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 Transient insulin production that resolves spontaneously in the postnatal period. IUGR is e vident at birth and FTT and hyperglycaemia occur in the \201 rst few days. Most patients will achieve remission and insulin independence within 1yr. However, in many, persistent di abetes recurs in late childhood/adulthood. TNDM is usually sporadic. Chromosome 6 abnormali ties are observed in many (paternal duplications; paternal isodisomy; methylation defects). Permanent associated with a number of clinical syndromes (IPEX syndrome \200\224 diffuse a utoimmunity; severe pancreatic hypoplasia associated with IPF-1 mutation; Walcott \200\223R allison syndrome). KCNJ11 related diabetes mellitus: activating mutations of the KCNJ11 gen e encoding the Kir62 subunit of pancreatic -cell K+-AJP sensitive channels. Typically pre sent in infancy and requires insulin initially. Later, treatment with oral sulphonylurea po ssible. Molecular genetic testing for this condition is recommended in all children with DM <1yr. This condition is associated with developmental delay and epilepsy in some cases (DE ND syndrome). neonatal diabetes mellitus (TNDM): disorder of developmental neonatal diabetes mellitus (PNDM): rare, and may be Cystic \201 brosis related diabetes (CFRD) The prevalence of CFRD increases with age (79% between ages 5 and 9yrs; 26% between ages 10 and 19yrs). It is primarily due to a defect i n pancre- atic insulin secretion, although modest insulin resistance is also recognized. In sulin is recommended for all patients with CFRD. Severe insulin resistance syndromes A rare, heterogeneous group of disorders. Genetic mutat ions resulting in insulin receptor and post-receptor signaling defects underlie the mechan- ism of severe insulin resistance. Hyperinsulinaemia is present. Common clinical features i nclude acanthosis nigricans and evidence of ovarian hyperandrogenism in females. Syndromes associated with severe insulin resistance include: \200 \200 \200 \200 type A insulin resistance; Donohue \200\231s syndrome; Rabson \200\223Mendenhal syndrome; p artial-lipodystrophy. 12_McClure_12.indd 418 11/14/2012 3:27:03 PM OTHER FORMS OF DIABETES MELLITUS 419 Box 12.3 Types of MODY MODY 1 \200 \200 \200 \200 \200 \200 5% of MODY cases HNF4 gene (20q) Mutation in Presents/onset at adolescence: <25yrs age Se vere hyperglycaemia Oral agents/insulin therapy often required Microvascular complications: frequent/high risk MODY 2 \200 \200 \200 \200 \200 \200 \200 10 \200\22363% of MODY cases Heterozygous for mutation in glucokinase gene (7p) B-cell Alte red glucose sensing by pancreatic Presents incidentally/onset early childhood Mild hypergly caemia Diet therapy alone Complications: rare MODY 3 \200 \200 \200 \200 \200 \200 20 \200\22370% of MODY cases Mutation in Presents/onset adolescence/<25yrs age Severe hyper glycaemia Oral agents/insulin therapy often required Microvascular complications: frequent/ high risk HNF1 gene (12q24) MODY 4 \200 Rare \200 Heterozygous for mutation in \200 Onset post-pubertal \200 Mo derately severe diabetes \200 Microvascular complications: rare IPF-1 gene (13q) MODY 5 \200 ? Rare \200 Mutation HNF-1 \200 Onset post-pubertal \200 Severe diabete s \200 Associated renal insuf \201 cency \200 Microvascular complications: unknown B/TCF2 gene (17cen-q21.3) MODY 6 \200 Rare \200 Mutation \200 Onset post-pubertal \200 ? Severe diabetes \200 Microvascular complications: unknown NeuroD1/ 2 gene (2q32) 12_McClure_12.indd 419 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 420 Goiter A goiter is an enlargement of the thyroid gland. It may be congenital or acquired. T hyroid function may be normal (euthyroid), underactive (hypothyroid), or overactive (hypert hyroidism). Enlargement is usually 2(cid:3) to increased pituitary secretion of TSH, but ma y, in certain cases, be due to an in \201 ltrative process that may be either in \202 amm atory or neoplastic. Congenital goiter The commonest causes of congenital goiter are due to the transplacental t ransmission of factors that interfere with fetal thyroid function from the mother to the fe tus: \200 \200 \200 maternal antithyroid drugs; maternal iodine exposure; maternal hyperthyroidism (Graves \200 \231s disease). Other rare causes include: \200 \200 \200 thyroid teratoma; endemic iodine de \201 ciency; thyroid hormone biosynthetic defects (e.g . Pendred syndrome). Acquired goiter \200 \200 \200 \200 \200 \200 Simple (colloid) goiter. Multinodular goiter. Acute thyroiditis. Graves \200\231s disease. Anti-thyroid chemical exposure: iodine intoxication. Anti-thyroid drugs: lithium, amiodaron e. Simple (colloid) goiter This is a euthyroid, non-toxic goiter of unknown cause. It is not a ssoci- ated with disturbance of thyroid function and is not associated with either in \202 ammation or neoplasia. Thyroid function tests and radioisotope scans are normal. It is mos t common in girls during or around the peripubertal years. Treatment is not needed, althoug h follow-up is recommended. Multinodular goiter \200 \200 \200 Rare. A \201 rm goiter with single or multiple palpable nodules. Thyroid function studies usually normal, although TSH and anti-thyroid antibody titres may be elevated. Abnormaliti es on thyroid US and areas of reduced uptake on radioisotope scanning may be seen. 12_McClure_12.indd 420 11/14/2012 3:27:03 PM SOLITARY THYROID NODULE 421 Solitary thyroid nodule Solitary nodules of the thyroid are uncommon. Approximately 15% may be associated with underlying thyroid cancer. Careful evaluation is required. Potential ca uses of a solitary thyroid nodule include: \200 \200 \200 \200 \200 \200 benign adenoma; thyroglossal cyst; ectopic, normal thyroid tissue; single median thyroid gl and; thyroid cyst or abscess; thyroid carcinoma. Investigation should include radioisotope (99mTc) scan. Cold nodules or nodules that feel h ard on palpation, or are rapidly growing should raise suspicion of thyroid cancer. Biopsy a nd surgical excision are indicated. Thyroid carcinoma Thyroid cancer is rare in childhood. Many carcinomas of the thyroid in th e past were associated with previous direct irradiation to the head and neck tissues for ot her conditions. Carcinomas of the thyroid are histologically classi \201 ed as being eithe r papillary, follicular, or mixed. They are usually slow growing. Girls are affected twice as often as boys. Presentation is usually with a painless thyroid nodule. Cervical lymph no de involvement is often evident at time of diagnosis. Metastases to the lung may be observe d radiologically, but are usually asymptomatic. Diagnosis is established by biopsy. Radiois otope scans (123I or 99mTc) demonstrate reduced uptake. Thyroid function tests are usually normal. Treatment and prognosis Thyroidectomy (subtotal or complete) is indicated. Radioiodine ther apy after surgery is often given. Post-ablative oral thyroid hormone replace- ment therapy is needed. Prognosis is usually very good, even with pres- ence of cervical node and/or met astases at diagnosis. Medullary thyroid cancer See b pp.440, 615. 12_McClure_12.indd 421 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 422 Congenital hypothyroidism Hypothyroidism may be due to a number of conditions that result i n in- suf \201 cient secretion of thyroid hormones. Congenital hypothyroidism is a relativ ely common condition, occurring in approximately 1/4000 births. It is twice as common in gi rls than in boys. Etiology The causes of congenital hypothyroidism include the following: \200 Thyroid dysgenesis hypoplasia, ectopic thyroid (lingual/sublingual). Thyroid hormone biosyn thetic defect syndrome. Iodine de \201 ciency (rare UK; but common worldwide). Congenital TSH de \201 ciency hormone de \201 ciencies. (85%): usually sporadic; resulting in thyroid aplasia/ (15%): hereditary, e.g. Pendred \200\231s \200 (rare): associated with other pituitary Clinical features Usually non-speci \201 c; they are dif \201 cult to detect in \201 rs t month of life. They include: \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 umbilical hernia; prolonged jaundice; constipation; hypotonia; hoarse cry; poor feeding; ex cessive sleepiness; dry skin; coarse faecies; delayed neurodevelopment. Diagnosis In most developed countries there are national neonatal biochemical screening pro grams. \200 \200 \200 Test in 1st week of life. Blood spot \200\224 \201 lter paper collection (e.g. \200\230Gu thrie card \200\231). TSH (high) and/or fT4 (low) estimation. Thyroid imaging is also recommended to determine whether the cause is due to thyroid dysgen esis or due to hormone biosynthetic disorder. \200 \200 Thyroid US. Radionucleotide scanning ( 99Tc or 131I). 12_McClure_12.indd 422 11/14/2012 3:27:03 PM CONGENITAL HYPOTHYROIDISM 423 Treatment Without early hormone replacement therapy a number of adverse seque- lae may occu r. \200 \200 \200 \200 \200 Neurodevelopmental delay and mental retardation. Poor motor coordination. Hypotonia. Ataxia . Poor growth and short stature. The earlier the treatment with oral thyroid hormone replacement therapy is initiated the be tter the prognosis: levothyroxine (initial dose 10 \200\22315micrograms/kg/day). Monitoring therapy Monitor serum TSH and T4 levels: \200 Every 1 \200\2232mths 1st year; every 2 \200\2233mths age 1 \200\2232yrs; every 4 \200\2236 mths age >2yrs. Maintain T4 level in upper half of normal range; TSH in lower end of normal range. Transient hyperthyrotropinaemia This is uncommon and is usually detected at the time of neo natal thy- roid screening. It is characterized by slightly elevated serum TSH level in pres ence of otherwise normal serum T4 levels. It is probably due the transplacental transmissio n of maternal thyroid antibodies to the child in utero. Presumed cases do not need treatmen t, but must be monitored. TSH levels that remain persistently elevated after a few months o r low T4 levels should be treated with oral levothyroxine. 12_McClure_12.indd 423 11/14/2012 3:27:03 PM CHAPTER 12 Endocrinology and diabetes 424 Acquired hypothyroidism A relatively common condition with an estimated prevalence of 0.1 \200\2230.2% in the population. The incidence in girls is 5 \200\22310 times greater than b oys. Etiology Acquired hypothyroidism may be due to a primary thyroid problem or indirectly to a central disorder of hypothalamic \200\223pituitary function. Primary hypothyroidism (raised TSH; low T4/T3) \200 \200 \200 \200 \200 Autoimmune (Hashimoto \200\231s or chronic lymphocytic thyroiditis). Iodine de \201 ciency : most common cause worldwide. Subacute thyroiditis. Drugs (e.g. amiodarone, lithium). Post -irradiation thyroid (e.g. bone marrow transplant \200\224total body irradiation). Post-abl ative (radioiodine therapy or surgery). Central hypothyroidism (low serum TSH and low T4) H ypothyroidism due to either pituitary or hypothalamic dysfunction. \200 \200 \200 Intracranial tumors/masses. Post-cranial radiotherapy/surgery. Developmental pituitary defe cts (genetic, e.g. isolated TSH de \201 ciency; multiple pituitary hormone de \201 cienci es. PROP-1, Pit-1 genes): Clinical features The symptoms and signs of acquired hypothyroidism are usually insidious a nd can be extremely dif \201 cult to diagnose clinically. A high index of sus- picion is n eeded. \200 \200 \200 \200 \200 \200 \200 \200 Goiter: Increased weight gain/obesity. Decreased growth velocity/delayed puberty. Delayed s keletal maturation (bone age). Fatigue: Constipation: Dry skin: Pseudo-puberty: testicular enlargement. Slipped upper (capital) femoral epiphysis: primary hypothyroidism. mental slowness; deteriorating school performance. cold intolerance; bradycardia. coarse hair. girls \200\224isolated breast development; boys \200\224isolated hip pain/limp. Diagnosis Diagnosis is dependent on biochemical con \201 rmation of hypothyroid state. \200 \200 Thyroid function tests: high TSH/low T4/low T3. Thyroid antibody screen. Raised antibody ti tres: \200 \200 \200 antithyroid peroxidase; anti-thyroglobulin; TSH receptor (blocking type). Treatment \200 \200 \200 Oral Levothyroxine (25 \200\223200 micrograms/day). Monitor thyroid function test every 4 \200\2236mths during childhood. Monitor growth and neurodevelopment. 12_McClure_12.indd 424 11/14/2012 3:27:04 PM HYPERTHYROIDISM (THYROTOXICOSIS) 425 Hyperthyroidism (thyrotoxicosis) \200 Thyrotoxicosis: \201 ndings that result when the tissues are exposed to excess thyroid ho rmones. Hyperthyroidism: the thyroid gland leading to a state of thyrotoxicosis. refers to the clinical, physiological, and biochemical denotes those conditions resulting in hyperfunction of Causes of thyrotoxicosis Due to hyperthyroidism \200 Excessive thyroid stimulation: \200 Graves \200\231s disease ( b p.428) \200 Hashimoto \200\231s disease (Hasitoxicosis; b pp.124, 427) \200 neonatal (transient) thyrotoxicosis ( \200 pituitary thyroid hormone resistance (excess TSH) \200 McCune \200\223Albright syndrome (McAS; \200 hCG-secreting tumors Thyroid nodules (autonomous): \200 \200 b p.426) b p.441) toxic nodule/multinodular goiter thyroid adenoma/carcinoma ( b p.421) Not due to hyperthyroidism \200 Thyroiditis: \200 subacute \200 drug-induced Exogenous thyroid hormones Clinical features (all causes) Thyrotoxicosis may be associated with the following symptoms : \200 \200 \200 \200 \200 \200 \200 \200 \200 hyperactivity/irritability; poor concentration; altered mood; insomnia; heat intolerance/fa tigue/muscle weakness/wasting; weight loss despite increased appetite; altered bowel habit \200\224diarrhea; menstrual irregularity; sinus tachycardia; increased pulse pressure; hype rre \202 exia; \201 ne tremor; pruritis. Investigations \200 \200 Thyroid function tests (serum): Thyroid antibodies: receptor antibody (stimulatory type). R adionucleotide thyroid scan: decreased uptake (thyroiditis). raised T4 and T3; suppressed TSH. antithyroid peroxidase; anti-thyroglobulin; TSH increased uptake (Graves \200\231s disease); 12_McClure_12.indd 425 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 426 Graves \200\231s disease Graves \200\231s disease is an autoimmune disorder with genetic an d environmen- tal factors contributing to susceptibility. Several HLA-DR gene loci (DR3; DQ A1*0501) have been identi \201 ed as susceptibility loci and there is often a family histo ry of autoimmune thyroid disease (girls > boys). Graves \200\231s disease occurs due to a p redominance of stimulating type autoantibodies to the TSH receptor. Clinical features In addition to those of hyperthyroidism (see b p.424), Graves \200\231s d isease is characterized by speci \201 c features: \200 \200 Diffuse goiter (majority). Graves \200\231s ophthalmopathy: retraction; periorbital oedema/ chemosis; ophthalmoplegia/extraocular muscle dysfunction. exophthalmos/proptosis; eyelid lag or Diagnosis Clinical suspicion of Graves \200\231s disease requires con \201 rmatory blood t est: \200 : high T4/high T3/low TSH. \200 Thyroid function tests Thyroid antibody screen: antithyroid peroxidase; anti-thyroglobulin +ve; TSH receptor antibody (stimulatory type) +ve; radionucleotide thyroid scan \200\224inc reased uptake. Treatment The aims of therapy are to induce remission of Graves \200\231s disease with anti - thyroid drugs (carbimazole or propylthiouracil) and, if necessary, to bring the symptoms of thyrotoxicosis (anxiety, tremor, tachycardia) under con- trol using a B-blocking agent ( propranolol). Two alternative regimens are practiced. \200 Dose thyroid function. Block a nd replace regimen: antithyroid treatment maintained at the lowest dose necessary to induce complete thyroid suppression and therapeutic hypothyroidism. In this situation replacement thyroxine therapy is also necessary to achieve euthyroidism. titration regimen: antithyroid treatment titrated to achieve normal Antithyroid therapy is usually given for 12 \200\22324mths in children, before con- siderin g a trial off treatment. Thyroid function (serum-free T4; TSH levels) should be monitored a t regular intervals (1 \200\2233mths). Prognosis Following completion of treatment 40 \200\22375% of children will relapse over th e next 2yrs. Relapses may be treated with a further course of antithyroid drugs, although d e \201 nitive therapy with radioiodine is being offered as the \201 rst-line treatment. Thyroid surgery is another approach for management of relapses. Following ablative treatmen t (either radioiodine or surgery), lifelong thyroxine replacement therapy will be required. 12_McClure_12.indd 426 11/14/2012 3:27:04 PM GRAVES \200\231S DISEASE 427 Neonatal thyrotoxicosis (see b p.124) \200 Rare and due to the passive transfer of maternal thyroid antibodies from a thyrotoxic mothe r to the fetus. Affected neonates are irritable, \202 ushed, and tachycardic. Weight gain is poor and cardiac failure may be present. The condition is self-limiting. Supportive tre atment, e.g. beta blocker therapy, is required. 12_McClure_12.indd 427 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 428 Thyroiditis In \202 ammation of the thyroid gland that may result in goiters. Initial thy- rotoxicosis is usually followed by hypothyroidism. Recognized causes in- clude: \200 \200 \200 autoimmune thyroiditis (Hashimoto \200\231s); acute suppurative (pyogenic) thyroiditis; sub acute (de Quervain) thyroiditis. Autoimmune thyroiditis (Hashimoto \200\231s) This is the most common cause of thyroid disea se in childhood and ado- lescence and is the most common cause of hypothyroidism in develop ed countries. \200 Characterized by lymphocytic in \201 ltration of the thyroid gland and early thyroid folli cular hyperplasia, which gives way to eventual atrophy and \201 brosis. Associated with a positive family history of thyroid disease. There is an increased risk of other autoimmune disorders (e.g. type 1 diabetes). 4 \200\2237 times more common in females than in males. Children with Down \200\231s or Turner \200\231s syndrome are at increased risk. Peak incid ence is in adolescence, although may occur at any age. \200 \200 Presentation Clinical presentation is usually insidious with a diffusely enlarged, non- ten der, \201 rm goiter. Most children are asymptomatic and biochemically eu- thyroid. Some c hildren may present with hypothyroidism. A few children may have symptoms suggestive of hyp erthyroidism, i.e. \200\230Hashitoxicosis \200\231. The clinical course is variable. Goiters may become smaller and disap- pear or may persist. Many children who are initially euthroid eventually develop hypothyroidism within a few mo nths or years of presentation. Periodic follow-up is therefore necessary. Investigations \200 \200 \200 Diagnosis can be established by thyroid biopsy (but not indicated). Thyroid biochemistry ma y be normal or abnormal. Anti-microsomal thyroid antibody titres are usually raised, wherea s anti-thyroglobulin titres are increased in only approximately 50%. Treatment Only required for the management of either hypothyroidism (see b p.424) or hypert hyroidism if present (see b p.426). 12_McClure_12.indd 428 11/14/2012 3:27:04 PM THYROIDITIS 429 Acute suppurative thyroiditis This is uncommon. Often preceded by respiratory tract infecti on. Organisms include Staphylococcus aureus, streptococci, and Escherichia coli (rarely, fungal infection). Abscess formation may occur. \200 Presentation is with p ainful tender swelling of thyroid. \200 Thyroid function is usually normal; however, hype rthyroidism may occur. Recurrent infection should raise suspicion of the presence of a thyr oglossal tract remnant. Treatment requires administration of antibiotics and surgical drain age of abscess if present. Subacute thyroiditis (de Quervain \200\231s) \200 A self-limiting condition of viral origin, associated with tenderness and pain overlying th e thyroid gland. Symptoms of thyrotoxicosis may be present initially, although hypothyroidi sm may develop later. Treatment includes non-steroidal anti-in \202 ammatory agents and, i n severe cases, corticosteroids (prednisolone). Beta-blocker therapy, e.g. propranolol, may help to control thyrotoxic symptoms. 12_McClure_12.indd 429 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 430 Adrenal insuf \201 ciency p \200 adrenal failure: results in both reduced glucocorticoid (cortisol) and mineralocorticoid (aldosterone) production. Adrenocorticotrophin (ACTH) levels are elevated due to reduced cortisol negative feedback drive. s \200 adrenal failure: is due to either reduced corticotrophin-releasing factor (CoRF) or reduced ACTH production (or both) and results in reduced cortisol production only. Mineralocortico id activity remains normal as this is mainly regulated by the angiotensin \200\223renin sys tem. Causes of adrenal insuf \201 ciency Primary Acquired \200 \200 \200 \200 Autoimmune adrenalitis (Addison \200\231s disease). Adrenal infection, e.g. tuberculosis. A drenal hemorrhage/infarction. Latrogenic: adrenolectomy; drugs (e.g. ketoconazole). Congenital \200 \200 \200 \200 b p.436). b p.439). Congenital adrenal hyperplasia ( Congenital adrenal hypoplasia ( Adrenoleucodystrophy. Fami lial glucocorticoid de \201 ciency. Secondary \200 Defects of hypothalamus/pituitary structures: \200 \200 congenital \200\224pituitary hypoplasia; intracranial masses: tumors (e.g. glioma, germinom a); craniopharyngioma; intracranial in \202 ammation: Langerhan \200\231s histiocytosis; i ntracranial infections; cranial radiotherapy/irradiation; neurosurgery; traumatic brain inj ury. \200 \200 \200 \200 Suppression of hypothalamic \200\223pituitary \200\223adrenal a xis: \200 \200 glucocorticoid therapy; Cushing \200\231s disease (after pituitary tumor removal). 12_McClure_12.indd 430 11/14/2012 3:27:04 PM ADRENAL INSUFFICIENCY 431 Clinical features The age of onset and manifestations will depend on the underlying cause. Clinical features may be subtle and a high index of suspicion is often re- quired. Typicall y, clinical features are gradual in onset with partial insuf- \201 ciency leading to comp lete adrenal insuf \201 ciency with impaired cortisol responses to stress and illness (adr enal crises): \200 \200 \200 \200 \200 \200 \200 anorexia and weight loss; fatigue and generalized weakness; dizziness (hypotension); salt c raving (primary adrenal insuf \201 ciency); hyperpigmentation (primary adrenal insuf \201 ciency); reduced pubic/axillary hair (primary adrenal insuf \201 ciency); hypoglycaemia ( neonates/infants). Diagnosis Basal serum cortisol and ACTH Note: Random basal cortisol levels are often within the normal range and cannot be relied on. Inappropriately low basal cortisol during \200 \230stress \200\231 sug- gests adrenal insuf \201 ciency. A basal cortisol level of >550nm ol/L usually excludes this diagnosis. An elevated early morning (09.00 hours) ACTH level fo r the level of cortisol is suggestive of primary adrenal insuf \201 ciency. Adrenal stimulation tests Usually required to establish a diagnosis of adrenal insuf \201 ciency and are used to demonstrate inappropriately low serum cortisol responses to physiolo gical or pharmacological stimulation of the adrenal glands. \200 Insulin tolerance test: mild hypoglycaemia is used to assess the integrity of the entire hy pothalamic \200\223pituitary \200\223adrenal axis. Serum cortisol response to hypoglycaemia (>550nmol/L) is normal. ACTH stimulation (synacthen) test: baseline and at +30 and +60min after IV/IM of synthetic ACTH (short synacthen test). Serum cortisol response >550nmol/L at 60min is considered normal. Recent onset secondary adrenal insuf \201 ciency may produce a normal response to a short synacthen test. considered the gold standard test. Insulin-induced serum cortisol is measured at Other investigations \200 Serum electrolytes: \200 Adrenal antibody titres (Addison \200\231s disease). \200 Adrenal imaging: US; CT scan. \200 Adrenal androgen pro \201 le: serum/urine. \200 Molecular genetic studies. \200 Pituitary imaging: serum sodium (low); serum potassium (high). CT or MRI scan. 12_McClure_12.indd 431 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 432 Adrenal insuf \201 ciency: treatment Primary adrenal insuf \201 ciency requires both gluc ocorticoid and mineralo- corticoid replacement therapy. s adrenal insuf \201 ciency requir es glucocor- ticoid therapy only. \200 Glucocorticoid therapy: \200 \200\224oral 12 \200\22315mg/m2/day in 2 \200\2233 divided doses per day. hydrocortisone U sually about two-thirds of the dose is given in the morning, in an attempt to mimic normal diurnal variation in cortisol secretion. During times of illness and stress (e.g. infection , trauma, surgery) patients are advised to increase their normal daily maintenance dose of hydrocortisone by 2 to 3 times. Mineralocorticoid therapy: day. Monitor BP and plasma renin levels. \202 udrocortisone \200\224oral 50 \200\223150micrograms/ Adrenal crises An adrenal (or Addisonian) crisis is an acute exacerbation of an underlying adrenal insuf \201 ciency brought on by \200\230stresses \200\231 that necessitate increa sed production and secretion of cortisol from the adrenal gland. This is a life- threatenin g emergency and should be treated if there is a strong clinical suspicion rather than waiti ng for con \201 rmatory test results. Typical causes include infection, trauma, and surger y. Symptoms include: \200 \200 \200 \200 nausea/vomiting; abdominal pain; lethargy/somnolence; hypotension. Treatment \200 Immediate IV bolus of hydrocortisone followed by 6-hourly repeat injections. IVI \202 uid s/glucose. 12_McClure_12.indd 432 11/14/2012 3:27:04 PM ADRENAL INSUFFICIENCY: TREATMENT 433 12_McClure_12.indd 433 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 434 Adrenal excess A state of glucocorticoid (cortisol) excess. The commonest cause of hy- perc ortisolaemia is iatrogenic, due to exogenous steroids. Hyperfunction of the adrenal cortex resulting in excess cortisol secretion may have p (adrenal or ACTH-independent) or s (ACTH- dependent) causes. The term Cushing \200\231s disease applies to an ACTH-secreting pituitar y tumor. All other causes of glucocorticoid excess are often referred to as Cushing \200 \231s syndrome. Causes of adrenal (cortisol) excess \200 p \200 \200 \200 \200 s \200 \200 \200 Iatrogenic. adrenal hyperfunction (ACTH-independent): adrenal tumor (carcinoma/adenoma); nodular adrena l hyperplasia; b p.441). McAS ( adrenal hyperfunction (ACTH-dependent): Cushing \200\231s d isease \200\224pituitary ademona/hyperplasia; ectopic ACTH secretion (tumor). In young children (<5yrs) adrenal disorders are the most common, non- iatrogenic, cause of hypercorticolism. In neonates and infants, McAS should be considered. In older children and adolescents Cushing \200\231s disease is most common. Clinical features All causes of hypercortisolaemia are characterized by the following pat- tern of clinical signs and symptoms. \200 \200 \200 Obesity: \200\230Moon \200\231 faecies. Buffalo hump: pads. Muscle wasting. Proximal muscl e weakness. Skin abnormalities: (abdomen/thighs). Hypertension. Growth impairment: Pubertal delay/amenorrhoea. Osteoporosis. central adiposity \200\224face, trunk, abdomen. prominent/enlarged posterior cervical/supraclavicular fat \200 \200 thinning (rare in children); easy bruising; striae \200 \200 \200 reduced growth velocity; short stature. Note: Other signs may be present depending on the underlying cause. Children with adrenal t umors may have signs of abnormal virilization and masculinization (early pubic hair, hirsui tism, acne, clitoromegaly) due to excess adrenal androgen secretion. 12_McClure_12.indd 434 11/14/2012 3:27:04 PM ADRENAL EXCESS 435 Investigations These are directed at establishing a diagnosis of hypercortisolism and there after at differentiating between ACTH-dependent and ACTH- independent causes (see Box 12.4) . Box 12.4 Investigations to determine the following Is hypercortisolism present or not? \200 Serum cortisol circadian rhythm: midnight serum cortisol. \200 sampling for test to be valid Loss of normal diurnal variation \200\224rai sed midnight value observed. Note: Patients must be asleep at time of Urinary free cortisol excretion: 24hr collection Dexamethasone suppression test: \200 \200 \200 \200 overnight test (1mg dexamethasone at midnight) low dose test (0.5mg every 6hr for 48hr) fai lure of suppression of plasma cortisol levels is observed Cause of hypercortisolism \200 \200 Plasma ACTH: high in ACTH-dependent causes Dexamethasone suppression test: \200 \200 high dose test (2mg every 6hr for 48hr) in Cushing \200\231s disease serum cortisol levels decrease by approximately 50%. Ectopic ACTH secretion: no suppression. \200 \200 \200 CoRF test CT scan of adrenal glands MRI scan of brain Bilateral inferior petrosal sinus sam pling Management Cushing \200\231s disease \200 Preoperative treatment in order to normalize blood cortisol levels: \200 \200 Pituitary surgery: transsphenoidal surgery. Pituitary radiotherapy. metyrapone; ketaconazole. \200 Adrenal disease/tumor \200 Surgery, i.e. adrenalectomy. 12_McClure_12.indd 435 11/14/2012 3:27:04 PM CHAPTER 12 Endocrinology and diabetes 436 Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a family of disorder s character- ized by enzyme defects in the steroidogenic pathways that lead to the bio- syn thesis of cortisol, aldosterone, and androgens. The relative decrease in cortisol productio n, acting via the classic negative feedback loop, results in increased secretion of ACTH fr om the anterior pituitary gland and to sub- sequent hyperplasia of the adrenals. All forms of CAH are inherited in an autosomal recessive manner, and their clinical manifestation is determined by the effects produced by the particular hormones that are de \201 cient and b y the excess production of steroids unaffected by the enzymatic block. The causes of CAH include de \201 ciencies in the following steroidogenic pathway enzymes: \200 A-hydroxylase (CYP21); \200 B-hydroxylase (CYP11); 3 \200 B-hydr oxysteroid dehydrogenase; \200 A-hydroxylase/17 \200\22320 lyase (CYP17); \200 21 11 17 side-chain cleavage (SCC/StAR). De \201 ciency of the 21-hydroxylase enzyme is the most common form of CAH, accounting for over 90% of cases. 21 -hydroxylase de \201 ciency CAH due to de \201 ciency of the 21A- hydroxylase enzyme arises as a result of deletions or deleterious mutations in the active g ene (CYP21) located on chromosome 6p. Many different mutations of the CYP21 gene have been identi \201 ed, causing varying degrees of impairment of 21A-hydroxylase ac- tivity that r esult in a spectrum of disease expression. CAH can be classi \201 ed according to symptoms and signs and to age of presentation. \200 