if duratio n of DM >5yrs). MA screening by EMU estimation of urinary albumin: creatinine ratio. Retino pathy screening by digital retinal photography. 12_McClure_12.indd 414 11/14/2012 3:27:03 PM TYPE 1 DIABETES MELLITUS: ASSOCIATED ILLNESSES 415 Type 1 diabetes mellitus: associated illnesses Patients with T1DM are at increased risk for a number of other autoim- mune disorders. The most important of these are the following: Autoimmune thyroiditis: u Coeliac disease: \200 \200 Adrenal insuf \201 ciency: uncommon. \200 p to 5% develop hypothyroidism. prevalence rate 5 \200\22310%; usually atypical symptoms or asymptomatic. Testing for thyroid autoantibodies, thyroid function tests (TSH and free T4), together with a coeliac disease antibody screen (transglutaminase or endomysial antibodies), should be c arried out on an annual basis for the early detection and treatment of these disorders. Screening and long-term monitoring Glycaemic control Glycated hemoglobin index (HbA1c) measured every 3 \200\2234mths. Growth and development \200 \200 Height/weight/BMI (regularly at clinic). Puberty stage (annual). Microvascular complications \200 Microalbuminuria screening: \200 \200 Retinopathy screening: retinal photography (annua l screening). Neuropathy (rare). Associated autoimmune disease: \200 \200 urine dipstick test (regularly at clinic); 3 early morning urinary albumin/creatinine ratio (annual screening). \200 \200 thyroid disease (annual); coeliac disease (annual). 12_McClure_12.indd 415 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 416 Type 2 diabetes mellitus T2DM is a multifactorial and heterogeneous condition in which the balance between insulin sensitivity and insulin secretion is impaired. The condition is cha racterized by hyperinsulinaemia; however, there is relative insulin in- suf \201 ciency to overcome underlying concomitant tissue insulin resistance. Epidemiology T2DM is emerging as a signi \201 cant health problem with increasing incidenc e in most developing countries. The increasing frequency of T2DM parallels the upward trend in childhood obesity in these populations. In the USA, T2DM now accounts for up to 45% of the new cases of diabetes diagnosed in childhood. Etiology T2DM is not an autoimmune disease. There is no association with HLA- linked genes; however, there is a strong genetic basis, which is thought to be polygenic. The known risk factors for the development of T2DM are as follows. \200 Obesity. \200 Family history of T2DM. \200 Ethnic origin: \200 Asian; \200 African-American; \200 Afro-Caribbean ; \200 Paci \201 c-Islander; \200 Mexican-American; \200 Native American. Polycystic ovarian syndrome. Small for gestational age (SGA). \200 Clinical features Clinical presentation ranges from mild incidental hyperglycaemia to the t ypical manifestations of insulin de \201 ciency. Presentation with DKA may occasionally be seen. Frequent clinical \201 ndings include evidence of obesity and acanthosis nigricans . Diagnosis Current diagnostic prerequisites for T2DM are: \200 presence of T2DM risk facto rs (see list in \200 lack of absolute/persistent insulin de \201 ciency; \200 absence of pancreatic autoantibodies. b \200\230Etiology \200\231 above); Not infrequently the distinction between T1DM and T2DM at initial pres- entation may be dif \201 cult. 12_McClure_12.indd 416 11/14/2012 3:27:03 PM TYPE 2 DIABETES MELLITUS 417 Management All patients with T2DM require the same type and degree of educational support a nd clinical follow-up as for patients with T1DM. Long-term man- agement goals are the same as for T1DM (see b p.408). Speci \201 c treatment goals should in addition include the following: aim to improve insu lin sensitivity and insulin secretion; manage obesity and its comorbidities via lifestyle c hanges; screening and management of T2DM comorbidities such as hyperlipdaemia and hypertens ion. \200 \200 Mild (incidental) T2DM should initially be managed with lifestyle inter- ventions aimed at lowering caloric intake (low fat; reduced CHO diet) and increasing physical activity. Where these interventions fail, pharma- cological therapy is added. In children, the oral insuli n sensitizing agent metformin is added as a \201 rst step; however, if glycaemic targets remain dif \201 cult to achieve insulin therapy should be included. 12_McClure_12.indd 417 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 418 Other forms of diabetes mellitus Maturity onset diabetes of young (MODY) A clinical heterog eneous group of disorders characterized by an autoso- mal dominant mode of inheritance, ons et usually before the age of 25yrs, and non-ketotic diabetes at presentation. The condition is due a primary defect in B-cell function and insulin secretion. Six different types have been identi \201 ed due to mutations in 6 different genes (see Box 12.3). Neonatal diabetes mellitus Rare (1/400 000 \200\223500 000 live births). De \201 ned as hy perglycaemia requiring insulin therapy occurring in the \201 rst few weeks of life, trans ient (50 \200\22360%) and permanent forms are recognized. \200 