Growth Hormone in Pediatrics - PDF

Growth hormone in pediatrics: indications and specificities in the child Dr. Alessandro Cattoni General and Specialistic Paediatrics School of Medicine and Surgery  Short stature Definition Stature below- 2 SD compared to the general population,...

Growth hormone in pediatrics: indications and specificities in the child Dr. Alessandro Cattoni General and Specialistic Paediatrics School of Medicine and Surgery  Short stature Definition Stature below- 2 SD compared to the general population, normalized by gender and chronological age Short stature  Short stature Auxological evaluation - Height (> 2 y.o) - Length (< 2 y.o.) - Weight - Sitting height - Span/height - Height velocity - Head circumference  Short stature Auxological evaluation - Height (> 2 y.o.) - Length (< 2 y.o.) - Weight - Sitting height - Span/height - Height velocity - Head circumference  Short stature Auxological evaluation - Height (> 2 y.o.) - Length (< 2 y.o.) - Weight - Sitting height - Span/height - Height velocity - Head circumference  Short stature Auxological evaluation  Short stature Familiar target Boys (Height M + 13 cm) + height P +/- 8 cm 2 Girls Height M + (height P – 13 cm) +/- 8 cm 2  Short stature Physiological conditions - Familiar short stature - Constitutional delay of growth and development Non-endocrine conditions - Intrauterine growth retardation - Systemic diseases - Causes of malabsorption (celiac disease, IBD, etc...) - Genetic syndromes (achondroplasia and many others) - Congenital defects of metabolism - Psychosocial Deprivation  Short stature Endocrinological conditions - GH deficiency - Hypothyroidism - Untreated precocious puberty - Untreated congenital adrenogenital syndromes - Insulin-dependent diabetes (poorly treated) - Untreated diabetes insipidus - Untreated rickets Idiopatic conditions  Short stature First level assessment 1. Blood tests - Full blood count + formula - tTG-reflex - TSH-reflex - General biochemistry (kidney function) - Urine examination - IGF-I (warning: low body weight, age < 4) 2. Non-dominant hand-wrist x-ray for bone age Short stature Assessment of the progression level of metaphyseal welding Short stature Bone age reading methods 1. Atlas of Greulich and Pyle 2. Tanner-Whitehouse II and III 3. FELS Short stature Assessment of the progression level of metaphyseal welding Evaluation of the morphology of the skeleton in order to exclude skeletal dysplasia Familiar short stature Constitutional delay of growth and puberty  Recombinant growth hormone GH can be administered to the following categories of patients: − Demonstrated GH deficiency − Turner syndrome − SGA without catch-up growth (Silver-Russel) − Haploinsufficiency of the SHOX gene or mutation of its promoter − Patients with Prader-Willi syndrome − Chronic renal failure − Noonan syndrome  Recombinant growth hormone GH can be administered to the following categories of patients: − Demonstrated GH deficiency − Turner syndrome − SGA without catch-up growth (Silver-Russel) − Haploinsufficiency of the SHOX gene or mutation of its promoter − Patients with Prader-Willi syndrome − Chronic renal failure − Noonan syndrome  GH deficiency: ætiology Primary causes (83.5%) - Idiopathic GH deficiency - Dysembryogenic anomalies - Septo-optic dysplasia, - midline abnormalities - cleft palate - Known genetic mutations (PROP-1, POUF-1, etc.) Secondary causes (16.5%) - Head trauma - Neoplasms: craniopharyngiomas, dysgerminomas; - Langherans cell histiocytosis; - CNS infections; - Radiation - Hydrocephalus GH deficiency: physiology  GH deficiency: diagnosis 1. Auxological / radiological criteria - stature ≤ -3 SD or - stature ≤ -2 SD and growth rate / year ≤-1.0 SD for age and sex assessed after at least 6 months or a reduction in stature of 0.5 SD / year or - stature ≤-1.5 SD with respect to the genetic target and growth rate / year ≤-2 SD or ≤-1.5 SD after 2 consecutive years; - growth rate / year ≤-2 SD or ≤-1.5 SD after 2 consecutive years or - MRI findings compatible with hypothalamic-pituitary pathology + 2. Biochemical criteria GH peak M (2:1) The most common preventable cause of mental retardation. In countries with a high social-health standard, newborn screening programs have been introduced in order to obtain an early diagnosis and the timely introduction of treatment. Dried blood spot  Congenital hypothyroidism Retest at 2 weeks: preterm infants LBW or VLBW infants twins children of a mother with hypothyroidism hospitalized in NICU may have a delayed rise in TSH.  Congenital hypothyroidism Transient Permanent Hypothyroidal mother in Thyroid dysgenesis pregnancy Endemic iodine deficiency Iodine deficiency in Defects of thyroid pregnancy hormonogenesis Isolated and transient TSH Central hypothyroidism deficiency in offspring of (congenital TSH deficiency) mothers with Graves' disease Transient (preterm) infant hyperthyroxinemia  Congenital hypothyroidism Thyroid morphology Ectopia 48% Agenesis 31% Hypoplasia 5% Hyperplasia 6% Normal 10% Congenital hypothyroidism Clinical findings Coarse appearance Persistence of lanugo Umbilical hernia Goiter Macroglossia Hoarse cry Prolonged jaundice Distended abdomen Floppyiness Hypersomnia and difficult sucking Noisy breathing Congenital hypothyroidism Clinical findings Constipation Tendency to hypothermia Poor weight gain After 3°month of age Poor height gain Delay of psycho-motor development Hoarse voice, bradylalia Bone age delay  Congenital hypothyroidism Treatment L-THYROXINE DOSES 0-3 months 10-15 mcg/kg/die 3-6 months 7-10 mcg/kg/die 6-12 months 6-8 mcg/kg/die 1-3 years 4-6 mcg/kg/die 4-10 years 2-3 mcg/kg/die Nihil by mouth 30 minutes after administering L-Thyroixin  Congenital hypothyroidism Follow-up - TSH and FT4 determination Between 7 and 14 days from the start of the treatment Every 2 weeks until TSH is normalized Every 1-3 months up to the age of 12 months Every 2-4 months from 12 to 36 months Every 6 months from 3 years to the end of pubertal development Once a year thereafter The growth, cognitive development and psycho-motor stages of a correctly treated child are similar to that of a healthy child.  Acquired hypothyroidism Hypothyroidism that occurs after the neonatal period is defined as acquired. The intellectual prognosis is normal. Causes: Hashimoto's thyroiditis Iodine deficiency Subacute thyroiditis Resistance to thyroid hormones TSH-deficient hypothyroidism Iatrogenic Cystinosis  Acquired hypothyroidism Signs and symptoms: Reduced height velocity Weight gain Asthenia/ sleepiness Constipation Cold intolerance Goiter Subcutaneous edema Bradycardia Pubertal delay / menstrual irregularity  Acquired hypothyroidism Laboratory findings: TSH ↑ and FT4 ↓ or normal: Primary hypothyroidism TSH ↓ or normal and FT4 ↓ Central hypothyroidism N.B. To rule out central hypothyroidism do not ask for TSHreflex, TSH and FT4 are needed!  Hashimoto's thyroiditis Hashimoto's thyroiditis (HT) is the most common autoimmune endocrine disease in children, along with type 1 diabetes Organ-specific autoimmune disorder caused by an immune- mediated destruction of the thyroid gland secondary to the infiltration of B and T lymphocytes with subesequent destruction of the follicles Familiar predisposition, secondary to a susceptibility on a polygenic basis  Hashimoto’s thyroiditis Epidemiology Most common cause of thyroid disease in children and adolescents 1-2% of school-age children, 4-6% of adolescents Most affected females (F: M = 8: 1) Peak incidence during adolescence Association with chromosomopathies: o Down syndrome o Turner syndrome o Klinefelter syndrome  Hashimoto’s thyroiditis Association with other autoimmune diseases: - Alopecia - Vitiligo - Type I DM - Celiac disease (the prevalence of celiac disease in children and adolescents with thyroiditis varies between 4 and 10%)  Hashimoto’s thyroiditis Laboratory exams: FT4 e FT3 ↓ or normal TSH ↑ or normal Ab anti-thyroglobulin Ab anti-thyroperoxidase More sensitive and specific  Hashimoto’s thyroiditis Thyroid ultrasound - Inhomogeneous parenchyma - hypoechoicity of the parenchyma, - hyperechoic septa (fibrosis), - thickened isthmus - Increased vascularization - pseudonodules.  Hashimoto’s thyroiditis Aetiopatogenesis Autoimmune disease histologically characterized by lymphocytic infiltration of the thyroid gland, follicle atrophy and fibrosis Variable clinical course A picture of overt hypothyroidism does not always develop Thyroid function at onset Euthyroidism Hyperthyroidism Overt hypothyroidism Subclinical hypothyroidism  Hashimoto’s thyroiditis Hyperthyroidism Caused by the inflammatory state that causes the release of preformed thyroid hormones, but if TSHr-Abs stimulating antibodies are present, then the hyperthyroid phase can be more severe and last many months (Hashitoxicosis). Treatment - If preformed hormone release => symptomatic treatment with beta blockers (propranolol) - In case of positive TSHr-Abs stimulants => methimazole  Hashimoto’s thyroiditis Overt hypothyroidism Thyroxine treatment should be started immediately in case of overt hypothyroidism, ie: - n fT4 below the normal range, - TSH > 10 µU / ml - signs and symptoms referable to hypothyroidism. Subclinical hypothyroidism Patients who have no signs and / or symptoms of hypothyroidism and who have an fT4 in the normal range and an elevated TSH, but always below the 10 µU / ml threshold.  Hashimoto’s thyroiditis Treatment Replacement therapy with L-thyroxine Improvement of symptoms after a few weeks from the start of treatment Taken on an empty stomach, approximately 30 minutes before a meal Initial dose: 1-3 mcg / kg / day (to be modulated)  Grave’s disease Hyperthyroidism is a rare clinical entity in pediatric age, characterized by excessive production of thyroid hormones In most cases, the etiology is autoimmune and mainly includes Graves' disease (with a prevalence of 1: 10,000 in pediatric age) due to the production of antibodies activating the TSH receptor (TRAb) This form of hyperthyroidism must be distinguished from Hashitoxicosis, i.e. the initial transient hyperthyroid phase of autoimmune thyroiditis, due to the release of thyroid hormones following the inflammatory destruction of the gland  Graves’ disease Anamnestic risk factors: Positive personal or family history of another autoimmune disease genetic / chromosomal syndromes associated with increased risk of autoimmune thyroid disease (S. Down, S. Turner) Signs and symptoms: Goiter Tachycardia, palpitations, arterial hypertension Behavior disorders, irritability, reduced school performance / attention skills Ophthalmopathy (exophthalmos) Tremors (usually fine), Increased appetite, weight loss Frequent stools  Graves’ disease Anamnestic risk factors: Positive personal or family history of another autoimmune disease genetic / chromosomal syndromes associated with increased risk of autoimmune thyroid disease (S. Down, S. Turner) Signs and symptoms: Goiter Tachycardia, palpitations, arterial hypertension Behavior disorders, irritability, reduced school performance / attention skills Ophthalmopathy (exophthalmos) Tremors (usually fine), Increased appetite, weight loss Frequent stools  Graves’ disease Laboratory results: FT3 and FT4 ↑ TSH ↓ Ab anti-TSH receptor Positive Ab anti-thyroglobulin Negative or positive Anti-thyroid peroxidase antibodies Negative or positive  Graves’ disease Additional investigations Thyroid ultrasound: - increased size - finely inhomogeneous, predominantly hypor- reflective structure - blood overflow Neuro-ophthalmological visit  Graves’ disease Therapy Methimazole (Tapazole cp 5 mg) - It inhibits thyroid hormone synthesis (interferes with the action of the thyroperoxidase enzyme). - "Titration regimen" consists in higher starting doses and subsequent titration to achieve the minimum effective dose  Graves’ disease Therapy Propylthiouracil Not recommended in pediatric age due to the high risk of severe hepatotoxicity, it could be used only in the first trimester of pregnancy (as it is considered associated with a lower risk of embryopathy) or in a bridge phase awaiting definitive therapy in a highly allergic patient.  Graves’ disease Medical therapy in pediatric patients is unfortunately characterized by a low frequency of long-term remissions In pediatric age, medical therapy is generally continued for 18-24 months, when it can be suspended (in case of good control of thyroid function) to check for possible remission of the disease. According to some authors, it is possible to propose a prolonged treatment (from 4 to 10 years, depending on the studies) for pediatric patients Surgery: total thyroidectomy. Iatrogenic hypothyroidism which will need to be treated with L-thyroxine replacement therapy Radio metabolic therapy: The iodine-131 (I-131) isotope is the radiopharmaceutical of choice. It must not be used under 5 years of age Graves’ disease  Thyroid nodules Rare in the first 3 years of life, the incidence increases in the second decade of life. Most of the nodules are not malignant, however the frequency of carcinomas is higher than in adults. Indications of malignancy: Hypoechoic nodule Diameter> 1 cm Uneven margins Diffuse "spray" microcalcifications Marked intranodal vascularization with Doppler ultrasound Satellite lymph node that has lost its ovoid structure Thyroid nodules Obesity in paediatrics Dr. Alessandro Cattoni General and Specialistic Paediatrics  Epidemiology Historically, «fat children» were regarded as «healthy children», able to cope with malnutrition and infections Over the past 10-15 years, obesity has become one of the major childhood health problems in industrialized countries Prevalence doubled in the last 20 years: contribution of environmental factors (lifestyle, unbalanced diet, reduced physical activity)  Epidemiology Changes in prevalence related to: Age: 6-10 y.o.: 34%M-35%F → 14-17 y.o.: 17%M- 10%F Geography: South > North (18% Lombardia-> 36% Campania) Gender: M:27% F:21% Socioeconomical status: augmented prevalence in low socio- economic status Family education: increased prevalence in children of parents with low educational level Family history: increased prevalence in case of obese parents;  Diagnostic Criteria BMI (Body Mass Index) is the recommended parameter: BMI= weight (in kg)/height2 (in m2) Weight excess (WE) – with reference to ideal weight (IW) WE(%)= (weight-IW)/IW x 100  Diagnostic Criteria BMI in children: BMI value must be estimated and compared to age- and gender- centiles BMI>85°pc -> overweight child BMI>95°pc -> obese child BMI in adults BMI>25-> overweight BMI>30 -> obese WE: obesity WE > 20% of IW OK135S060  Multifactorial Etiopathogenesis Environmental factors: sedentary lifestyle, excessive nutrition Genetic factors: 40-50% in etiopathogenesis monozygotic twins : correlation 74%; dizygotic twins--> 32%; Biological parents and children -->19%; Adoptive parents and children --> 6%. Leptin, synthesized by adipose tissue, reduces hunger and increases energy expenditure  Etiopathogenesis Syndromic forms: Prader Willi (hyperphagia, mental retardation, neonatal hypotonus) Bardet Biedl (retinal dystrophy, polydactyly, obesity, hypogonadism) Endocrine forms: Cushing, hypothyroidism, GH deficiency Monogenic forms: missense Leptin gene mutation, (obesity, wearable leptin, hyperinsulinism) Others: leptin receptor mutation, POMC  Environmental factors Breastfeeding: protective. Eating habits: diet rich in simple sugars (soft drinks, juices), proteins and low in fruit and vegetables; often poor breakfast, eccessive snacking Physical activity: outdoor games reduced in favor of TV, computers, video games Educational issues: use of food as reward; little time dedicated to children; few possibilities for sporting activity; parents separation  Complications Orthopedic: functional flat-valgus foot, valgus knee, hyperlordosis, scoliosis, femoral head epiphysiolysis Neurological: pseudotumor cerebri Respiratory: dyspnea, OSAS Gastrointestinal: fatty liver (25%) with> transaminases (10%), cholelithiasis, hiatal hernia Dermatological: rubrous and atrophic striae, intertrigo, acne, eczema, acanthosis nigricans Complications Complications  Complications Auxological: accelerated growth, sometimes early puberty Endocrinological: reduced spontaneous or stimulated secretion of GH; TSH↥ with normal FT4 and FT3; anticipated puberty; ovarian polycystosis; hyperandrogenism; oligomenorrhea; insulin resistance -> type 2 diabetes. Metabolic syndrome: association of hyperinsulinism, obesity, hypertension; Metabolic: triglycerides, LDL cholesterol  Complications Cardiocirculatory: metabolic risk factors associated with arterial hypertension> predictive of atheromatous lesions - >>> risk in adulthood Psychological: especially in adolescence -> increased risk of psychological / psychiatric problems. 34% obese adolescents: reduced self-esteem (8% non-obese); anger  Clinical Approach Family history: obesity, type 2 diabetes, endocrinopathies, dyslipidemia, hypertension Psychological and social history : depression, eating disorders academic performance usual diet: restaurants / fast-food, distribution of meals/ sugary drinks during the day/ snacks  Clinical Approach Past medical history delayed psychomotor development (genetic disorders) Poor height growth (hypothyroidism, GH deficiency, S. Cushing) Headache (pseudotumor cerebri) Hypoglycemia (hyperinsulinism) Breathing difficulties at night Constipation: hypothyroidism Menstrual disorders: polycystic ovary  Clinical Approach Physical examination: Measurement of weight, height, BMI, BP, plicometry Dysmorphic features (e.g. Prader Willi) Acanthosis nigricans (insulin resistance) Hirsutism (polycystic ovary, Cushing) Cryptorchidism (PWS); fat sunken penis Osteoarticular system (knee valgus, scoliosis) Blood chemistry: Fasting lipid profile, glycemia and insulin, glycosylated Hb, liver function, f. thyroid, uric acid, ev. OGTT for people at risk of diabetes  Clinical Approach Family approach to problem management: not using food as a reward, enhancing positive changes, setting meal times, letting the child choose between 'healthy' foods, eliminating 'wrong' foods, behaving as a model, consistent Increased physical activity: reduce TV (1-2 hours / day max), daily physical activity (climbing stairs, biking, outdoor games, housework), organized sports Healthy diet: 'traffic light diet' (low calorie green foods at will); family participation in the diet, diet check at school Medications: GLP-1 inhibitors, metformin