Other complications and associated conditions with diabetes in children and adolescents

Abstract

Monitoring of growth and development and the use of percentile charts is a crucial element in the care of children and adolescents with diabetes. Increased height at diagnosis of type 1 diabetes has been frequently reported 1-4. The precise mechanism for this and whether or not this increased height is maintained is unclear. Some studies report that poorly controlled patients show a decrease in height standard deviation score over the next few years, whilst better controlled patients maintain their height advantage 3, 4. Others have not shown this relationship with diabetic control 1. In a recent Australian study, children treated with modern regimens (diagnosed after 1990) maintained their increased height better than children diagnosed before 1991 2. Although the median HbA1c did not differ significantly, those diagnosed after 1990 had a significantly higher number of insulin injections per day. Poor gain of height and weight, hepatomegaly (NASH non alcoholic steatosis hepatis) and late pubertal development (Mauriac syndrome) might be seen in children with persistently poorly controlled diabetes. Insulin insufficiency, celiac disease and other gastrointestinal disorders should be considered in this setting. There is no role for human growth hormone therapy in the poorly growing child with diabetes, unless it is associated with documented growth hormone deficiency. Once the child or adolescent has reached a satisfactory weight after diagnosis, excessive weight gain may indicate high energy intake, and this may be related to excessive exogenous insulin. Excessive weight gain is more common during and after puberty 5. The Diabetes Control and Complications Trial and other studies have reported increased weight gain as a side effect of intensive insulin therapy with improved metabolic control 6-8. As obesity is a modifiable cardiovascular risk factor, careful monitoring and management of weight gain should be emphasised in diabetes care. Girls seem to be more at risk of overweight and as well of eating disorders, In association with increased weight is the risk of hyperandrogenism and polycystic ovarian syndrome 9. As increased doses of insulin are required during the adolescent growth spurt, it is important to remember to reduce the dose, when pubertal development is completed. Islet cell antibodies (ICA) as well as autoantibodies to insulin, the 65 kDa isoform of glutamic acid decarboxylase (GAD65), and/or the protein tyrosine phosphatase (PTP) related molecules IA-2 (ICA512) and IA-2ß (phogrin) are observed in the overwhelming majority of children en route to clinical type 1 diabetes 10, 11. A higher proportion of children with type 1 diabetes have also other detectable organ-specific autoantibodies (e.g. thyroid, adrenal) than children from the general population. Family members of children with diabetes are more likely to have autoantibodies and other manifestations of autoimmune disease than the general population 12, 13. Primary hypothyroidism due to autoimmune thyroiditis occurs in approximately 3–8% 14 or 0.9 per 100 patient years 15 of children and adolescents with diabetes. Antithyroid antibodies have been shown to occur during the first years of diabetes in up to 25% of individuals with diabetes 16-20, and to be predictive for the development of clinical or compensated hypothyroidism 20. Thyroid antibodies are observed more frequently in girls than in boys, often emerging along with pubertal maturation 20. Clinical features may include the presence of a painless goitre, increased weight gain, retarded growth, tiredness, lethargy, cold intolerance and bradycardia. Diabetic control may not be significantly affected. Hypothyroidism is confirmed by demonstrating a low free thyroxine and a raised TSH concentration. Compensated hypothyroidism may be detected in an asymptomatic individual with a normal thyroxine level and a modestly increased TSH. The treatment is based on replacement with oral L-thyroxine (T4) sufficient to normalise TSH levels and usually this allows regression of the goitre if present. Hyperthyroidism is less common than hypothyroidism in association with diabetes 18, 21, but still more common than in the general population. It may be due to Grave's disease or the hyperthyroid phase of Hashimoto's thyroiditis. Hyperthyroidism should be considered if there is unexplained difficulty in maintaining glycaemic control, weight loss without loss of appetite, agitation, tachycardia, tremor, heat intolerance, thyroid enlargement or characteristic eye signs. Treatment is anti-thyroid drugs such as carbimazole or propylthiouracil. Beta-adrenergic blocking drugs are helpful during the acute phase of thyrotoxicosis to control tachycardia and agitation. Treatment options for persistent or recurrent hyperthyroidism include surgery or radio-active iodine. Celiac disease occurs in 1–10% of children and adolescents with diabetes or 0.7 per 100 patient years 15, 22-30. Celiac disease is often asymptomatic(26,28,31) and not necessarily associated with poor growth or poor diabetes control (although it should be excluded in such situations). Any child with gastrointestinal signs or symptoms including diarrhoea, abdominal pain, flatulence, dyspeptic symptoms, recurrent aphthous ulceration, unexplained poor growth or anaemia should be investigated. Undiagnosed celiac disease has also been associated with increased frequency of hypoglycaemic episodes and a progressive reduction in insulin requirement over a 12 month period prior to diagnosis 32. The screening for celiac disease is based on the detection of IgA antiendomysial (EmA) antibodies and IgA antibodies against tissue transglutaminase (tTG). Although experience with a recently introduced assay for tissue transglutaminase (tTG) antibodies suggests that tTG may be more sensitive than EMA (91% vs 86%), the latter is slightly more specific for celiac disease (100% vs 96%) 33. Antigliadin antibodies might be more sensitive for celiac disease than EMA and tTg antibodies in very young children (<2 years), although their specificity remains modest. IgA deficiency (which is present in 1:500 people) should be excluded when screening for celiac disease by measuring the total IgA level. IgA antibodies may not be detected in IgA deficiency, resulting in a false negative test. If the child is IgA deficient, then IgG antigliadin and IgG tTG antibodies need to be used for screening 34. This is particularly important because celiac disease is more common in those with IgA deficiency than in the general population (1.7% compared with 0.25%) 35. In the presence of an elevated antibody level, a small bowel biopsy is needed to confirm the diagnosis of celiac disease (MARSH Classification) 36. A gluten-free diet normalises the bowel mucosa and frequently leads to disappearance of antibodies, but may not necessary lead to improved diabetic control 37. In an asymptomatic child with proven celiac disease gluten-free diet can be considered justified with the aim of reducing the risk of subsequent gastrointestinal malignancy and conditions associated with subclinical malabsorption (i.e. osteoporosis and iron deficiency). Whilst this is a prudent recommendation, there is no literature documenting the long-term benefit of a gluten-free diet in asymptomatic children diagnosed with celiac disease by routine screening. One paediatric case series has shown an increase in height-for-weight following the introduction of gluten-free diet 31. Another demonstrated a non-significant increase in BMI and a non-significant reduction in HbA1c38. Some studies have demonstrated short term benefits in other patient groups in terms of improved wellbeing and increased bone mineral density 39-41. The risk of celiac disease is negatively and independently associated with age at onset of diabetes, with a threefold higher risk being seen in children age <4 years than in those age >9 years; 42. It is also more common at diagnosis and in the first five years after diagnosis: in one study using annual EmA screening and biopsy 3.3% were positive at diabetes diagnosis; 3.3% at 1 year, 1.7% at 2 years, 1.7% at 3 years and 0.3% at 5 years 43. Children with proven celiac disease should be referred to a paediatric gastroenterologist and receive support from a paediatric dietician with experience of gluten-free diets. Vitiligo is an acquired pigmentary disorder characterised by a loss of melanocytes resulting in white spots or leukoderma 44. It is a common autoimmune condition associated with type 1 diabetes and is present in about 6% of diabetic children 45. Treatment is difficult and multiple therapies have been tried with little success. Up to 2% of patients with type 1 diabetes have detectable antiadrenal autoantibodies 16, 46, 47. Addison's disease is occasionally associated with type 1 diabetes in the Autoimmune Polyglandular Syndromes (APS I and 11). APS 1 is associated with mucocutaneous candidiasis and hypoparathyroidism and is caused by a mutation in the Autoimmune regulator gene (AIRE) on chromosome at chromosome 21q22.3 48, 49. APS II is more common in adults but is also seen in children in association with autoimmune thyroiditis 50. The condition is suspected by the clinical picture of frequent hypoglycaemia, unexplained decrease in insulin requirements, increased skin pigmentation, lassitude, weight loss, hyponatraemia and hyperkalaemia. The diagnosis is based on the demonstration of a low cortisol response to a ACTH test. Treatment with a glucocorticoid is urgent and lifelong. In some cases the therapy has to be supplemented with a mineralocorticoid. In asymptomatic children with positive adrenal antibodies detected on routine screening, a rising ACTH level suggests a failing adrenal cortex and the development of primary adrenal insufficiency. The immunodysregulation polyendocrinopathy x-linked syndrome (IPEX) is another rare disorder associated with diabetes in early childhood, severe enteropathy and autoimmune symptoms due to a clear genetic defect (FOX-P3) 51. Lipoatrophy is now seen infrequently with the use of human insulin. Recent case reports have described lipoatrophy also occurring in pump patients treated with lispro insulin and in patients treated with Lantus 52-54 it is still a rare side effect. Lipohypertrophy is a frequent complication of insulin therapy. It has been found in up to 48% of those with type 1 diabetes and has associated with higher HbA1c, more injections and longer duration but not the needle length 55-57. Non-rotation of injection sites has been consistently reported as an independent risk factor for lipohypertrophy 55, 57. Not only is it unsightly, but insulin may be absorbed erratically and unpredictably from these areas 58, 59. These are well circumscribed, raised reddish lesions sometimes progressing to central ulceration, usually seen in the pre-tibial region. The reported prevalence in children varies from 0.06% to 10% 45, 60. The aetiology is not clearly understood. Necrobiosis lipoidica diabeticorum has been associated with underlying microvascular complications 61, 62. A wide variety of treatments have been used over the years in adults including: topical, systemic or intra-lesional steroids, aspirin, cyclosporin, mycophenolate, becaplermin, excision and grafting, laser surgery, hyperbaric oxygen, topical granulocyte-macrophage colony-stimulating factor and photochemotherapy with topical PUVA 63-70. None has been proven useful in controlled clinical trials and many of these treatments have significant side effects. Limited joint mobility (LJM) is the earliest clinically apparent long-term complication of type 1 diabetes in childhood. It is a bilateral painless, but obvious, contracture of the finger joints and large joints, associated with tight waxy skin. Following its initial description associated with short stature, and early microvascular complications, it was recognized to be a common feature of both type 1 and type 2 diabetes, with a wide range of limitation, affecting ∼ 30% of youngsters and correlating with diminished stature 71, 72. Changes begin in the metacarpophalangeal and proximal interphalangeal joints of the fifth finger and extend radially with involvement of the distal interphalangeal joints as well. Involvement of larger joints includes particularly the wrist and elbow, but also ankles and cervical and thoracolumbar spine. The limitation is only mildly disabling even when severe. A simple examination method is to have the patient attempt to approximate palmar surfaces of the interphalangeal joints 73. Passive examination is essential to confirm that inability to do so is due to LJM. With rare exception, LJM appears after the age of 10 years. The interval between the detection of mild LJM and progression to moderate or severe changes in those who progress beyond mild changes, ranges from a few months to four years, following which stabilization occurs 72. Skin biopsy specimens have shown active fibroblasts and extensive collagen polymerization in the rough endoplasmic reticulum 74. The biochemical basis for LJM is likely glycation of protein with the formation of advanced glycation end products (AGE). This results in increased stiffness of the periarticular and skin collagen with decreased range of motion. Fluorescence of skin collagen, reflecting the accumulation of stable end products of the glycation reaction, with increased cross-linking, dehydration, and condensation of collagen. increases linearly with age but with abnormal rapidity in type 1 diabetes, correlating with the presence of retinopathy, nephropathy, and LJM 75. LJM is associated with a 3–4 fold risk for retinopathy, nephropathy, and neuropathy 72, 76, 77. Although cross-sectional studies showed no relationship to diabetes control as measured by HbA1c, longitudinal study of average HbA1c from onset of diabetes showed that for every unit increase in average HbA1c, there was an approximately 46% increase in the risk of developing LJM 78. There has been a >4 fold reduction in frequency of LJM between the mid-70s and mid-90s, in children 79 and a lesser decline in adults 80, with a marked decrease in severity in the fewer children who are affected, most likely the result of improved glucose control during this era. Generalised oedema due to water retention is a rare complication of insulin therapy. Oedema may be seen during establishment of improved glycaemic control after prolonged periods of poor metabolic control, particularly if there has been significant omission of insulin 81, 82. The oedema spontaneously resolves over a period of days to weeks with continued good glycaemic control. Monitoring of growth and physical development and the use of growth charts is an essential element in the continuous care of children and adolescents with type 1 diabetes. Screening of thyroid function by analysing circulating TSH and antibodies is recommended at the diagnosis of diabetes and, thereafter, every second year in asymptomatic individuals without goitre or in the absence of thyroid autoantibodies. More frequent assessment is indicated otherwise. Screening for celiac disease should be carried out at the time of diagnosis, annually for the first five years and every second year thereafter. More frequent assessment is indicated if the clinical situation suggests the possibility of celiac disease or the child has a first-degree relative with celiac disease. Children with type 1 diabetes detected to have celiac disease on routine screening, should be referred to a paediatric gastroenterologist and on confirmation of the diagnosis receive support from a paediatric dietician with experience of gluten-free diets. Routine clinical examination should be undertaken for skin and joint changes. Regular screening by laboratory or radiological methods is not recommended. There is no established therapeutic intervention for lipodystrophy, necrobiosis lipoidica or limited joint mobility.