Blood and endocrine system diseases in children .
Thyroid diseases in children. Classification of thyroid diseases in children. Etiology, pathogenesis, clinical manifestations, diagnosis, differential diagnosis, treatment, prevention of diffuse toxic goiter, hypothyroidism, autoimmune thyroiditis, endemic goiter in children. Degrees of goiter. Emergency care for thyrotoxic crisis in children.
Disease of the hypothalamic-pituitary and gonads in children. Etiology, pathogenesis, clinical manifestations, diagnosis, differential diagnosis, treatment and prevention of various clinical forms of disease growth (exogenous-constitutional, pituitary, somatogenic) obesity (exogenous-constitutional, hypothalamic) dispituitarizmu puberty in children, various pathologies of gonads in children (congenital disorders of sexual differentiation, impaired sexual development in boys and girls). Outlook.
Definition. A goiter is an enlargement of the thyroid gland resulting from several different pathogenic mechanisms (Fig. 1, Fig. 2). The incidence of goiter increases with advancing age and is more common in girls at all ages. The presence of goiter does not correlate with thyroid function, i.e. patients may be euthyroid, hypothyroid or hyperthyroid, although most children are clinically euthyroid.
Fig. 1. Thyroid gland structure (normal).
Fig. 2. A diffusely enlarged thyroid gland associated with hyperthyroidism is known as Grave's disease. At low power here, note the prominent infoldings of the hyperplastic epithelium.
The WHO proposes a simplified classification based on the significance of goitre:
Group 0: normal thyroid, no palpable or visible goitre
Group 1: enlarged thyroid, palpable but not visible when the neck is in the normal position
Group 2: thyroid clearly visible when the neck is in the normal position
Fig. 3. Secretion of thyroid hormons.
Fig. 4. Synthesis of thyroid hormones.
A. Simple goiter (the convertible terms are - colloid goiter, adolescent goiter, nontoxic goiter) is an acquired enlargement of the thyroid gland with normal function that is not caused by an inflammatory process or a tumor. At least 25 % of all children with thyroid enlargement have a simple goiter. The gland tends to be symmetric, smooth and of normal texture. For diagnosis we need normal function tests, negative thyroid antibodies, normal radioactive iodine (RAI) scan (not usually indicated).
Treatment. Thyroxin is usually not advocated when the gland is cosmetically insignificant. No other treatment is recommending exept periodic reassessment.
B. Endemic goiter occurs predominantly in iodine-deficient areas. Extreme deficiency occurs when daily urine contains less then 25 mg of iodine; moderate deficiency occurs when it is 25-50 mg and an adequate intake is reflected by an excretion of 100-200 mg/day.
Treatment. We use iodine and (or) T4, which either interrupts the cycle, leading to a decrease in TSH secretion and regression of the goiter.
For prevention in populations living in iodine deficient areas where iodised salt is not available and for curative treatment of patients with goitre: use iodised oil, according to national protocols. For information (according to the WHO):
In children, goitre disappears after several months. It disappears more slowly (or never) in adults despite restoration of normal thyroid function in 2 weeks. Surgery is only indicated for patients with local mechanical dysfunction.
C. Diffuse toxic goiter (the convertible terms are - thyrotoxicosis, Graves disease) is the most common cause of hyperthyroidism. Toxic multinodular goiter is rare in children. It is found mainly in the elderly and the middle-aged. The clinical symptoms are nervousness, tachycardia, muscle tremor, insatiable appetites, weight loss, wide-eyed stare, warm and moist skin.
Fig. 7. Thyrotoxicosis.
Treatment. We use antithiroid drugs (propylthiouracil, mercasolil, methimazole), beta-adrenergic blockers (propranolol), sometimes corticosteroids and sedatives. The effective therapy of hyperthyroidism is subtotal thyroidectomy.
Definition. Hypothyroidism is the condition resulting from a lack of the effects of thyroid hormone on body tissues. Because thyroid hormone affects growth and development and regulates many cellular processes, the absence or deficiency of thyroid hormone has many detrimental consequences.
Etiology. The main causes of hypothyroidism in children are:
ü Maldevelopment - hypoplasia or aplasia of thyroid gland
ü Inborn deficiencies of biosynthesis or action of thyroid hormone
ü Hashimoto thyroiditis
ü Hypopituitarism or hypothalamic disease
ü Severe iodine deficiency
Clinical features. Patients with hypothyroidism may complain of forgetfulness, reduced memory, mental slowing, depression, paresthesia. There may be bradycardia, quiet heart sounds, constipation, oedemata, anemia. Dry cool skin and hypothermia are common. Growth and development of children are retarded.
Fig.8. Congenital hypothyroidism. Fig. 9. Acquired hypothyroidism.
Laboratory findings. Because of the sensitivity of the serun TSH level as an indicator of primery hypothyroidism, serum TSH may be the best method to screen for the disorder. Its range is elevated usually, with the exception of central hypothyroidism. Serum T3 and T4 are low as a rule but their ranges may be normal or subnormal too.
Therapy. The most adequate is the therapy of replacement: synthetic triodothyronine and T3-T4 combination. Also we use vitamins, neurotropic drug, therapeutic physical training, speech therapist.
A. Hashimoto thyroiditis (chronic thyroiditis, autoimmune thyroiditis)
Etiology. Hashimoto thyroiditis is an organ-specific autoimmune disorder. The basic defect underlying this disease is not entirely clear, although current evidence suggests an abnormality in suppressor T lymphocytes that allows helper T lymphocytes to interact with specific antigens directed against the thyroid cell. A genetic predisposition is also suggested.
Clinical features. Physical examination usually discloses a symmetrically enlarged, very firm goiter; a pebby or knobby consistency is common.
Laboratory findings. Approximately 80 % of patients with Hashimoto thyroiditis have normal circulating T3, T4 and TSH levels at the time of diagnosis. Antithyroglobulin antibodies and antithyroperoxidase antibodies are measurable in more than 85 % of patients with Hashimoto thyroiditis.
Treatment. Thyroid hormone in full replacement dosages is the treatment of choice. The aim is to decrease the goiter, especially in patients with significant enlargement goiter, which causes the symptoms of dysphagia or other discomfort. When there is a rapidly enlarging goiter we use glucocorticoids. Surgery is indicated only if significant pressure symptoms occur.
Etiology. This rare disorder is usually due to a bacterial pathogen, most commonly Staphylococcus hemolitica, Streptococcus hemolitica, Streptococcus pneumoniae or anaerobic streptococcal organisms.
Clinical features. Fever, chills and other systemic signs or symptoms of abscess formation are present. Anterior neck pain and swelling are usual, with pain occasionally radiating to the ear or mandible. The physical examination suggests the presence of an abscess, with erythema of the skin, marked tenderness to palpation and at times fluctuance.
Laboratory findings. Leukocytosis with a left shift is usually present. Patients are euthyroid usually.
Treatment. Parenteral antibiotics should be administrated according to the specific pathogen identified. If fluctuance is present, incision and drainage might be required.
Hypoparathyroidism. Etiology. The causes of parathyroid failure and resistance to parathyroid hormone (PTH) are absence or genetic defect in PTH biosynthesis, autoimmune destruction of parathyroid gland, reduced PTH secretion and resistance to PTH as a consequence of hypomagnesemia.
Fig. 5. Parathyroid gland structure (normal).
Clinical features. There may be tetany, convulsive syndrome (titanic more typical), karpopedal spasm, paresthesiae, muscle weakness, tiredness, Trousseau and Hvostek symptoms, cataract; hair, nails and skin affection, growth failure, hypocalcemia, hyperphosphatemia.
A. Idiopathic hypoparathyroidism is a rare form of hypoparathyroidism. Several varieties of the disorder exist, both as sporadic and familiar condition. This disorder occurs as part of type I autoimmune polyglandular syndrome, as isolated idiopatic hypoparathyroidism, as part of Kearns-Sayre syndrome or due to congenital aplasia or dysgenesis of the parathyroids. The diagnosis of idiopatic hypoparathyroidism is generally one of exclusion. Demonstration of low to absent levels of PTH in the presence of hypocalcemia, frequently with hyperphosphatemia and with no evidence for magnesium depletion, strongly supports this diagnosis.
B. Surgical hypoparathyroidism. Surgical damage to or removal of parathyroid tissue accounts for the majority of cases of loss of parathyroid function.
Treatment. The aim of the hypoparathyroidism therapy is the correction of hypocalcemia. Although mild hypocalcemia might not require therapy, any neonate with a serum calcium level below 7,5 mg/dl (Ca2+ less then 2,8 mg/dl) or an older child with a serum calcium level less then 8-8,5 mg/dl should be treated to prevent tetany and other symptoms.
ü Acute. In acute symptomatic hypocalcemia intravenous therapy is required. It should be used 20-50 mg/kg /day of elemental calcium. When a central line is available, the calcium gluconate can be diluted with saline or dextrose infusion fluids and given continuosly.
ü Chronic. In the absence of tetany, seizures and severe degrees of hypocalcemia, oral therapy will suffice. A dosage of 50 mg/kg/day of elemental calcium is generally prescribed. Chronic hypocalcemia, exept in the mildest cases, is treated by the administration of vitamin D or its metabolites. Also the terapy of replacement by parathyroidin is used.
Hyperparathyroidism. Etiology. The main causes of the hyperparathyroidism are: primery congenital PTH hyperproduction, hyperplasia of hyperparathyroid glands, chronic renal diseases, Fankoni syndrome and malignant processes in hyperparathyroid glands.
Clinical features. Patients with hyperparathyroidism may suffer from “renal stones, painful bones, abdominal groans, psychic moans and fatigue overtones”. Symptoms often include polydipsia, polyuria, nocturia, constipation, increases fatigue, weakness and musculosceletal aches and pains.
ü Hydrocortisone suppression test
ü 1,25-Dihydroxyvitamin D
ü Tubular resorption of phosphorus
Treatment. There is a general agreement that patients with symptomatic hyperparathyroidism and all patients with a serum calcium level 1 mg/dl above the upper limits of normal should be treated by parathyroidectomy. Operative treatment, however is not urgent and in all patients the diagnosis must be certain.
The patients with hypercalcemic crisis should be treated with vigorous hydration. Calcium antagonists, calcitrinum, glucocorticoids and hemodialysis are applied if nessesary.
Laboratory tests. For diagnostic of hyperparathyroidism if patient have hypercalcemia are usefull:
General tests (serum): Other tests:
ü Calcium, phosphorus - Urinalisis
ü Parathyroid hormone - 24-hour urinary calcium
ü Chloride - Chest radiograph
ü Alcaline phosphatase, pH - Intravenous pyelogram
ü Protein electrophoresis
ü Uric acid
ü Creatinine, hematocrit
Etiology. The most frequent causes of thymus disorders are: genetic defect, fetal (prenatal) infection, chronic adrenal insufficiency, severe form of toxic goiter, ionized exposure.
Pathogenesis. The main links of pathogenesis are: congenital or acquired immune system defect, cellular component of immune system deficiency, low rate of gammaglobulines in the blood.
ü Congenital thymus aplasia (Di George syndrome). The clinical features are: congenital hypothyroidism, hypertelorism, antimongoloid slant of palpebral fissures, micrognathia, congenital heart troubles, vessels diseases, oesophagus troubles, stomach diseases, infectious complications, normal rate of immunoglobulines in the blood.
ü Thymomegaly. The clinical features are: tiredness, apathy, skin and subcutaneous fat changes (paleness, oedemata), overweight, muscle hypotonia, tonsil and lymphatic glands hyperplasia, low blood pressure, collapses, susceptibility to infectious and cutaneous diseases, attacks of thymus asthma.
ü Thymoma. A neoplasm of the thymus is not considered a thymoma unless it contains neoplastic epithelial components. Such tumors are rare in adults and even rare in children. Thymomas are slow-growing tumors that extend locally and rarely metastasize. The clinical features are: pressure sense in the thorax, chest pain, cardiac abnormalities, cough, breathlessness, anemic syndrome. Autoimmune disorders that have been reported (rarely) in association with thymomas include (but are not limited to) myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, cytopenias and thyroiditis.
An enlarged thymus is the most common cause of widened anterior mediastinum in neonates. However, such children will be asymptomatic unless the hyperplastic thymus is located in an abnormal position.
The thymus is maximal in size on computed tomography scan in infancy and may be differentiated from tumor by its texture and contour by an experienced interpreter. Additionally, normal thymus should not displace or compress other structures. Thymic enlargement is sometimes the result of a thymic cyst, which can be well delineated by computed tomography scan.
- anamnesis (frequent infectious diseases from the first life days, blood relationship at the marriage);
- clinical features;
- immunologic analeses;
- histological study of the lymphatic glands;
- blood disturbances (lymphopenia, granulocytopenia, anemia, thrombocytopenia;
- computed tomography scan;
- rontgenography of the brest.
ü Thymus hypoplasia: thymus transplantation, immunomodulators (correction of the cellular component of immune system), antibacterial therapy.
ü Thymomegaly: glucocorticoids, rontgeno-therapy, thymectomy, vitamin-therapy, emergency surgery if the attack of thymus asthma appears.
ü Thymoma: surgical removal of thymoma, postoperative X-ray therapy.
Primary prophylaxis: prenatal diagnostic, medical-genetic consulting room, social measures (ecology).
Secondary prophylaxis: prevention of the infectious complications and sudden death.
Congenital adrenal hyperplasia
Definition. The convertible terms are - congenital virilizing adrenal hyperplasia, adrenogenital syndrome. The term congenital adrenal hyperplasia encompasses several autosomal recessive disorders that share complete or partial deficiency of an enzyme involved in cortisol or aldosterone synthesis. All disorders of this group share the common feature of a deficiency or relative defect in cortisol or aldosterone synthesis resulting in some degree of cortisol or aldosterone deficiency, or both.
Pathophysiology. The clinical manifestations of the disease relate to the degree of cortisol deficiency, aldosterone deficiency, or deficiency of both and, in some cases, to the accumulation of precursor adrenocortical hormones. These precursors cause abnormalities such as virilization or hypertension when present in supraphysiologic concentrations. The phenotype depends on which particular protein is affected and the severity of the mutation or degree of deletion of the particular gene encoding for the protein involved in steroidogenesis. The phenotype can vary from clinically inapparent disease (occult or cryptic adrenal hyperplasia) to a mild form of disease, which is expressed in adolescence or adulthood (nonclassic adrenal hyperplasia), to severe disease resulting in adrenal insufficiency in infancy, with or without virilization and salt wasting (classic adrenal hyperplasia).
Most Likely Causes of Primary Adrenal Insufficiency in Children
Gender of Child
Age at Presentation
Most Likely Cause4
primary adrenal insufficiency
under age 2
psychomotor retardation, muscular dystrophy, hypogonadism, hypertelorism
over age 2
Idiopathic Autoimmune Adrenalitis, APS1, APS2, X-AHC, X-ALD
chronic mucocutaneous candidiasis, hypoparathyroidism
autoimmune thyroiditis, type 1 diabetes
under age 2
over age 2
Idiopathic Autoimmune Adrenalitis, APS1, APS2
chronic mucocutaneous candidiasis, hypoparathyroidism
autoimmune thyroiditis, type 1 diabetes
APS1: autoimmune polyglandular syndrome type 1; APS2: autoimmune polyglandular syndrome type 2; CAH: congenital adrenal hyperplasia; CGDS: contiguous gene deletion syndrome; X-AHC: X-linked adrenal hypoplasia congenitl; X-ALD: X-linked adrenoleukodystrophy
Clinical features. Physical findings are dependent on the nature and severity of the deficient enzyme activity. Deficiencies of enzyme activity involved in cortisol synthesis result in elevations in concentrations of adrenocorticotropic hormone (ACTH) that often causes hyperpigmentation. This hyperpigmentation may be subtle and is observed best in the genitalia and areolae. In virilizing forms females have ambiguous genitalia at birth. In less severe forms, genitalia may be normal at birth, but early pubic hair and clitoromegaly (often accompanied by tall stature) may appear in childhood. In more mild forms, excess facial or body hair often appears.
Laboratory studies. The diagnosis of congenital adrenal hyperplasia depends upon the demonstration of inadequate production of cortisol or aldosterone, or both. Salt-wasting forms of adrenal hyperplasia are accompanied by low serum aldosterone concentrations, hyponatremia, hyperkalemia, and elevated plasma renin activity (PRA) indicating hypovolemia. In contrast, hypertensive forms of adrenal hyperplasia (i.e, 11-beta-hydroxylase deficiency, 17-alpha-hydroxylase deficiency) are associated with suppressed PRA and often hypokalemia.
Treatment. Patients with dehydration, hyponatremia, or hyperkalemia who are suspected of having a salt-wasting form of adrenal hyperplasia should receive an intravenous bolus of isotonic sodium chloride solution over the first hour as needed to restore intravascular volume and blood pressure. Once stabilized, treat all patients who have adrenal hyperplasia with long-term glucocorticoid or aldosterone replacement (or both) depending upon what enzyme is involved and whether cortisol or aldosterone synthesis (or both) is affected. Infants with ambiguous genitalia require surgical evaluation and, if needed, plan for corrective surgery.
Definition. Adrenal insufficiency can be classified as primary or secondary. Primary adrenal insufficiency occurs when the adrenal gland itself is dysfunctional. Secondary adrenal insufficiency, also termed central adrenal insufficiency, occurs when lack of corticotropin-releasing hormone (CRH) secretion from the hypothalamus or adrenocorticotropic hormone (ACTH) secretion from the pituitary is responsible for hypofunction of the adrenal cortex. Adrenal insufficiency can be classified further as congenital or acquired.
Clinical features. Patients with acute adrenal insufficiency generally present with acute dehydration, hypotension, hypoglycemia, or altered mental status. These signs usually occur in an acutely ill patient with sepsis or disseminated intravascular coagulation or following a traumatic delivery. Patients with chronic adrenal insufficiency may demonstrate increased skin pigmentation, particularly in areolae, genitalia, scars, and moles. Typically, recent scars are affected more than those preceding onset. Areas unexposed to sun (eg, palmar creases, axillae) often are hyperpigmented. The patient also may have pigmentary lines in the gums. Signs of weight loss may be evident. If not frankly hypotensive, the patient may demonstrate orthostatic hypotension. Some patients also may lose pubic and axillary hair (but not become totally alopecic) because adrenal androgens support growth of body hair in these areas.
Laboratory studies. Clinical suspicion is important because presentation of the disorder may be insidious and subtle. When adrenal insufficiency is suspected, the following laboratory studies help establish the diagnosis:
ü Fasting blood sugar
ü Serum ACTH
ü Plasma renin activity
ü Serum cortisol
ü Serum aldosterone
ü When hyponatremia or hyperkalemia is found, conduct a spot urine or 24-hour urine test for sodium, potassium, and creatinine, along with a simultaneous serum creatinine test to determine whether inappropriate natriuresis is occurring.
Treatment. Initial therapy consists of intravenous saline and dextrose. The main treatment is the glucocorticoid replacement therapy. The diet is very important too.
Disorders of the thyroid gland
The main function of the thyroid gland is to synthesize T4 and T3. The only known physiologic role of iodine is in the synthesis of these hormones; the recommended dietary allowance of iodine is 30 mkg/kg/24 hr for infants, 90-120 mkg/24 hr for children, and 150 mkg/24 hr for adolescents and adults.
Thyroid tissue has an avidity for iodide and is able to trap (with a gradient of 100 : 1), transport, and concentrate it in the follicular lumen for synthesis of thyroid hormone. Entry of iodide from the circulation into the thyroid is carried out by the sodium-iodide symporter. Before trapped iodide can react with tyrosine, it must be oxidized; this reaction is catalyzed by thyroidal peroxidase.
The thyroid cells also elaborate a specific thyroprotein, a globulin with approximately 120 tyrosine units (thyroglobulin). Iodination of tyrosine forms monoiodotyrosine and diiodotyrosine; 2 molecules of diiodotyrosine then couple to form 1 molecule of T4, or 1 molecule of diiodotyrosine and 1 of monoiodotyrosine to form T3. Once formed, hormones are stored as thyroglobulin in the lumen of the follicle (colloid) until ready to be delivered to the body cells. T4 and T3 are liberated from thyroglobulin by activation of proteases and peptidases.
The metabolic potency of T3 is 3 to 4 times that of T4. Thyroid hormones increase oxygen consumption, stimulate protein synthesis, influence growth and differentiation, and affect carbohydrate, lipid, and vitamin metabolism.
The thyroid is regulated by TSH, a glycoprotein produced and secreted by the anterior pituitary. This hormone activates adenylate cyclase in the thyroid gland and is important in all steps of thyroid hormone biosynthesis, from trapping of iodine to release of thyroid hormones. TSH synthesis and release are stimulated by TSH-releasing hormone (TRH), which is synthesized in the hypothalamus and secreted into the pituitary. TRH is found in other parts of the brain besides the hypothalamus and in many other organs; aside from its endocrine function, it may be a neurotransmitter. TRH is a simple tripeptide. In states of decreased production of thyroid hormone, TSH and TRH are increased. Exogenous thyroid hormone or increased thyroid hormone synthesis inhibits TSH and TRH production. Except in the neonate, levels of TRH in serum are very low.
Further control of the level of circulating thyroid hormones occurs in the periphery. In many nonthyroidal illnesses, extrathyroidal production of T3 decreases; factors that inhibit thyroxine-type I 5′-deiodinase include fasting, chronic malnutrition, acute illness, and certain drugs. Levels of T3 may be significantly decreased, whereas levels of free T4 and TSH remain normal. Presumably, the decreased levels of T3 result in decreased rates of oxygen production, of substrate use, and of other catabolic processes.
Hypothyroidism results from deficient production of thyroid hormone, either from a defect in the gland itself (primary hypothyroidism) or a result of reduced thyroid-stimulating hormone (TSH) stimulation (central or hypopituitary hypothyroidism). The disorder may be manifested from birth (congenital) or acquired. When symptoms appear after a period of apparently normal thyroid function, the disorder may be truly acquired or might only appear so as a result of one of a variety of congenital defects in which the manifestation of the deficiency is delayed.
Most cases of congenital hypothyroidism are not hereditary and result from thyroid dysgenesis. Some cases are familial; these are usually caused by one of the inborn errors of thyroid hormone synthesis and may be associated with a goiter. Most infants with congenital hypothyroidism are detected by newborn screening programs in the first few weeks after birth, before obvious clinical symptoms and signs develop. In infants born in areas with no screening program, severe cases manifest features in the first few weeks of life, but in cases of lesser deficiency, manifestations may be delayed for months.
Etiology of congenital hypothyroidism
Thyroid Dysgenesis. Some form of thyroid dysgenesis (aplasia, hypoplasia, or an ectopic gland) is the most common cause of congenital hypothyroidism, accounting for 80-85% of cases; 15% are caused by an inborn error of thyroxine synthesis (dyshormonogeneses), and 2% are the result of transplacental maternal thyrotropin-receptor blocking antibody (TRBAb). In about 33% of cases of dysgenesis, even sensitive radionuclide scans can find no remnants of thyroid tissue (aplasia). In the other 66% of infants, rudiments of thyroid tissue are found in an ectopic location, anywhere from the base of the tongue (lingual thyroid) to the normal position in the neck (hypoplasia).
The cause of thyroid dysgenesis is unknown in most cases. Thyroid dysgenesis occurs sporadically, but familial cases occasionally have been reported. The finding that thyroid developmental anomalies, such as thyroglossal duct cysts and hemiagenesis, are present in 8-10% of 1st-degree relatives of infants with thyroid dysgenesis supports an underlying genetic component.
Defective Synthesis of Thyroxine (Dyshormonogenesis). A variety of defects in the biosynthesis of thyroid hormone can result in congenital hypothyroidism; these account for 15% of cases detected by neonatal screening programs (1/30,000-1/50,000 live births). These defects are transmitted in an autosomal recessive manner. A goiter is almost always present. When the defect is incomplete, compensation occurs, and onset of hypothyroidism may be delayed for years.
Defect of Iodide Transport. Defect of iodide transport is rare and involves mutations in the sodium-iodide symporter. In the past, clinical hypothyroidism, with or without a goiter, often developed in the first few months of life; the condition has been detected in neonatal screening programs.
Thyroid Peroxidase Defects of Organification and Coupling. Thyroid peroxidase defects of organification and coupling are the most common of the T4 synthetic defects. After iodide is trapped by the thyroid, it is rapidly oxidized to reactive iodine, which is then incorporated into tyrosine units on thyroglobulin. This process requires generation of H2O2, thyroid peroxidase, and hematin (an enzyme cofactor); defects can involve each of these components, and there is considerable clinical and biochemical heterogeneity. In the Dutch neonatal screening program, 23 infants were found with a complete organification defect (1/60,000), but its prevalence in other areas is unknown.
Defects of Thyroglobulin Synthesis. Defects of thyroglobulin synthesis is a heterogeneous group of disorders characterized by goiter, elevated TSH, low T4 levels, and absent or low levels of thyroglobulin (TG). It has been reported in approximately 100 patients. Molecular defects, primarily point mutations, have been described in several patients.
Defects in Thyroid Hormone Transport. Passage of thyroid hormone into the cell is facilitated by plasma membrane transporters. The defective transporter appears to impair passage of T3 into neurons; this syndrome is characterized by elevated serum T3 levels, low T4 levels, normal or mildly elevated TSH levels, and psychomotor retardation.
Thyrotropin Receptor-Blocking Antibody. Maternal thyrotropin receptor-blocking antibody (often measured as thyrotropin-binding inhibitor immunoglobulin), is an unusual cause of transitory congenital hypothyroidism. Transplacental passage of maternal TRBAb inhibits binding of TSH to its receptor in the neonate. The incidence is approximately 1/50,000-100,000 infants. It should be suspected whenever there is a history of maternal autoimmune thyroid disease, including Hashimoto thyroiditis or Graves disease, maternal hypothyroidism on replacement therapy, or recurrent congenital hypothyroidism of a transient nature in subsequent siblings. In these situations, maternal levels of TRBAb should be measured during pregnancy.
Radioiodine Administration. Hypothyroidism can occur as a result of inadvertent administration of radioiodine during pregnancy for treatment of Graves disease or cancer of the thyroid. The fetal thyroid is capable of trapping iodide by 70-75 days of gestation. Whenever radioiodine is administered to a woman of childbearing age, a pregnancy test must be performed before a therapeutic dose of 131I is given. Administration of radioactive iodine to lactating women also is contraindicated because it is readily excreted in milk.
Thyrotropin and Thyrotropin-Releasing Hormone Deficiency. Deficiency of TSH and hypothyroidism can occur in any of the conditions associated with developmental defects of the pituitary or hypothalamus. More often in these conditions, the deficiency of TSH is secondary to a deficiency of thyrotropin-releasing hormone (TRH). TSH-deficient hypothyroidism is found in 1/30,000-50,000 infants; most screening programs are designed to detect primary hypothyroidism, so most of these cases are not detected by neonatal thyroid screening. The majority of affected infants have multiple pituitary deficiencies and present with hypoglycemia, persistent jaundice, and micropenis in association with septo-optic dysplasia, midline cleft lip, midface hypoplasia, and other midline facial anomalies.
Iodine-Deficiency Endemic Goiter. Iodine deficiency or endemic goiter is the most common cause of congenital hypothyroidism worldwide. Despite efforts at universal iodizination of salt in many countries, economic, political, and practical obstacles make achieving this objective difficult. Borderline iodine deficiency is more likely to cause problems in preterm infants who depend on a maternal source of iodine for normal thyroid hormone production.
Thyroid Function in Preterm Babies
Postnatal thyroid function in preterm babies is qualitatively similar but quantitatively reduced compared with that of term infants. The cord serum T4 is decreased in proportion to gestational age and birthweight. The postnatal TSH surge is reduced, and infants with complications of prematurity, such as respiratory distress syndrome, actually experience a decrease in serum T4 in the 1st wk of life. As these complications resolve, the serum T4 gradually increases so that generally by 6 wk of life it enters the T4 range seen in term infants. Serum free T4 concentrations seem less affected, and when measured by equilibrium dialysis, these levels are often normal. Preterm babies also have a higher incidence of transient TSH elevations and apparent transient primary hypothyroidism. Premature infants <28 wk of gestation might have problems resulting from a combination of immaturity of the hypothalamic-pituitary-thyroid axis and loss of the maternal contribution of thyroid hormone and so may be candidates for temporary thyroid hormone replacement; further studies are needed.
Most infants with congenital hypothyroidism are asymptomatic at birth, even if there is complete agenesis of the thyroid gland. This situation is attributed to the transplacental passage of moderate amounts of maternal T4, which provides fetal levels that are approximately 33% of normal at birth. Despite this maternal contribution of thyroxine, hypothyroid infants still have a low serum T4 and elevated TSH level and so will be identified by newborn screening programs.
The clinician depends on neonatal screening tests for the diagnosis of congenital hypothyroidism. Congenital hypothyroidism is twice as common in girls as in boys.
It can be suspected and the diagnosis established during the early weeks of life if the initial but less characteristic manifestations are recognized. Birthweight and length are normal, but head size may be slightly increased because of myxedema of the brain. Prolongation of physiologic jaundice, caused by delayed maturation of glucuronide conjugation, may be the earliest sign. Feeding difficulties, especially sluggishness, lack of interest, somnolence, and choking spells during nursing, are often present during the 1st mo of life. Respiratory difficulties, due in part to the large tongue, include apneic episodes, noisy respirations, and nasal obstruction. Affected infants cry little, sleep much, have poor appetites, and are generally sluggish.
There may be constipation that does not usually respond to treatment. The abdomen is large, and an umbilical hernia is usually present.
The temperature is subnormal, often lower, and the skin, particularly that of the extremities, may be cold and mottled. Edema of the genitals and extremities may be present. The pulse is slow, and heart murmurs, cardiomegaly, and asymptomatic pericardial effusion are common.
Macrocytic anemia is often present and is refractory to treatment with hematinics. Because symptoms appear gradually, the clinical diagnosis is often delayed.
Approximately 10% of infants with congenital hypothyroidism have associated congenital anomalies. Cardiac anomalies are most common, but anomalies of the nervous system and eye have also been reported. Infants with congenital hypothyroidism may have associated hearing loss.
If congenital hypothyroidism goes undetected and untreated, these manifestations progress. Retardation of physical and mental development becomes greater during the following months, and by 3-6 mo of age the clinical picture is fully developed.
When there is only partial deficiency of thyroid hormone, the symptoms may be milder, the syndrome incomplete, and the onset delayed. Although breast milk contains significant amounts of thyroid hormones, particularly T3, it is inadequate to protect the breast-fed infant who has congenital hypothyroidism, and it has no effect on neonatal thyroid screening tests.
The child's growth will be stunted, the extremities are short, and the head size is normal or even increased. The anterior and posterior fontanels are open widely; observation of this sign at birth can serve as an initial clue to the early recognition of congenital hypothyroidism. Only 3% of normal newborn infants have a posterior fontanel larger than 0.5 cm. The eyes appear far apart, and the bridge of the broad nose is depressed. The palpebral fissures are narrow and the eyelids are swollen. The mouth is kept open, and the thick, broad tongue protrudes. Dentition will be delayed. The neck is short and thick, and there may be deposits of fat above the clavicles and between the neck and shoulders. The hands are broad and the fingers are short. The skin is dry and scaly, and there is little perspiration. Myxedema is manifested, particularly in the skin of the eyelids, the back of the hands, and the external genitals. The skin shows general pallor with a sallow complexion. Carotenemia can cause a yellow discoloration of the skin, but the sclerae remain white. The scalp is thickened, and the hair is coarse, brittle, and scanty. The hairline reaches far down on the forehead, which usually appears wrinkled, especially when the infant cries.
Development is usually delayed. Hypothyroid infants appear lethargic and are late in learning to sit and stand. The voice is hoarse, and they do not learn to talk. The degree of physical and mental retardation increases with age. Sexual maturation may be delayed or might not take place at all. The muscles are usually hypotonic, but in rare instances generalized muscular pseudohypertrophy occurs.
Some infants with mild congenital hypothyroidism have normal thyroid function at birth and so are not identified by newborn screening programs. In particular, some children with ectopic thyroid tissue (lingual, sublingual, subhyoid) produce adequate amounts of thyroid hormone for many years, or it eventually fails in early childhood.
Manifestation of the light forms of congenital hypothyroidism can be observed in any age of children, but mostly in the period of the first growth jump (4-6 years).
In many countries, infants with congenital hypothyroidism are identified by newborn screening programs. Blood obtained by heel-prick between 2 and 5 days of life is placed on a filter paper card and sent to a central screening laboratory. Many newborn screening programs in North America and Europe measure levels of T4, followed by measurement of TSH when T4 is low. This approach identifies infants with primary hypothyroidism, some with hypothalamic or pituitary hypothyroidism, and infants with a delayed increase in TSH levels. Other neonatal screening programs in North America, Europe, Japan, Australia, and New Zealand are based on a primary measurement of TSH. This approach detects infants with primary hypothyroidism and can detect infants with subclinical hypothyroidism (normal T4, elevated TSH), but it misses infants with delayed TSH elevation and with hypothalamic or pituitary hypothyroidism.
Serum levels of T4 or free T4 are low; serum levels of T3 may be normal and are not helpful in the diagnosis. If the defect is primarily in the thyroid, levels of TSH are elevated, often to >100 mU/L. Serum levels of thyroglobulin are usually low in infants with thyroid agenesis or defects of thyroglobulin synthesis or secretion, whereas they are elevated with ectopic glands and other inborn errors of thyroxine synthesis, but there is a wide overlap of ranges.
Retardation of osseous development can be shown radiographically at birth in about 60% of congenitally hypothyroid infants and indicates some deprivation of thyroid hormone during intrauterine life. The distal femoral epiphysis, normally present at birth, is often absent.
X-ray of the skull show large fontanels and wide sutures; intersutural bones are common. The sella turcica is often enlarged and round; in rare instances, there may be erosion and thinning. Formation and eruption of teeth can be delayed. Cardiac enlargement or pericardial effusion may be present.
Scintigraphy can help to pinpoint the underlying cause in infants with congenital hypothyroidism, but treatment should not be unduly delayed for this study.
Ultrasonographic examination of the thyroid is helpful, but studies show it can miss some ectopic glands shown by scintigraphy. The electrocardiogram may show low-voltage P and T waves with diminished amplitude of QRS complexes and suggest poor left ventricular function and pericardial effusion. Echocardiography can confirm a pericardial effusion. The electroencephalogram often shows low voltage. In children >2 yr of age, the serum cholesterol level is usually elevated. Brain MRI before treatment is reportedly normal, although proton magnetic resonance spectroscopy shows high levels of choline-containing compounds, which can reflect blocks in myelin maturation.
Levothyroxine L-thyroxine is considered to be the best drug. Initial dose of it - 10-14 mkg/kg/day provides normalization of level Ò4 for newborns during 1 week. Total dose of levothyroxine with age is gradually increased, and dose per kilogram of body mass is reduced.
Table. Levothyroxine doses for treatment of congenital hypothyroidism
More then 12 years
Evaluation of the treatment efficiency and correction of levothyroxine dose is conducted approximately monthly in the first 6 mo of life, and then every 2-3 mo between 6 mo and 2 yr. The dose of levothyroxine on a weight basis gradually decreases with age. ain criteria are speed of growth of a child, levels Ò4 and TSH, detection of bone age (every 1-2 years).
Treatment is being added by neuro- and cardiotrophic drugs, vitamins, massage, therapeutic physical training.
Studies of school-aged children report that hypothyroidism occurs in approximately 0.3% (1/333). Subclinical hypothyroidism (TSH >4.5 mU/L, normal T4 or free T4) is more common, occurring in approximately 2% of adolescents. Acquired hypothyroidism is most commonly a result of chronic lymphocytic thyroiditis; 6% of children aged 12-19 yr have evidence of autoimmune thyroid disease, which occurs with a 2 : 1 female : male preponderance.
Autoimmune (acquired hypothyroidism)
· Hashimoto thyroiditis
· Polyglandular autoimmune syndrome, types I and II
· Propylthiouracil, methimazole, iodides, lithium, amiodarone
· Langerhans cell histiocytosis
Hemangiomas (large) of the liver
The most common cause of acquired hypothyroidism is chronic lymphocytic thyroiditis. Autoimmune thyroid disease may be part of polyglandular syndromes; children with Down, Turner, and Klinefelter syndromes and celiac disease or diabetes are at higher risk for associated autoimmune thyroid disease. In children with Down syndrome, anti-thyroid antibodies develop in approximately 30%, and subclinical or overt hypothyroidism occurs in approximately 15-20%. In girls with Turner syndrome, anti-thyroid antibodies develop in approximately 40%, and subclinical or overt hypothyroidism occurs in approximately 15-30%, rising with increasing age. In children with type 1 diabetes mellitus, approximately 20% develop anti-thyroid antibodies and 5% become hypothyroid. Williams syndrome is associated with subclinical hypothyroidism; this does not appear to be autoimmune, as anti-thyroid antibodies are negative.
Irradiation of the area of thyroid that is incidental to the treatment of Hodgkin disease or other head and neck malignancies or that is administered before bone marrow transplantation often results in thyroid damage. About 30% of such children acquire elevated TSH levels within a yr after therapy, and another 15-20% progress to hypothyroidism within 5-7 yr. Some clinicians recommend periodic TSH measurements, but others recommend treatment of all exposed patients with doses of T4 to suppress TSH.
Protracted ingestion of medications containing iodides—for example, expectorants—can cause hypothyroidism, usually accompanied by goiter. Amiodarone, a drug used for cardiac arrhythmias and consisting of 37% iodine by weight, causes hypothyroidism in about 20% of treated children. It affects thyroid function directly by its high iodine content. Children treated with this drug should have serial measurements of T4, T3, and TSH. Children with Graves’ disease treated with anti-thyroid drugs (methimazole or propylthiouracil) can develop hypothyroidism. Additional drugs that can produce hypothyroidism include lithium carbonate, interferon alpha, stavudine, thalidomide, valproate (subclinical), and aminoglutethimide.
Children with nephropathic cystinosis, a disorder characterized by intralysosomal storage of cystine in body tissues, acquire impaired thyroid function. Hypothyroidism may be overt, but subclinical forms are more common, and periodic assessment of TSH levels is indicated. By 13 yr of age, two thirds of these patients require T4 replacement.
Histiocytic infiltration of the thyroid in children with Langerhans cell histiocytosis can result in hypothyroidism.
Hypothyroidism can occur in children with large hemangiomas of the liver, because of increased type 3 deiodinase activity, which catalyzes conversion of T4 to rT3 and T3 to T2. Thyroid secretion is increased, but it is not sufficient to compensate for the large increase in degradation of T4 to rT3.
Any hypothalamic or pituitary disease can cause acquired central hypothyroidism. TSH deficiency may be the result of a hypothalamic-pituitary tumor (craniopharyngioma most common in children) or a result of treatment for the tumor. Other causes include cranial radiation, head trauma, or diseases infiltrating the pituitary gland, such as Langerhans cell histiocytosis.
Deceleration of growth is usually the first clinical manifestation, but this sign often goes unrecognized. Goiter, which may be a presenting feature, typically is nontender and firm, with a rubbery consistency and a pebbly surface. Weight gain is mostly fluid retention (myxedema), not true obesity. Myxedematous changes of the skin, constipation, cold intolerance, decreased energy, and an increased need for sleep develop insidiously.
Additional features include bradycardia, muscle weakness or cramps, nerve entrapment, and ataxia. Osseous maturation is delayed, often strikingly, which is an indication of the duration of the hypothyroidism. Adolescents typically have delayed puberty; older adolescent girls manifest menometrorhhagia. Younger children might present with galactorrhea or pseudoprecocious puberty. Galactorrhea is a result of increased TRH stimulating prolactin secretion. The precocious puberty, characterized by breast development in girls and macro-orchidism in boys, is thought to be the result of abnormally high TSH concentrations binding to the FSH, receptor with subsequent stimulation.
Children with suspected hypothyroidism should undergo measurement of serum free T4 and TSH. Because the normal range for thyroid tests is slightly higher in children than adults, it is important to compare results to age-specific reference ranges. Measurement of antithyroglobulin and antiperoxidase (formerly, antimicrosomal) antibodies can pinpoint autoimmune thyroiditis as the cause. Generally, there is no indication for thyroid imaging. In cases with a goiter resulting from autoimmune thyroid disease, an ultrasound examination typically shows diffuse enlargement with scattered hypoechogenicity.
There are hyponatremia, macrocytic anemia, hypercholesterolemia. All these changes return to normal with adequate replacement of T4.
Ultrasound examination is the most accurate method to follow nodule size and solid vs. cystic nature.
In children with a nodule and suppressed TSH, a radioactive iodine uptake and scan is indicated to determine if this is a “hot” or hyperfunctioning nodule.
A bone age X-ray at diagnosis is useful, in that the degree of delay approximates duration and severity of hypothyroidism.
Levothyroxine is the treatment of choice in children with hypothyroidism. The dose on a weight basis gradually decreases with age. For children 1-3 yr, the average l-T4 dosage is 4-6 mkg/kg/day; for 3-10 y4, 3-5 mk/kg/day; and for 10-16 yr, 2-4 mk/kg/day. Treatment should be monitored by measuring serum free T4 and TSH every 4-6 mo as well as 6 wk after any change in dosage. In children with central hypothyroidism, where TSH levels are not helpful in monitoring treatment, the goal should be to maintain serum free T4 in the upper half of the normal reference range for age.
Hyperthyroidism results from excessive secretion of thyroid hormone; during childhood, with few exceptions, it is due to Graves disease. Graves disease is an autoimmune disorder; production of thyroid-stimulating immunoglobulin (TSI) results in diffuse toxic goiter.
In the thyroid gland, T helper cells (CD4+) predominate in dense lymphoid aggregates; in areas of lower cell density, cytotoxic T cells (CD8+) predominate. The percentage of activated B lymphocytes infiltrating the thyroid is higher than in peripheral blood. A postulated failure of T suppressor cells allows expression of T helper cells, sensitized to the TSH antigen, which interact with B cells. These cells differentiate into plasma cells, which produce thyrotropin receptor–stimulating antibody (TRSAb). TRSAb binds to the receptor for TSH and stimulates cyclic adenosine monophosphate, resulting in thyroid hyperplasia and unregulated overproduction of thyroid hormone.
The ophthalmopathy occurring in Graves disease appears to be caused by antibodies against antigens shared by the thyroid and eye muscle. TSH receptors have been identified in retro-orbital adipocytes and might represent a target for antibodies. The antibodies that bind to the extraocular muscles and orbital fibroblasts stimulate the synthesis of glycosaminoglycans by orbital fibroblasts and produce cytotoxic effects on muscle cells.
About 5% of all patients with hyperthyroidism are <15 yr of age; the peak incidence in these children occurs during adolescence.
The clinical course in children is highly variable. Symptoms develop gradually; the usual interval between onset and diagnosis is 6-12 mo and may be longer in prepubertal children compared with adolescents. The earliest signs in children may be emotional disturbances accompanied by motor hyperactivity. The children become irritable and excitable, and they cry easily because of emotional lability. They are restless sleepers and tend to kick their covers off. Their schoolwork suffers as a result of a short attention span and poor sleep. Tremor of the fingers can be noticed if the arm is extended. There may be a voracious appetite combined with loss of or no increase in weight. Recent height measurements might show an acceleration in growth velocity.
The size of the thyroid is variable. It may be so minimally enlarged that it initially escapes detection, but with careful examination, a diffuse goiter, soft with a smooth surface, is found in almost all patients.
Exophthalmos is noticeable in most patients but is usually mild. Lagging of the upper eyelid as the eye looks downward, impairment of convergence, and retraction of the upper eyelid and infrequent blinking may be present. Ocular manifestations can produce pain, lid erythema, chemosis, decreased extraocular muscle function, and decreased visual acuity (corneal or optic nerve involvement).
The skin is smooth and flushed, with excessive sweating. Muscular weakness is uncommon but may be severe enough to result in clumsiness. Reflexes are brisk, especially the return phase of the Achilles reflex. Many of the findings in Graves disease result from hyperactivity of the sympathetic nervous system.
Tachycardia, palpitations, dyspnea, and cardiac enlargement and insufficiency cause discomfort but rarely endanger the patient's life. Atrial fibrillation is a rare complication. Mitral regurgitation, probably resulting from papillary muscle dysfunction, is the cause of the apical systolic murmur present in some patients. The systolic blood pressure and the pulse pressure are increased.
Thyroid crisis, or thyroid storm, is a form of hyperthyroidism manifested by an acute onset, hyperthermia, severe tachycardia, heart failure, and restlessness. There may be rapid progression to delirium, coma, and death. Precipitating events include trauma, infection, radioactive iodine treatment, or surgery.
Serum levels of thyroxine (T4), triiodothyronine (T3), free T4, and free T3 are elevated. In some patients, levels of T3 may be more elevated than those of T4. Levels of TSH are suppressed to below the lower range of normal. Antithyroid antibodies, including thyroid peroxidase antibodies, are often present.
Most patients with newly diagnosed Graves disease have measurable TRSAb; the two methods to measure TRSAb are thyroid-stimulating immunoglobulin (TSI) or thyrotropin-binding inhibitor immunoglobulin (TBII). Measurement of TSI or TBII is useful in confirming the diagnosis of Graves disease.
Differential diagnosis of Graves disease is conducted for diseases accompanied by hyperthyroidism, goiter, tachycardia. Toxic adenoma and hyper functioning cancer of thyroid gland, TTG productive pituitary adenoma developing thyrotoxicosis are rarely registered for children.
Differentiation of Graves disease with autoimmune thyroiditis has current importance. The last one, differently from Graves disease, is characterized by: thickening of capsule, presence of nodules, heterogeneity of echogenic structure during ultrasonic examination, mosaic accumulation of radioactive isotope during scanning, reduction of iodine absorption function of thyroid gland, increase of the antibody titer to thyreoglobulin and peroxidase, more easy course of thyrotoxicosis which has good results of conservative therapy and can terminate spontaneously.
Sporadic (non-toxic) goiter is characterized by absence of thyrotoxicosis, sometimes even hypothyroidism is possible conversely, which is confirmed by detection of hormone levels.
When hyperthyroxinemia is caused by exogenous thyroid hormone, levels of free T4 and TSH are the same as those seen in Graves disease, but the level of thyroglobulin is very low, whereas in patients with Graves disease, it is elevated.
Conservative therapy is the main method of Graves disease treatment for children. On the first stage child must be admitted to hospital. Thyreostatic drugs are being prescribed, and methimazole is preferred. It is highly effective (not only blocks synthesis of thyroid hormones, but inhibits creation of auto antibodies as well) and is less toxic. The initial dosage of methimazole is 0.25-1.0 mg/kg/24 hr given once or twice daily. Smaller initial dosages should be used in early childhood. Careful surveillance is required after treatment is initiated. Rising serum levels of TSH to greater than normal indicates overtreatment and leads to increased size of the goiter. Clinical response becomes apparent in 3-6 wk, and adequate control is evident in 3-4 mo. The dose is decreased to the minimal level required to maintain a euthyroid state.
Most studies report a remission rate of approximately 25% after 2 years of antithyroid drug treatment in children. Some studies find that longer treatment is associated with higher remission rates, with one study reporting a 50% remission rate after 4.5 years of drug treatment. If a relapse occurs, it usually appears within 3 mo and almost always within 6 mo after therapy has been discontinued. Therapy may be resumed in case of relapse. Patients older than 13 yr of age, boys, those with a higher body mass index, and those with small goiters and modestly elevated T3 levels appear to have earlier remissions.
A β-adrenergic blocking agent such as propranolol (0.5-2.0 mg/kg/24 hr orally, divided 3 times daily) or atenolol (1-2 mg/kg orally given once daily) is a useful supplement to antithyroid drugs in the management of severely toxic patients.
Radioiodine treatment or surgery is indicated when adequate cooperation for medical management is not possible, when adequate trial of medical management has failed to result in permanent remission, or when severe side effects preclude further use of antithyroid drugs. Either of these treatments may also be preferred by the patient or parent.
Subtotal thyroidectomy is done only after the patient has been brought to a euthyroid state. This may be accomplished with methimazole over 2-3 mo. After a euthyroid state has been attained, a saturated solution of potassium iodide, 5 drops/24 hr, are added to the regimen for 2 wk before surgery to decrease the vascularity of the gland. Complications of surgical treatment are rare and include hypoparathyroidism (transient or permanent) and paralysis of the vocal cords. The incidence of residual or recurrent hyperthyroidism or hypothyroidism depends on the extent of the surgery. Most recommend near-total thyroidectomy. The incidence of recurrence is low, and most patients become hypothyroid.
The ophthalmopathy remits gradually and usually independently of the hyperthyroidism. Severe ophthalmopathy can require treatment with high-dose prednisone, orbital radiotherapy (of questionable value), or orbital decompression surgery. Cigarette smoking is a risk factor for thyroid eye disease and should be avoided or discontinued to avoid progression of eye involvement.
Autoimmune thyroiditis (lymphocytic thyroiditis, Hashimoto thyroiditis)
Autoimmune thyroiditis (synonyms: chronic lymphocytic thyroiditis, Hashimoto's thyroiditis) is an autoimmune disease of thyroid gland with gradual progressive destruction of thyroid cells and development of hypothyroidism. Mostly it is being detected for school age children mainly for girls.
This typical organ-specific autoimmune disease is characterized histologically by lymphocytic infiltration of the thyroid. Early in the course of the disease, there may be hyperplasia only; this is followed by infiltration of lymphocytes and plasma cells between the follicles and by atrophy of the follicles. Lymphoid follicle formation with germinal centers is almost always present; the degree of atrophy and fibrosis of the follicles varies from mild to moderate.
A variety of different thyroid antigen autoantibodies are also involved. Thyroid antiperoxidase antibodies (TPOAbs; formerly called antimicrosomal antibodies) and antithyroglobulin antibodies are demonstrable in the sera of 90% of children with lymphocytic thyroiditis and in many patients with Graves disease. TPOAbs inhibit enzyme activity and stimulate natural killer cell cytotoxicity. Antithyroglobulin antibodies do not appear to play a role in the autoimmune destruction of the gland. Thyrotropin receptor–blocking antibodies are often present, especially in patients with hypothyroidism, and it is now believed that they are related to the development of hypothyroidism and thyroid atrophy in patients with autoimmune thyroiditis. Antibodies to pendrin, an apical protein on thyroid follicular cells, have been demonstrated in 80% of children with autoimmune thyroiditis.
The disorder is 2-4 times more common in girls than in boys. It can occur during the first 3 yr of life but becomes sharply more common after 6 yr of age and reaches a peak incidence during adolescence.
The most common clinical manifestations are goiter and growth retardation. The goiter can appear insidiously and may be small or large. In most patients, the thyroid is diffusely enlarged, firm, and nontender. In about 30% of patients, the gland is lobular and can seem to be nodular.
Most of the affected children are clinically euthyroid and asymptomatic; some may have symptoms of pressure in the neck, including difficulty swallowing and shortness of breath. Some children have clinical signs of hypothyroidism, but others who appear clinically euthyroid have laboratory evidence of hypothyroidism. A few children have manifestations suggesting hyperthyroidism, such as nervousness, irritability, increased sweating, and hyperactivity, but results of laboratory studies are not necessarily those of hyperthyroidism.
The clinical course is variable. The goiter might become smaller or might disappear spontaneously, or it might persist unchanged for years while the patient remains euthyroid. Most children who are euthyroid at presentation remain euthyroid, although a percentage of patients acquire hypothyroidism gradually within months or years. In children who initially have mild or subclinical hypothyroidism (elevated serum TSH, normal free T4 level), over several years about 50% revert to euthyroidism, about 50% continue to have subclinical hypothyroidism, and a few develop overt hypothyroidism. Thyroiditis is the cause of most cases of nongoitrous (atrophic) hypothyroidism.
Thyroid function tests (free T4 and TSH) are often normal, although the level of TSH may be slightly or even moderately elevated in some patients, termed subclinical hypothyroidism. The fact that many children with lymphocytic thyroiditis do not have elevated levels of TSH indicates that the goiter may be caused by the lymphocytic infiltrations or by thyroid growth-stimulating immunoglobulins. Young children with lymphocytic thyroiditis have serum antibody titers to TPO, but the antithyroglobulin test for thyroid antibodies is positive in <50%. Levels in children and adolescents are lower than those in adults with lymphocytic thyroiditis, and repeated measurements are indicated in questionable instances because titers might increase later in the course of the disease.
Thyroid scans and ultrasonography usually are not needed. If they are done, thyroid scans reveal irregular and patchy distribution of the radioisotope, and in about 60% or more, the administration of perchlorate results in a >10% discharge of iodide from the thyroid gland. Thyroid ultrasonography shows scattered hypoechogenicity in most patients.
The definitive diagnosis can be established by biopsy of the thyroid; this procedure is rarely clinically indicated.
If there is evidence of hypothyroidism (overt or subclinical), replacement treatment with levothyroxine (at doses specific for size and age) is indicated. The goiter usually shows some decrease in size but can persist for years.
In a euthyroid patient, treatment with suppressive doses of levothyroxine is unlikely to lead to a significant decrease in size of the goiter. Antibody levels fluctuate in both treated and untreated patients and persist for years.
Because the disease is self-limited in some instances, the need for continued therapy requires periodic reevaluation. Untreated patients should also be checked periodically.
Prominent nodules, i.e. >1.0 cm, that persist despite suppressive therapy should be examined histologically using fine needle aspiration (FNA), because thyroid carcinoma or lymphoma has occurred in patients with lymphocytic thyroiditis.
Disorders of the parathyroid glands
Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany (involuntary muscle contraction), and several other symptoms. The condition can be inherited, but it is also encountered after thyroid or parathyroid gland surgery, and it can be caused by immune system-related damage as well as a number of rarer causes.
- Removal of or trauma to the parathyroid glands in thyroid surgery (thyroidectomy) or other neck surgeries is a recognized cause. It is now uncommon, as surgeons generally can spare them during procedures after identifying them. In a small percentage of cases, however, they can become traumatized during surgery and/or their blood supply can be compromised. When this happens the parathyroids may cease functioning for a while or stop altogether.
- Autoimmune invasion and destruction is the most common non-surgical cause. It can occur as part of autoimmune polyendocrine syndromes.
- Hemochromatosis can lead to iron accumulation and consequent dysfunction of a number of endocrine organs, including the parathyroids.
- Absence or dysfunction of the parathyroid glands is one of the components of chromosome 22q11 microdeletion syndrome (other names: DiGeorge syndrome, Schprintzen syndrome).
- Magnesium deficiency
- Idiopathic (of unknown cause), occasionally familial.
Signs and symptoms
The main symptoms of hypoparathyroidism are the result of the low blood calcium level, which interferes with normal muscle contraction and nerve conduction. As a result, children with hypoparathyroidism can experience paresthesia, an unpleasant tingling sensation around the mouth and in the hands and feet, as well as muscle cramps and severe spasms known as "tetany" that affect the hands and feet. Many also report a number of subjective symptoms such as fatigue, headaches, bone pain and insomnia. Crampy abdominal pain may occur. Physical examination of someone with hypocalcemia may show tetany, but it is also possible to provoke tetany of the facial muscles by tapping on the facial nerve (a phenomenon known as Chvostek's sign) or by using the cuff of a sphygmomanometer to temporarily obstruct the blood flow to the arm (a phenomenon known as Trousseau's sign of latent tetany).
Diagnosis is by measurement of calcium, serum albumin (for correction) and PTH in blood.
If necessary, measuring cAMP (cyclic AMP) in the urine after an intravenous dose of PTH can help in the distinction between hypoparathyroidism and other causes.
Severe hypocalcemia, a potentially life-threatening condition, is treated as soon as possible with intravenous calcium (e.g. as calcium gluconate). Generally, a central venous catheter is recommended, as the calcium can irritate peripheral veins and cause phlebitis. In the event of a life-threatening attack of low calcium levels or tetany (prolonged muscle contractions), calcium is administered by intravenous (IV) infusion. Precautions are taken to prevent seizures or larynx spasms.
The heart is monitored for abnormal rhythms until the person is stable. When the life-threatening attack has been controlled, treatment continues with medicine taken by mouth as often as four times a day.
Long-term treatment of hypoparathyroidism is with vitamin D analogs and calcium supplementation may be ineffective in some due to potential renal damage.
Hyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone (PTH). The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels. Excessive PTH secretion may be due to problems in the glands themselves, in which case it is referred to as primary hyperparathyroidism and which leads to hypercalcaemia (raised calcium levels). It may also occur in response to low calcium levels, as encountered in various situations such as vitamin D deficiency or chronic kidney disease; this is referred to as secondary hyperparathyroidism. In all cases, the raised PTH levels are harmful to bone, and treatment is often needed.
Primary hyperparathyroidism results from a hyperfunction of the parathyroid glands themselves. There is oversecretion of PTH due to adenoma, hyperplasia or, rarely, carcinoma of the parathyroid glands.
Secondary hyperparathyroidism is due to physiological (i.e. appropriate) secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels). The most common causes are vitamin D deficiency (caused by lack of sunlight, diet or malabsorption) and chronic renal failure.
Tertiary hyperparathyroidism is seen in patients with long-term secondary hyperparathyroidism which eventually leads to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. This disorder is most often seen in patients with chronic renal failure and is an autonomous activity.
Quaternary and Quintary
Quaternary and quintary are rare conditions that may be observed after surgical removal of primary hyperparathyroidism, when it has led to renal damage that now again causes a form of secondary (quaternary) hyperparathyroidism that may itself result in autonomy (quintary) hyperparathyroidism.
Symptoms and signs
In primary hyperparathyroidism about 50% of patients have no symptoms and the problem is picked up as an incidental finding (via a raised calcium or characteristic X-ray appearances). Many other patients only have non-specific symptoms. Symptoms directly due to hypercalcaemia are relatively rare. If present, common manifestations of hypercalcaemia include weakness and fatigue, depression, bone pain, muscle soreness (myalgias), decreased appetite, feelings of nausea and vomiting, constipation, polyuria, polydipsia, cognitive impairment, kidney stones.
In secondary hyperparathyroidism the parathyroid gland is behaving normally; clinical problems are due to bone resorption and manifest as bone syndromes such as rickets, osteomalacia and renal osteodystrophy.
In primary hyperparathyroidism, parathyroid hormone (PTH) levels will be either elevated or "inappropriately normal" in the presence of elevated calcium. Typically PTH levels vary greatly over time in the affected patient and (as with Ca and Ca++ levels) must be retested several times to see the pattern. The currently accepted test for PTH is "Intact PTH" which is intended to detect only relatively intact and biologically active PTH molecules.
Serum calcium or Ionized Calcium (Ca++). In cases of primary hyperparathyroidism or tertiary hyperparathyroidism heightened PTH leads to increased serum calcium.
Serum phosphate. In primary hyperparathyroidism, serum phosphate levels are abnormally low as a result of decreased renal tubular phosphate reabsorption. However, this is only present in about 50% of cases. This contrasts with secondary hyperparathyroidism, in which serum phosphate levels are generally elevated because of renal disease.
Alkaline phosphatase. Alkaline phosphatase levels are usually elevated in hyperparathyroidism. In primary hyperthyroidism, levels may remain within the normal range, however this is 'inappropriately normal' given the increased levels of plasma calcium.
The gold standard of diagnosis is the Parathyroid immunoassay.
Treatment depends entirely on the type of hyperparathyroidism encountered. Patients with primary hyperparathyroidism who are symptomatic benefit from surgery to remove the parathyroid tumor (parathyroid adenoma).
In patients with secondary hyperparathyroidism, the high PTH levels are an appropriate response to low calcium and treatment must be directed at the underlying cause of this (usually vitamin D deficiency or chronic renal failure).
The increasing numbers of severely obese patients (body mass index BMI >40 kg/m2) represent a significant management challenge. These patients are at risk of obesity-related complications that may be driven by changes in endocrine function. Their care may potentially be complex at times, and therefore, an appropriate assessment strategy will be relevant to timely diagnosis and management. In this article, we discuss an approach to the endocrine assessment of the severely obese patient. We consider the clinical question in three categories that may also represent different complexities in terms of subsequent management: (i) obesity as a consequence of structural lesions at the hypothalamic–pituitary region; (ii) obesity as a consequence of inherited and genetic syndromes; and (iii) functional neuroendocrine hormone abnormalities relating to obesity. The first two categories are associated with hypothalamic dysfunction, of which hypothalamic obesity is a consequence. Additionally, the implications and difficulties associated with imaging severely obese patients are discussed from an endocrinological perspective and we provide practical guidance on which to base practice.
High levels of obesity pose challenges to healthcare providers worldwide because of the associated complications such as diabetes, cardiovascular disease, cancers and sleep-related breathing disorders that increase morbidity and mortality. Adults with a body mass index (BMI) of 40 kg/m2 or more are considered to have severe (previously termed 'morbid') obesity (Class III obesity by WHO classification). In the USA, the estimated prevalence of severe obesity is approximately 5·1%; in England, 3·8% of females and 1·6% of males are affected. These patients increasingly present in clinical practice, and questions concerning endocrine testing and interpretation may arise. It is known that changes in neuroendocrine function are associated with severe obesity. However, the effects of these changes may be subtle or symptoms experienced attributed solely to the presence of obesity per se, with potential for delayed identification and investigation. In this article, an approach to this clinical question is discussed. Additionally, it is important to highlight potential considerations that should be borne in mind when requesting imaging investigations for these patients.
In all cases, a detailed history and examination are essential parts of the assessment of the severely obese patient and further investigations and management should be directed accordingly. The features of disease that are associated with (for example) hypogonadism or overlap with obesity (for example, polycystic ovary syndrome and Cushing's syndrome) should be sought. Initial investigations that should be performed include a full blood count, renal, liver and lipid profile, blood glucose, HbA1c and thyroid function, while further tests should be guided by clinical judgement based on the findings.
A useful approach when considering the underlying aetiology would be to consider three categories that represent different mechanisms that lead to hypothalamic–pituitary dysregulation: (i) structural hypothalamic lesions; (ii) inherited conditions; and (iii) patients with functional hypothalamic–pituitary changes that may develop as a result of obesity (Fig. 1). Clinical Endocrinology
In all cases, a detailed history and examination are essential parts of the assessment of the severely obese patient and further investigations and management should be directed accordingly. The features of disease that are associated with (for example) hypogonadism or overlap with obesity (for example, polycystic ovary syndrome and Cushing's syndrome) should be sought. Initial investigations that should be performed include a full blood count, renal, liver and lipid profile, blood glucose, HbA1c and thyroid function, while further tests should be guided by clinical judgement based on the findings.
A useful approach when considering the underlying aetiology would be to consider three categories that represent different mechanisms that lead to hypothalamic–pituitary dysregulation: (i) structural hypothalamic lesions; (ii) inherited conditions; and (iii) patients with functional hypothalamic–pituitary changes that may develop as a result of obesity (Fig. 1).
Decision-tree representing potential under-lying causes and routes of testing.
Neuroendocrine signals are integrated by the hypothalamus that controls the anterior pituitary, but also has a key role in the regulation of energy balance and body weight. The arcuate nucleus, ventromedial nucleus, paraventricular nucleus and lateral hypothalamic area are considered the principal homoeostatic brain areas responsible. Lesions of the hypothalamic–pituitary region may cause weight gain and obesity This 'hypothalamic obesity' that occurs with such lesions is associated with hormonal dysregulation that is concomitant with the underlying hypothalamic–pituitary pathology. Structural lesions commonly arise from space occupying lesions such as craniopharyngioma, pituitary tumours and aneurysms, inflammatory and infiltrative diseases and trauma Patients may give a history of cranial surgery or irradiation. Studies have shown that weight gain and obesity are a common consequence of hypothalamic structural lesions. A sudden presentation of obesity may indicate acquired structural hypothalamic disease as seen in relapsed childhood CNS disease such as leukaemia. The underlying mechanisms are not fully understood but are characterized by hyperphagia with food-seeking behaviours, autonomic dysfunction with hyperinsulinaemia, altered thermoregulation and energy expenditure and hormonal deficiencies. Where a structural lesion is suspected, appropriate pituitary function testing and imaging should be requested.
A variety of genetic syndromes have been identified that are associated with severe obesity. These include Prader–Willi syndrome, due to an imprinting defect on chromosome 15, as well as syndromes associated with single-gene disorders, including leptin deficiency, leptin receptor deficiency, proopiomelanocortin (POMC) mutation and melanocortin-4 receptor mutations. These genetic syndromes result in obesity as a result of specific disruption to appetite regulatory pathways and are often also associated with neurohormonal dysregulation depending on the roles of the specific gene concerned (Table 1).
Potential indicators that should increase consideration of a genetic syndrome include a history of early-onset childhood obesity (<5 years of age), severe food-seeking behaviour and hyperphagia, developmental delay or learning difficulties or a history of consanguineous relationships. The health of siblings should be considered, and in adults as well as children, a detailed developmental history can be useful and subsequent physical examination tailored accordingly. When considering genetic/inherited syndromes, these should be assessed by molecular and genetic testing, with appropriate genetic counselling and advice. Subsequent testing for associated endocrine pathology in genetic conditions would be guided by the underlying diagnosis (see Table 1).
In those patients without structural lesions but with clinical evidence of hormonal dysregulation (for example, Cushingoid habitus, hypogonadal features in men, menstrual disturbances, hirsutism in women), confirmed by appropriate endocrine testing, the presence of 'functional' neuroendocrine pathology may be considered. Abnormalities of the endocrine system include increased activity of the hypothalamic–pituitary–adrenal (HPA) axis, impaired growth hormone axis, gonadal and thyroid dysfunction, all may be a consequence of severe obesity, but in some cases may also contribute to its development.
Cushing's syndrome is a rare cause of obesity in secondary care obesity clinics. The presence of thin skin, easy bruising, proximal weakness and decreased linear growth in children may aid distinguishing Cushing's syndrome from simple obesity. Cyclical Cushing's syndrome should be considered in patients with features that suggest the presence of hypercortisolism but who may have normal responses to initial testing.Screening for occult Cushing's syndrome in severely obese patients is not routinely recommended, but should be considered according to clinical judgement.
It is known that circulating GH is low in obesity and that somatotrophic responses are impaired. These deficiencies in GH and insulin-like growth factor-1 secretion are reversible with significant weight loss. Conversely, adult GH deficiency is associated with fat accumulation. There has been no clear evidence for the efficacy of GH use in achieving weight loss in obese subjects, as similar fat reductions may be achieved by diet or exercise interventions. Overall, it is difficult to justify GH replacement in the absence of structural hypothalamic–pituitary defects.
Hypogonadism is common in male obese subjects, but is usually a consequence rather than a cause of obesity. In the presence of symptoms such as erectile dysfunction or clinical evidence indicating hypogonadism, patients should be assessed and treated accordingly. Individual heterogeneity renders diagnosis difficult, and there is a need for the use of accurate methodology in determining hormone levels and in systematic patient assessment. Obesity affects gonadotrophin releasing hormone (GnRH) and gonadotrophin hormone release, and there are decreased testosterone and sex hormone binding globulin levels. There may be a role for dynamic GnRH stimulation testing to distinguish hypothalamic and pituitary lesions.
The 'hypogonadal-obesity cycle' describes the increased peripheral conversion of testosterone to oestradiol by aromatase activity in adipose tissue leading to the inhibition of gonadotrophin releasing hormone secretion with consequent hypogonadism and obesity. In a recent study, hypogonadism in males with severe obesity was found to improve following weight loss by bariatric surgery with increases in both testosterone and sex hormone binding globulin, and a fall in oestradiol. A trial of testosterone replacement may be warranted in the absence of contraindications when testosterone levels are low and correlate with clinical symptoms. It should be noted that testosterone replacement is relatively contraindicated in the presence of sleep breathing disorders such as obstructive sleep apnoea (OSA), which is more prevalent in the severely obese, with studies showing worsening of OSA with testosterone replacement. Therefore, treatment of OSA with continuous positive airway pressure (CPAP) therapy should be considered prior to testosterone therapy in severely obese hypogonadal patients.
In polycystic ovarian syndrome (PCOS), characteristic clinical findings include hyperandrogenism, oligo-amenorrhoea and polycystic ovaries and may be associated with obesity through insulin resistance. Decreased sex hormone binding globulin levels and increased aromatization of androgens to oestrogens occur with perturbations in the hypothalamic–pituitary ovarian (HPO) axis, affecting gonadotrophin secretion and subsequent follicular development and ovulation. Anovulatory obese women may not meet the criteria for PCOS, as obesity itself may affect the HPO axis leading to problems such as oligo-amenorrhoea and infertility. When assessing patients, the exclusion of nonovarian causes (such as hyperprolactinaemia, nonclassical congenital adrenal hyperplasia, androgen-secreting neoplasms and Cushing's syndrome) should be considered.
Hypothyroidism is no more common than in the nonobese population and is unlikely to be the cause of obesity. Thyroid function should be tested and treated as appropriate, but rarely results in significant
Decision-tree representing potential under-lying causes and routes of testing.
It is also important to establish if there is a history of eating disorders and document previous attempts to lose weight, physical activity and mobility as these may influence subsequent weight management plans. Assessing the patient for symptoms of associated complications of obesity, including diabetes and cardiovascular disease, should be actively sought, and a sleep history (such as snoring and excessive somnolence or a high score on the Epworth Sleepiness Questionnaire) is important as sleep-disordered breathing such as OSA would need to be treated. Many patients may be on medications such as psychotropic drugs (including several antidepressants, mood stabilizers and antipsychotics) and antiepilepsy drugs that may induce weight gain. Potential psychological and mood difficulties faced by the patient should be assessed with sensitivity. It may become evident from the assessment that a multidisciplinary perspective may be needed when managing patients with complex problems.
When ordering imaging tests, it is important to be aware of the limitations associated with imaging the obese patient. Access to suitable diagnostic imaging such as magnetic resonance and computed tomography scanners may depend on available capacity and weight or body diameter limitations. Conventional MR systems are limited at 160 kg and 60 cm body diameter (CT scanners, 200 kg and 70 cm diameter), whereas vertical field open MR systems offer greater weight and horizontal diameter capacity (250 kg and 160 cm, respectively), although vertical diameter limits have been described between 40 and 55 cm. As such, there is a need to identify potential open MRI sources as these can be used to image severely obese patients.
In considering the impact of severe obesity on imaging, the use of open MR systems was previously described as having lower resolution due to signal-to-noise ratio and weaker magnetic fields compared with traditional systems. However, more recently, horizontal wide-bore high-field open MR systems have been developed that are capable of facilitating high-quality MR imaging. When considering use of other modalities such as ultrasound and conventional X-ray, these are limited by decreased penetration and increased attenuation. CT images are limited by beam-hardening artefact and radiation scatter, and obese patients may be exposed to higher radiation doses. Due emphasis on maintaining patient dignity are important considerations, and therefore, selection of appropriate imaging studies for the severely obese should be based on local radiological guidance and protocols.
In conclusion, an adequate endocrine assessment of severely obese patients is essential. Underlying primary causes of hypothalamic obesity such as the rare inherited syndromes and structural hypothalamic–pituitary causes should always be considered, although functional neuroendocrine hormone abnormalities are more common. An appreciation of the limitations of local radiological imaging equipment is also necessary and may pose a challenge to investigation and subsequent management. Crucially, a thorough assessment of the severely obese patient will enable clinicians to identify and treat those patients with clinically important neuroendocrine dysfunction and potentially improve health outcomes.
Objectives To evaluate the usefulness of continuous glucose monitoring (CGM) to identify nocturnal hypoglycaemia in children affected by combined ACTH and GH deficiency and to optimize the hydrocortisone replacement therapy in these patients.
Study design Eleven patients with ACTH and GH deficiency (five boys and six girls, age 1·6–16·8 years) underwent CGM for 36 h, including two nights. At least two consecutive glucose levels <2·78 mm were considered hypoglycaemic episodes. The differences in age and doses of hydrocortisone and recombinant human growth hormone (rhGH) between children with and without hypoglycaemia were analysed. The percentage of the glucose values <3·33 mm and the mean glucose levels were also evaluated.
Results Continuous glucose monitoring demonstrated nocturnal hypoglycaemia lasting from 30 to 155 min (1·5% of the total monitoring time) in three cases (27%). No statistically significant differences in age and rhGH dose were observed between children with or without hypoglycaemia. Conversely, the difference in the hydrocortisone doses between the patients with and without hypoglycaemia resulted statistically significant (5·9 vs 8·5 mg/m2/day; P = 0·04). Eight patients presented glucose values less than 3·33 mm during 5% of the total monitoring time. Hydrocortisone dose showed significant positive linear relation with mean glucose level (r = 0·79, P = 0·0035) and inverse relation with time lags of glucose levels under 3·33 mm (r = −0·65, P = 0·03).
Conclusions Our study shows that CGM may represent a valuable tool to detect nocturnal asymptomatic hypoglycaemic episodes and optimize the hydrocortisone therapeutic regimen in children with ACTH and GH deficiency.
Congenital central adrenal insufficiency (CAI), presenting alone or, more frequently, associated with GH deficiency (GHD), is a rare condition. It is characterized either by impaired synthesis and release of ACTH from the pituitary gland, or by impaired release or action of hypothalamic corticotropin-releasing factor, eventually leading to blunted cortisol secretion. It can be associated with abnormalities in hypothalamus-pituitary development, isolated or part of more complex cerebral malformations, such as septo-optic dysplasia (SOD).
In children affected by CAI, isolated or associated with GHD, the optimal regimen of glucocorticoid replacement therapy is still controversial. The most important reason is the inability to reproduce the physiological cortisol circadian rhythm, characterized by very low or undetectable circulating levels at midnight, increasing between 2:00 AM and 4:00 AM, peaking early in the morning, and then declining over the day. Hydrocortisone, at a dose of 6–8 mg/m2/day, subdivided into three oral doses, is now considered the optimal regimen of replacement therapy in adults and children with CAI. However, this currently recommended regimen reduces, but does not eliminate, nocturnal hypocortisolaemia. Consequently, children with CAI may have nocturnal hypoglycaemia. This is especially true in children with associated GHD, which represents an additional risk factor for hypoglycaemia.,
Continuous glucose monitoring (CGM) is a sophisticated method, which measures interstitial glucose concentrations. Recently, a Consensus Statement about the use of CGM in children and adolescents with diabetes was published. The usefulness of this method was also evaluated in very low birth weight infants, in newborn babies at risk of hypoglycaemia and in children with other hypoglycemic disorders, such as hyperinsulinism or glycogen storage diseases. Only one study recently described the use of CGM in adults affected by Addison's Disease.So far, no experience with CGM in children with CAI and GHD has been described.
The first aim of our study was to verify if children with combined ACTH and GH deficiency on replacement therapy present hypoglycaemic episodes detected using CGM. The second aim was to investigate the potential risk factors for hypoglycaemia, assessing the relationships with the doses of hydrocortisone and recombinant human GH (rhGH), to establish the more appropriate replacement therapy in these patients.
Our study population comprised patients with combined congenital CAI and GHD, who were regularly followed at the Bambino Gesù Children's Hospital. The diagnosis of CAI had been based on low or normal ACTH levels and morning cortisol value <82·77 nm or cortisol peak <441·44 nm after standard-dose ACTH tests.The diagnosis of GHD had been considered when peak GH responses to conventional stimulation tests (arginine and clonidine) were <8 μg/l. Other pituitary hormones had been evaluated and any hormone deficiencies adequately replaced. MRI of the hypothalamo-pituitary region had been performed in all patients enrolled in the study.
In the years 2010–2011, after informed parental consent, the children were enrolled in a Cross-sectional study, approved by the local Ethical Committee, and underwent CGM (Gold Medtronic; MiniMed Inc., Sylmar, CA, USA) for 36 h, including two nights because of the higher risk of nonsymptomatic hypoglycaemia during nighttime. Morning fasting serum glucose was evaluated when CGM was removed. During the assessment, the patients were asked to maintain their usual life and eating habits.
The Continuous Glucose Monitor System (CGMS) Gold Medtronic comprises a pager-sized glucose monitor, a sterile disposable subcutaneous glucose sensor with an external electrical connector, a connecting cable and a communication device enabling data stored in the monitor to be downloaded to a personal computer. The monitor analyses the data at 10-s intervals and reports mean glucose values every 5 min. The system has been described elsewhere. Capillary blood glucose measurements obtained using a Precision QID Blood Glucose Sensor (Abbott, MediSense, Baar, Switzerland) were used to calibrate the sensor readings. A minimum of four capillary blood glucose samples were entered into the monitor for calibration each day.
Hypoglycaemia was defined as glucose value <2·78 mm, severe hypoglycaemia as glucose levels <2·22 mm and hypoglycaemic episode was defined as minimum of two consecutive sensor glucose readings <2·78 mm.
Children presenting hypoglycaemia were given a higher hydrocortisone dose and underwent a second CGM.
Data for continuous variables were expressed as median and interquartile range, and categorical data as counts and percentages. Age, height, height velocity (HV) and BMI SDS, GH, and hydrocortisone dose were compared between patients with or without hypoglycaemia. Univariate analysis was performed using appropriate nonparametric test. Analysis of correlation of minimum and mean glucose value, and time of glucose values <2·78 and <3·33 mm with hydrocortisone dose was performed using Pearson's correlation coefficient. A two-tailed P value of less than 0·05 was considered statistically significant in all the analyses. Statistical analysis was carried out using Prism 4.0 (GraphPad Software, Inc, La Jolla, CA, USA).
Eleven patients affected by combined congenital CAI and GHD (five male patients; mean age 5·3 years, range 1·6–16·8 years) were included in the study. The patients had been receiving replacement therapy with hydrocortisone for a mean of 3·8 years (range 0·5–13·9) and with hrGH for a mean of 4·2 years (range 0·5–14·2). All patients were treated with a thrice-daily dosing regimen of hydrocortisone at a dose ranging from 5·9 to 10·8 mg/m2/day, and with a daily dose of rhGH ranging from 0·021 to 0·036 mg/kg/day. All but one (patient no. 9) were given replacement l-thyroxine therapy for central hypothyroidism. Patient no. 3 presented also FSH and LH deficiency on replacement therapy. No patient had diabetes insipidus. In all patients, MRI showed abnormalities of the hypothalamic-pituitary region, associated with SOD in one case. The patients' clinical and neuroimaging data with hydrocortisone and GH treatment doses are reported in Table 1.
The continuous glucose sensor was well tolerated in all children, with no local adverse events. All patients were on regular diet during CGM monitoring. All children showed normal fasting morning glucose serum level, but CGM demonstrated hypoglycaemia (glucose <2·78 mm) in three cases (27%). Hypoglycaemia occurred predominantly in the early hours of the morning and lasted from 30 to 155 min (1·3% of total time monitoring of all patients). In one case, it was particularly severe, persisting at 2·22 mm for 60 min (Fig. 1). Children who presented hypoglycaemia had had dinner properly. None of them had recently started rhGH or hydrocortisone therapy: in fact patient no.1 had been receiving replacement therapy with rhGH and hydrocortisone for 5·3 years, patient no. 2 with rhGH for 5·7 and hydrocortisone for 2·3 years, patient no. 3 with rhGH for 14·2 and hydrocortisone for 13·9 years.
Continuous glucose monitoring 36-h profile of glucose, in patients with hypoglycaemia and without hypoglycaemia. The patients with hypoglycaemia are cases 1, 2, 3 described in Table 1.
No statistically significant differences in age, height, BMI and height velocity (HV) SDS, morning serum glucose and GH dose were observed between children with or without hypoglycaemia. Conversely, the difference in hydrocortisone doses between the patients with hypoglycaemia (Group A) and without it (Group B) resulted statistically significant (5·9 vs 8·5 mg/m2/day; P = 0·04) (Table 1). Eight out of 11 patients presented glucose values less than 3·33 mm accounting for 5% of the total monitoring time of all cases. Hydrocortisone dose showed significant positive linear relation with mean glucose level (r = 0·79, P = 0·0035) and inverse relation with time lags of glucose levels under 3·33 mm (r = −0·65, P = 0·03). It was only slightly associated with minimum glucose level (r = 0·56, P = 0·07). Hydrocortisone dose had no positive linear relation with BMI SDS nor negative linear relation with HV SDS (Fig. 2).
Analysis of the association between hydrocortisone dose (mg/m2/day) and continuous glucose monitoring (CGM) mean glucose level (a), time of glucose value <3·33 mm (b), CGM minimum glucose value (c), Body Mass Index (BMI) (d), and Height Velocity (HV) (e).
The three children with hypoglycaemia were given a higher mean dose of hydrocortisone (8·7 mg/m2/day). The second CGM performed after the hydrocortisone dose increment did not show hypoglycaemia.
Congenital ACTH and GH deficiency is a rare condition that can manifest with hypoglycaemia at birth and/or in early life, both cortisol and GH playing a key role in glucose homeostasis. The tendency to hypoglycaemia secondary to suboptimal circulating levels of cortisol and GH may affect neurocognitive development in these children. It is well established that the child's developing brain is more susceptible to severe hypoglycaemia compared with the adult brain. Recurrent severe hypoglycaemia in children with type 1 diabetes seems to have a selective negative effect on cognitive functions. In a study on 10 children with isolated GHD or combined MPHD, IQ was below the average when compared to the normal population and performance IQ was reduced when compared to sibling controls.
Therefore, ascertainment of the effectiveness of replacement therapy in preventing nonsymptomatic hypoglycaemic episodes in ACTH/GH deficient children is crucial for their neurological outcome. Data on this issue are conflicting, some authors reporting multiple hypoglycaemic episodes, others providing reassuring results. The heterogeneity of the study populations (including both isolated and combined ACTH and GH deficiency), the different cut-off values for defining hypoglycaemia and the use of different methods for recording glucose levels may account for the discrepancies. In this study, we selected a homogeneous group of children with combined congenital ACTH and GH deficiency because of their higher risk of presenting hypoglycaemia.
Hypoglycemia was defined as glucose values <2·78 mm to reduce the risk of overestimation, and CGM, which is a sensitive, accurate and minimally invasive method, was used to study diurnal and nocturnal glucose fluctuations. We found asymptomatic hypoglycaemia in three out of 11 patients (27%), whereas no patient showed glucose levels <2·78 mm at routine blood tests performed in morning fasting conditions. Three of the hypoglycaemic episodes, probably due to the nadir of cortisol levels, occurred in the early hours of the day. It is more difficult to explain the single episode of hypoglycaemia that happened before midnight.
In normal adult populations, glucose levels <3·89 mm at CGM were rarely reported and in healthy children, glucose levels <3·33 mm account for only 0·2% of the observation time. In our patients, duration of hypoglycaemia (glucose levels <2·78 mm) was 1·5% of the total observation time, and the time with glucose levels <3·33 mm accounted for 5·0% of the total observation time, i.e. 25-fold more than in healthy children.
Although a limitation of our study is the lack of an age-matched healthy control population to compare the circadian glucose fluctuations with appropriate reference data, our results nevertheless clearly show an increased risk of reduced glucose levels in children with ACTH and GH deficiency, even when receiving appropriate replacement therapy. However, the clinical significance of this tendency to be susceptible to reduced glucose values is not known and requires further research. In particular, short- and long-term neurocognitive studies in these children are necessary to determine the impact of low blood glucose concentration on neurodevelopment outcome. A study on neurocognitive aspects and quality of life is ongoing in our patients.
The risk of hypoglycaemia was inversely related to the dose of hydrocortisone. Moreover, we detected a significant positive linear correlation between the dose of hydrocortisone and the mean glucose values. Two of the three children who had hypoglycaemia were receiving a dose around the lower limit currently recommended (5·9 mg/m2/day). The patients treated with higher doses of hydrocortisone did not present side effects, such as increased BMI or reduced height velocity.
In children presenting hypoglycaemia, the dose of hydrocortisone was increased to the upper end of the range, and administration of the last dose shifted to late evening. After these adjustments, a second CGM did not show any episodes of nocturnal hypoglycaemia.
All together, these data, to be confirmed by larger studies, support the efficacy of using hydrocortisone doses at the upper end of the recommended therapeutic range (8 mg/m2/day) to reduce the risk of hypoglycaemia.
Recently, it has been demonstrated that, using modified release preparations of hydrocortisone, it is possible to simulate the overnight rise in cortisol release. A article by Johansson on once-daily oral hydrocortisone dual-release in adults with adrenal insufficiency, showed a more circadian-based serum cortisol profile, reduced body weight and blood pressure, improved glucose metabolism and quality of life in comparison with conventional treatment. However, persistent low cortisol levels in the late evening and night were demonstrated. In the future, new pharmaceutical formulations may provide a more physiological and personalized replacement therapy in children with CAI and, perhaps, reduce the risk of nocturnal hypoglycaemia.
In conclusion, our study shows that continuous glucose monitoring may represent a valuable tool for detecting asymptomatic hypoglycaemic episodes and optimizing the hydrocortisone therapeutic regimen in children with ACTH and GH deficiency.
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