Ghai Essential Pediatrics8th

Inefficient aldosterone action. These include adrenal insufficiency, isolated aldosterone deficiency or aldosterone resistance. They present with hyponatremia, hyperkalemia and dehydration. The condition may be lethal. Failure to thrive is common. Pigmentation is characteristic of adrenal insufficiency. Polyuria and salt wasting in the neonatal period should prompt evaluation for congenital adrenal hyperplasia. Genital ambiguity in girls may be the only clue to this diagnosis.

Excessive water drinking (psychogenic polydipsia). The condition is extremelyrareandis a diagnosis of exclusion.

Evaluation

Subjective estimates of urine output and nocturia may suggestpolyuria;however,thesecannotsubstituteformea­ surementof24hrurineoutputandfluidintake.Urineoutput in excess of 2 L/m2/ dayor 5 ml/kg/hr confirmspolyuria.

Clinical. Diabetes mellitus is suggested by polyphagia, recurrent infections and failure to thrive. Renal tubular acidosis is suspected when acidotic breathing, bony deformitiesor muscleweaknessarepresent. Neurological and fundus examination should be performed. Careful search for features of histiocytosis like ear discharge, proptosis, rash, organomegaly, lymphadenopathy, bony defects and seborrheic dermatitis is essential(Table 17.4.)

Investigations. Initial investigations should include testing for urine sugar and early morning specific gravity or osmolality. Blood gas, urea, electrolytes, calcium and creatinine should be estimated. High plasma osmolality (>300 mOsm/kg or serumsodium>146mmol/L) and low urine osmolality (<300mOsm/kgandurinespecificgravity <1.005) suggest the diagnosis of DI, which needs further classification on the basis of response to arginine vasopressin. Patients with normal plasma osmolality and low urine osmolality (<800 mOsm/kg) should undergo water deprivation test. Urinary osmolality >800 mOsm/ kg (specific gravity >1.010) excludes DI.

MRI of the hypothalamic-pituitary region and anterior pituitary evaluation should be done in central DI. Evaluation of nephrogenic DI includes renal imaging and serum electrolytes.

Water deprivation test. The testis indicatedin children with polyuria, low urinary osmolality and normal plasma

Table 1 7.4: Pointers to diagnosis of polyuria

Endocrine and Metabolic Disorders -

osmolality.Theaimistoincreaseplasmaosmolalityabove 300m0sm/kg (orserumsodiumabove146mEq/l)toallow opportunityformaximalrenalconcentration.Renalfailure and RTA should be excluded before the test. Water depri­ vationtestisnotrequiredinthepresenceofhypernatremia. Thetestshouldbe done on an inpatient basis dueto risk of dehydration. Water deprivation is started early in the morning. The child should be weighed and target weight losscalculated(5%oftotalbodyweight).Bodyweight,urine outputandurineandbloodosmolalityshouldbemonitored hourly. The test should be stopped when urine osmolality increases above 800 mOsm/kg or specific gravity is more than 1.010. Since this excludes DI, plasma osmolality increases above 300 mOsm/kg or serum sodium is above 146mEq/1 (targetachieved)orweightlossismorethan5% (risk of dehydration). Urine osmolality below 300 mOsm/kg inthepresenceofplasmaosmolalityabove300mOsm/kgconfirms

DI. Thesepatientsshouldbeevaluatedfurtherwithresponse to vasopressin. Children with urine osmolality between 300-800 mOsm/kg with plasma osmolality above 300 mOsm/kg mayhavepartialcentral or nephrogenic DI.

Vasopressin responsetest. Thistestisperformedfor differen­ tiation of complete central DI from nephrogenic DI. Urine osmolalityis measured oneandfour hoursaftervasopres­ sin injection (0.1 unit/kg).Anincreasein urine osmolality by more than50% ofbaselinelevelsisdiagnosticof central DI while a smaller increase suggests nephrogenic DI.

Management

Management of polyuria is guided by the underlying cause. Treatment of diabetes mellitus (insulin), adrenal insufficiency (hydrocortisone) and renal tubular acidosis (bicarbonate supplementation) is effective in reducing urine output. Behavioral therapy is recommended for psychological polydipsia.

Central DI. Central DI is managed with vasopressin analogs. Desmopressin (ODAVP), a vasopressin analoghas high potency and prolonged duration of action. It can be given by intranasal (2.5-10 µg 12hourly), or sublingual or oral (50-200 µg 12 hourly) route. Patients with idiopathic DI should be followed for evolving brain tumors.

Nephrogenic DI. Hydrochlorothiazide and amiloride combination (1-2 mg/kg/day of thiazide) reduces urine output by 40%. This paradoxical effect results from decreased delivery of free water to collecting ducts and distal tubule (site of AVP action) dueto increased sodium absorption in the proximal tubule. Addition of indomethacin to this regimen reduces urine output to 50-70%.This shouldbecombinedwith salt restrictionand reduction in solute load.

Suggested Reading

Bajpai A, Kabra M, Menon PSN. Central diabetes insipidus in chil­ dren: Clinical profile and factors indicating organic etiology. Indian Pediatr 2008; 45: 463-8

Ghirardello S, Malattia C, Scagnelli P, Maghnie M. Current perspec­ tives on the pathogenesis of central diabetes insipidus. J Pediatr Endocrinol Metab 2005;18:631-45

Majzoub JA, Srivatsa A. Diabetes insipidus: Clinical and basic as­ pects. Pediatr Endocrinol Rev 2006 Suppl 1:60-5

Muglia LJ. Majzoub JA. Disorders of the posterior pituitary. In: Pe­ diatric Endocrinology, Eds: Sperling MA. WB Saunders 2002, Philadel­ phia, 289-22

DISORDERS OF THYROID GLAND

Physiology

Thyroid hormone biosynthesis involvesinteractionof iodine, tyrosine, thyroglobulin and thyroid peroxidase enzyme. Thyroid peroxidase is the rate-limiting enzyme in thyroid hormonesynthesis. This process is controlled by TSH. TSH secretion is, in turn, under directcontrol of the thyrotropin­ releasing hormone released from the hypothalamus and feedback control of thyroxine. Thyroid hormones bind to intracellular receptors and activate transcription factors. Most triiodothyronine (T3) in the circulation is produced by peripheral conversion of thyroxine (T4) by the enzyme monodeiodinase. This process is stimulated in thyroid depleted states as a protective mechanism to produce more T3. Thus T3 levels are the last to fall in hypothyroidism, and are not a reliable indicator of the disease.

Thyroid hormones are involved in the regulation of somaticand intellectual growth, intermediary metabolism and thermoregulation. There is a critical phase in the early neonatal period for theeffect of thyroidhormoneonmental development.This underscores the need of early diagnosis andappropriate managementof congenitalhypothyroidism. TSH levels increase immediately after birth, resulting in increase in T3 and T4 levels, and reach their maximum by 24 hr. Their level fall to normal in the next few weeks. TSH levels should therefore be estimated after 48 hr as part of neonatal screening for congenital hypothyroidism.

Assessment of Thyroid Function

Thyroid function is assessed by estimation of serum TSH and free and/or total T3 and T4. TSH is the most sensitive indicator of primary hypothyroidism, but is not as helpful in the diagnosis of central hypothyroidism. T4 level is a better indicator of thyroid status than T3 due to increased conversion of T4 to T3 during thyroid depleted states. Considering the wide variability in the levels of circulating thyroid binding globulin, estimation of free (F) thyroid hormone is superior to total levels in thediagnosisof hypo­ thyroidism. Low FT4 and TSH levels suggest central hypothyroidism while high TSH levels indicate primary hypothyroidism. Persistent elevation of TSH in the presence of normal FT4 suggests subclinical hypo­ thyroidism. Elevated FT4and undetectable TSH levels are indicative of hyperthyroid state.

Hypothyroidism

Decreased production of thyroid hormones has significant impact on growth and development. Untreated congenital

hypothyroidism has devastating intellectual and developmental consequences. Acquired hypothyroidism adversely affects growth and school performance.

Hypothyroidism could be caused by defects in the hypothalamic-pituitary axis (central hypothyroidism), thyroid gland or the peripheral sensitivity to thyroxine (Table 17.5).

Congenital Hypothyroidism

Congenital hypothyroidism is the most common preventable cause of mental retardation. Iodine deficiency is the commonest cause of congenital hypothyroidism in certain parts of India, while thyroid dysgenesis is the most common etiology in non-endemic areas (75% of all cases). The disorder encompasses a spectrum ranging from complete agenesis, partial agenesis to ectopic thyroid. Increased incidence of thyroid dysgenesis is noted in Down syndrome. Biosynthetic defects include disorders affecting iodine transport, peroxidation, thyroglobulin synthesis and deiodination. Pendred syndrome, a disorder of the pendrin gene, is associated with decreased intracellular transport of iodine and deafness. Transient congenital hypothyroidism may occur following transplacental passage of TSH receptor blocking anti­ bodies, iodine exposure and treatment with drugs like amiodarone.

Clinical features Features of congenital hypothyroidism are nonspecific and difficult to identify in the neonatal period. They become prominent with increasing age. However, the window period for neurological intervention has elapsed in most patients by this time. This underscores theneedforneonatal screening. Clinical manifestations include hoarse cry, facial puffiness, umbilical hernia, hypotonia, mottling of skin and lethargy (Fig. 17.6.) Prolonged jaundice, constipation and unexplained hypothermia may

Table 17.5: Etiology of hypothyroidism

Primary (Thyroid, >95%)

Autoimmune thyroiditis

Enzyme defects: Trapping, organification, thyroglobulin synthesis, deiodination

Iodine deficiency: Endemic goiter

Dysgenesis: Aplasia, dysplasia, ectopic Thyroid injury: Surgery, radiation, infection

Goitrogens: Thiocyanates, thionamides, lithium, amiodarone Transient causes: Maternal TSH receptor blocking antibody, iodine excess, maternal antithyroid drug

Secondary or Tertiary (Hypothalamus or pituitary, <5%)

Malformations: Septo-optic dysplasia, holoprosencephaly

Genetic defects

CNS insults: Trauma, surgery, radiation, infection CNS tumors: Craniopharyngioma, germinoma

Peripheral (Extremely rare)

Resistance to thyroxine

TSH thyroid stimulating hormone

Fig. 17.6: Congenital hypothyroidism: Note the characteristic facial features

also indicate hypothyroidism. Open posterior fontanel is an important indicator of congenital hypothyroidism (Table 17.6.)

History of maternal thyroid disease or ingestion of antithyroid medications should be enquired.Familyhistory of hypothyroidism suggests dyshormonogenesis, while recurrenttransient hypothyroidismindicates disease related to maternal TSH receptor antibody. Residence in iodine deficient area maysuggest thediagnosisofiodinedeficiency. Goiter should prompt evaluation for transplacental passage of antithyroid drugs or disorders of thyroid hormone biosynthesis. Hypoglycemia, micropenis and midline facial defects suggest hypothalamic causes.

Evaluation Initial investigations in a child with high TSH levels should include evaluation of radionuclide uptake and thyroid ultrasound to confirm the presence of thyroid gland. Thyroid dysgenesis should be diagnosed if no thyroid tissue is visualized on ultrasound. Radiotracer uptake study with radioactive iodine or technetium should be done as soon as the diagnosis of primary congenital hypothyroidism has been established (Fig. 17.7). Children with absent radiotracer uptake but

Table 17.6: Clinical features of hypothyroidism

Endocrine and Metabolic Disorders --

Thyroid scan

Fig. 17.7: Approach to congenital hypothyroidism. TPO thyroid peroxidase; TSH thyroid stimulating hormone

normal thyroid on ultrasound could be suffering from defects in iodine transport, TSH receptor defects or transplacental passage of TSH blocking antibody. Increased radioactive tracer uptake is indicative of iodine deficiency or dyshormonogenesis (Table 17.7). Children with low TSH levels should be worked up for other pituitary defects.

Management Thyroid replacement should be started immediately after diagnosis. In central hypothyroidism cortisol replacement should precede thyroid replacement as it couldprecipitateadrenalinsufficiency. Thyroxine (T4) should be initiated at a dose of 10-15 µg/kg/day. T4 and TSH levels are expected to normalize over one week and one month, respectively, with this treatment. FT4 andTSH should be measured at each visit. Thyroxine dose should be adjusted to achieve FT4 levels in the upper normal rangefor the age. Lifelongthyroidreplacement is required in most cases.

Thyroid replacementshould be stopped for one month at the age of 3 yr in suspected transient congenital hypothyroidism. Treatment may be discontinued in the absence of persistent abnormality on investigations and normal levels of thyroid hormones.

Outcome Early diagnosis and treatment following neonatal screening has resulted in normal intellectual outcomes.

Outcome is however poor in children with congenital hypothyroidism who have been diagnosed beyond the neonatal period. Mental retardation and short stature are common sequelae.

Screening Difficulty in early identification of congenital hypothyroidism and the disastrous consequences of delayed diagnosis have led to neonatal screening for

hypothyroidism. Screening programs use dried blood sample collected at postnatal age of 2 to 4 days. The most commonly used strategy screens first for TSH . This stra­ tegyhashighersensitivitycomparedto T4basedapproach. Primary TSH approach does not identify central hypo­ thyroidism. T4 first approach can identify these children, but has the disadvantage of missing cases with compensated hypothyroidism.

Acquired Hypothyroidism

Etiology Autoimmune thyroiditis is the most common cause of acquired hypothyroidism. This is more common in girls. Goiter is often nodular and firm unlike the soft and uniform goiter in dyshormonogenesis. Thyroid peroxidase antibodies are usually present. Autoimmune thyroiditis may be associated with other autoimmune endocrinopathies such as adrenal insufficiency, type 1 diabetes mellitus (DM) and hypoparathyroidism. Rarely, congenital abnormalities like thyroid dysgenesis or an inborn error of thyroid hormone synthesis may present in older childrenand at adolescence.Iodinedeficiencyand goitrogens are other causes of primary hypothyroidism in older children. Secondary hypothyroidism due to combined hypothalamic-pituitary defects could be a manifestation of neurological injury insults or tumors.

Cl/nica/ features Features of acquired hypothyroidism are subtle compared to congenital hypothyroidism. Short stature may be the only manifestation. Cold intolerance, lethargy, constipation, delay in dentition and poor school performance may suggest hypothyroidism. All children with unexplained mental retardation and short stature should be evaluated for hypothyroidism. Most patients with hypothyroidism have delayed puberty; however, uncontrolled long-standing hypothyroidism may trigger precocious puberty. Goiter is common in iodine deficiency, chronic lymphocytic thyroiditis or dyshormo­ nogenesis. Hypothyroidism has been associated with Down syndrome, Turner syndrome, celiac disease and type 1 DM. All children with these disorders should be periodically screened for hypothyroidism even in the absence of symptoms.

Evaluation Severe short stature and mental retardation suggest congenital hypothyroidism. Round uniform smooth goiter is suggestive of iodine deficiency or disorder of thyroid hormone synthesis; firm nodular goiter

indicates autoimmune thyroiditis. Family history of acquired hypothyroidism suggests autoimmune thyroi­ ditis. Children with central hypothyroidism should be evaluated with pituitary function tests and MRI of the hypothalamic-pituitary region. Antibodies to thyroid peroxidase enzyme (anti-TPO) should be estimated in acquired primary hypothyroidism.

Management Treatment of acquired hypothyroidism should be gradual. A dose of 100 µg/m2 / day is recom­ mended (Table 17.8). In long-standing cases initial treatment should be started at 25-50% of these doses with gradual build up every 3-4 weeks. Thyroxine should be given empty stomach in the morning. Followup should be done every three months during the first two years of therapy and six monthly thereafter. The doses should be modified to maintain TSHlevels in the normal range. Most children require life long therapy. Mild elevation of TSH (below 10 mIU/1) in the setting of normal FT4 levels (subclinical hypothyroidism) is usually self resolving and does not require treatment.

Table 17.8: Recommended dose schedule of thyroxine

Goiter

Goiter refers to the enlargement of the thyroidgland. From a clinical standpoint, thyromegaly is diagnosed when the lateral lobe of the thyroid is larger than the terminal phalanx of the thumb of the child (Fig. 17.8).

Etiology Goiter may be congenital or acquired sporadic, or endemic. Goiter may be associated with diminished, normal or increased thyroid function (Table 17.9). Thyroid enlargement may represent increase in size in response to compensatory TSH secretion (hypothyroidism), infiltration (autoimmune thyroiditis, neoplasms or hemo­ chromatosis), or presence of TSH receptor stimulatory antibody(Graves disease).Importantcauses of congenital

j

Fig. 17.8: Diffuse goiter in a child due to dyshormonogenesis

goiter include maternal antithyroid medications, dys­ hormonogenesis and iodine deficiency. Autoimmune thyroiditis is the most common cause in childhood, followed by iodine deficiency, dyshormonogenesis and Graves disease. Differential diagnosis includes diffuse nodular goiter, benign adenoma, thyroid cyst and, occasionally, a carcinoma.

Evaluation During clinical evaluation goiter is usually classified into diffuse and nodular goiter. Either form can beproducedby autoimmunethyroiditisandcolloid goiter. An acutely painful thyroid enlargement is usually due to hemorrhage or activeinflammation, whereas a firm goiter is characteristic of chronic lymphocytic thyroiditis. Multinodular goiter may be seen in chronic lymphocytic thyroiditis, iodine deficiency and colloid goiter. Isolated enlargement of one lobe indicates hemiagenesis. A well­ circumscribed nodule is usually due to a benign cyst. A single firm or hard painless irregular nodule issuggestive of malignancy. Diffuse goiter in the newborn may be due to Graves' disease, dyshormonogenesis or goitrogenic drugs. Investigations should include thyroid function tests.Anti-TPOantibodiesshouldbemeasuredto identify autoimmunethyroiditis. Positive antibodiesindicate a risk of hypothyroidism even if the thyroid functions are normal. Ultrasound and fine needle aspiration should be performed if no clue to etiology is identified.

Table 17.9: Causes of goiter

Inflammatory: Acute suppurative thyroiditis, subacute thyroiditis

Infiltration: Autoimmune thyroiditis, neoplasm, hemo­ chromatosis

Increased TSH levels: Dyshormonogenesis, iodine deficiency, unilateral agenesis

TSH stimulating antibody: Graves' disease Colloid goiter

Endocrine and Metabolic Disorders -

Management Treatmentshould be directedto thecause (antithyroid medications in Graves disease; thyroxine in hypothyroidism). Children with autoimmune thyroiditis should be followed with annual thyroid function tests. Early trial of thyroxine at a dose of 100-200 µg daily may be given in children with 'physiological goiter'. This pro­ duces complete regression in about 30% of cases by two years. Caution should be taken as the dose may induce hyperthyroidism along with clinical symptoms. Surgery should be avoided unless the goiter is large enough to cause respiratory embarrassment.

Iodine Deficiency Disorders

The term iodine deficiency disorders refers to the wide spectrum of effects of iodine deficiency on growth and development. These include endemic goiter, endemic cretinism, impaired mental function in children and adults with goiter and increased rates of stillbirth and perinatal and infant mortality. These conditions can be prevented by correcting iodine deficiency. Endemic goiter is present when the prevalence of goiter in a defined population exceeds 5%. Endemic goiter is graded by the method of WHO (Table 17.10). Screening estimates of iodine intake are usually derived from 24-hr urinary iodine excretion values or urinary iodine concentration expressed in relation tocreatinineconcentration as given in Table 17.11.

Endemic goiter does not differ from nontoxic diffuse sporadic goiter and the diagnosis is established by epidemiologic criteria. Usually TSH is elevated with low T4 and T3 levels.

Endemic cretinism isa disorder associated withendemic goiter and severe iodine deficiency with characteristic clinical features, which include deaf-mutism, squint, mental retardation and characteristic spastic or rigid neuromotor disorder. Twotypes of endemic cretinism are described. Neurological cretinism is characterized by deaf­ mutism, squint, proximal spasticity and rigidity more in the lower extremities, disorders of stance and gait with preservation of vegetative functions, occasional signs of cerebellar or oculomotor disturbance and severe mental deficiency. Myxedematous cretinism is characterized by retarded psychomotor development, severe short stature, coarse facial features and myxedema without deaf-

Table 17.10: Estimation of thyroid size by palpation

mutism. The pathogenesis of endemic cretinism is poorly understood. Iodine deficiency is also associated with poor school performance in children and recurrent pregnancy loss in women.

Prevention and control Iodine deficiency disorders are best prevented as treatment is usually ineffective. Iodinated salt or iodized oil are highly efficacious in preventing iodine deficiency. Treatment of endemic cretinism may eliminate signs of hypothyroidism but neuromotor and intellectual deficiency are irreversible. Surgical removal of large goiters is indicated only to relieve airway obstruction or for cosmetic reasons.

The NationalGoiter Control Program of the Ministry of HealthinIndiabegan in 1962 withthe establishment of salt iodinationplants. The programisdirected towards control of iodine deficiency disorders and working to ensure that only iodized salt will be used in India. The recommended dailyintakeof iodineis40-120 µgforchildrenup to theage of10;150µgforolderchildrenandadultsandanadditional 25 and 50 µg during pregnancy and lactation respectively. Based onan assumptionofa meanintakeof saltof5g/day, the recommended level of iodination is one part of iodine in 25,000 to 50,000 parts of salt.

Hyperthyroidism

Hyperthyroidism is relatively uncommon in children. It is most commonly seen in young girls, caused by Graves' disease (Table 17.12).

The condition should be suspected in children with weight loss with increased appetite, tremors, diarrhea, warmextremities, increased sweating and anxiety. Inability to concentrate, personality changes, mood instability and poorschoolperformancearecommon.Examinationreveals firm homogeneous goiter. Eye signs are common and are related to sympathetic overactivity (lid lag, ophthalmo-

Table 17.12: Etiology of hyperthyroidism

Infancy

Transplacental passage of thyroid antibodies TSH receptor activating mutation

After infancy

Graves' disease (TSH receptor stimulating antibody) Release of preformed thyroid hormone: Subacute thyroiditis Toxic thyroid nodule, toxic multinodular goiter Iatrogenic

Pituitary resistance to T3

plegia, absence of wrinkling) or auto-immune infiltration (chemosis,proptosis).Tachycardia,cardiacarrhythmiaand high output cardiac failure may occur.

The diagnosis is confirmed by the demonstration of elevatedserumfreeT4andT3levels.Thepresenceofgoiter, infiltrative eyesigns and hyperthyroidism is suggestive of Graves' disease. Absence of goitershould raise the possi­ bilityoftransient hyperthyroidism as part of autoimmune thyroiditis. TSHlevels are usually undetectable inGraves' disease.Ultrasonography andnuclearscan forradioactive iodine uptake (RAIU) are helpful in diagnosing toxic nodule or diffuse goiter.

Antithyroid drugs are ineffective in the acute phase due to lag period in their onset of action. Propylthiouracil is contraindicated in children due to hepatotoxicity. Treat­ ment should be started with methimazole (0.5-1.0 mg/ kg/day). Beta-blockers (propranolol 2 mg/kg/day in two divided doses) are effective in ameliorating of sympathetic symptoms. Iodinated contrast (idopate 0.001 µg/kg/day) and Lugol's iodine (5% iodine and 10% potassium iodide; 126 mg/ml iodine, 1 drop 8 hourly) are effective in reversing of features of hyperthyroidism. Prednisolone (1-2 mg/kg/day) inhibits peripheral conversion of T4 to T3 and is useful in treatment of hyperthyroid storm. Cardiac failure refractory to these measures requires treatment with digitalis.

Surgery and radioiodine ablation should be considered in patients showing failure of medical management. Pati­ ents with large or toxic nodular goiter require partial or totalthyroidectomy.Radioiodine(1311)isnowincreasingly used in the management of childhood Graves' disease.

Congenital Hyperthyroidism

One percent of babies born to mothers with Graves' disease show fetal thyrotoxicosis and cardiac failure. Management includes maternal anti-thyroid drugs and digitalization. This usually occurs within the first week of life but may be delayed if mother is on antithyroid medications or has concomitant TSH receptor blocking antibody. Treatment should include antithyroid drugs, propranolol and corticosteroids. The condition is self limiting and resolves over 3-6 months.

Suggested Reading

Bajpai A, Sharma J, Menon PSN, Eds. Hypothyroid.ism. In: Practical Pediatric Endocrinology.Jaypee Medical Publishers Pvt Ltd, New Delhi. 2003;25-9

Balhara B, Misra M, Levitsky LL. Clinical monitoring guidelines for congenital hypothyroidism: laboratory outcome data in the first year of life. J Pediatr 2011;158:532-37

Fisher DA, Grueters A. Disorders of the thyroid in the newborn and infant. InSperlingMA, eds. PediatricEndocrinology. 3rd edn., Saunders Elsevier, Philadelphia, 198-226

Mathai S, Cutfield WS, Gunn AJ, Webster D, et al. A novel therapeu­ tic paradigm to treat congenital hypothyroidism. Clin Endocrinol (Oxf) 2008;69:142-7

Nair PS, Sobhakumar S, Kailas L. Diagnostic re-evaluation of chil­ dren with congenital hypothyroidism. Indian Pediatr 2010;47:757--oO Rose SR; Section on Endocrinology and Committee on Genetics, American Thyroid association. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006;117:2290-303

DISORDERS OF CALCIUM METABOLISM------

Physiology

Calcium homeostasis involves interaction of gastro­ intestinal absorption,bone resorption and renal excretion. Most (99%) body calcium is stored in the bone and is in constant equilibrium with serum calcium. Parathyroid hormone (PTH), vitamin D and calcitonin are the key regulators of calcium metabolism (see Fig. 5.7).

Calcium sensing receptors present in the parathyroid gland and kidneys sense serum calcium levels. Reduced action of the receptor in the presence of low serum calcium levels results in increased PTH secretion and inhibition of renal calcium excretion.

PTH increases serum calcium by stimulating bone resorption (osteoblast), calcitriol production (proximal tubule) and renal calcium resorption (distal tubule).

Calcitriol is the only hormone that regulates calcium absorption. Calcitriol is formed by activation of vitamin D in the liver (25-hydroxylation) and kidney (la-hydroxy­ lation). Sunlight is the major source of vitamin D with minor contribution from dietary sources.

la.-hydroxylase enzyme in the kidneys is the rate limiting step of calcitriol synthesis.

Calcitonin, secreted by the parafollicular cells of thyroid in response to elevated calcium levels, lowers serum calcium levels by decreasing bone resorption and increas­ ing urinary calcium excretion.

Hypocalcemia

Hypocalcemia (total calcium <8 mg/dl) is an important metabolic situation. Estimation of ionic calcium is important for confirmationofhypocalcemia (ionic calcium <1.1 mmol/1). Empirical formula for calculation of ionic calcium may be used if ionic levels are not available.

Ionized Ca++ = Total Ca++ - 0.8 x (albumin g/dl- 4)

Clinical Features

In the neonatal period, subtleclinicalfeatures like lethargy, jitteriness and poor feeding are characteristic of hypo-

Endocrine and Metabolic Disorders -

calcemia. Seizures are common and hypocalcemia is the commonest biochemical abnormality associated with neonatal seizures.

In the postneonatal period, the commonest presentation is tetany (simultaneouscontractionofgroupsofmuscles).This is most commonly observed in hands (adduction ofthumbs along with extension of the proximal interphalangealjoints and flexion of distalinterphalangealjoints)andfeet (flexion andinternal rotationoflowerlimbs)resultingincarpopedal spasm. Inmildercases,latent tetanycan be detectedbytests ofneuromuscularexcitability.Tappingthefacialnerveatthe angleofjawresultsincontractionoffacialmuscles (Chvostek sign). Inflating blood pressure cuff above the systolic blood pressureformorethan5minutes triggersspasmofthehand muscles (Trousseau sign). Hypocalcemia should be consideredinchildrenwithseizures,dilatedcardiomyopathy and unexplained stridor.

The diagnosis is confirmed by the demonstration of prolonged QT interval on ECG, as suggested by Q0Tc more than 0.2 seconds, where

Q T QOT

0 C = .JRfi..

Q0T = Interval from beginning of Q wave to beginning of T wave; RR = RR interval

Etiology

Hypocalcemia may be caused by chelation of calcium or inefficient action of PTH or vitamin D (Table 17.13).

PTH related. Inefficient PTH action caused by decreased production (hypoparathyroidism) or action (pseudohypo­ parathyroidism) is an important cause of hypocalcemia.

Table 17.13: Etiology of hypocalcemia

Deficiency of ionic calcium (chelation)

Phosphate load

Tumor lysis

Rhabdomyolyis

Top feeds

Total calcium deficiency

PTH deficiency (hypoparathyroidism) Aplasia: DiGeorge syndrome

Autoimmune: Polyglandular endocrinopathy types I and II Infiltration: Wilson disease, hemochromatosis, thalassemia Transient: Hypomagnesemia, maternal hyperparathyroidism, post-surgery

PTH resistance (pseudohypoparathyroidism)

Vitamin D deficiency Nutritional

la:-hydroxylase deficiency: Renal failure, VDDR* type I Calcitriol resistance: VDDR type II

Increased inactivation: Phenytoin, phenobarbitone

*VDDR Vitamin D dependent rickets

These disorders are characterized by high phosphate levels due to impaired phosphaturic action of PTH.

Hypoparathyroidism may occur as part of congenital malformation or acquired destruction of the parathyroid glands. Autoimmune hypoparathyroidism is the most commonform in older childrenandfrequently associated with autoimmune polyendocrinopathy type l.

DiGeorge syndrome characterized by abnormal deve­ lopment of third andfourth pharyngeal pouchesis caused by deletion of part of chromosome 22q. This results in maldevelopment of thymus (resulting in T cell immun­ odeficiency), parathyroids (resulting in hypo­ parathyroidism), heart (resulting in conotruncal defects) and face (abnormal facies).

Hypomagnesemia is an important cause of transient hypoparathyroidism and should be excluded in children with refractory hypocalcemia.

PTH resistance (pseudohypoparathyroidism, PHP), is caused by inactivating mutation in the gene encoding for stimulatory subunitof G protein (Gsa.). This presents with clinical features of hypoparathyroidism in the wake of elevated PTH levels. PHP may be associated with the phenotype of Albright hereditary osteodystrophy such as round facies, brachydactyly, short stature, obesity, short fourth and fifth metacarpals (brachymetacarpia), osteodystrophy and heterotopic ossification

Vitamin D related. Vitamin D deficiency (nutritional, malabsorption), decreased la.-hydroxylase action (renal failure, vitamin D dependent rickets type I), increased inactivation of vitamin D (antiepileptic drugs) and calcitriol resistance (vitamin D dependent rickets type II) are associated with hypocalcernia. Phosphate levels are low due to secondary hyperparathyroidism. Vitamin D deficiency is the most common cause of hypocalcemia in children. Rickets may be absent. Maternal vitamin D deficiency is common in India and results in reduced calcium and vitamin D stores in children. These infants develop hypocalcemia during periods of rapid bone growth (4-8 weeks of life). Vitamin D dependent rickets presentswithearly onset severehypocalcerniaandrickets.

Increased chelation. Increased calcium binding results in reduction of ionic calcium and features of hypocalcernia. This is most commonly related to high phosphate levels (renal failure or release of intracellular phosphate due to hemolysis, tumor lysis or rhabdomyolysis). Increased phosphate levels in cow milk and commercial formula is

an important cause of neonatal hypocalcemia. Metabolic or respiratoryalkalosis increases albumin binding of calcium resulting in hypocalcernia.

Evaluation

Evaluation is directed towards identification of etiology and assessment of the severity of illness.

Clinical. Detailed history of the age of onset, presenting features, frequency of episodes of hypocalcemia and family history should be obtained. Neonates should be screenedforprematurity, birth asphyxia, maternal hyper­ parathyroidism and initiation of top feeds. Congestive cardiac failure, recurrent infections and abnormal facies are suggestive of DiGeorge syndrome.

Investigations. Initial evaluation should include serum phosphate levels, renalandliver function tests and serum alkaline phosphatase (Table 17.14 and Fig. 17.9). Phos­ phateregulation is dependent onPTH andinefficient PTH action results in hyperphosphaternia. Hypocalcemia due to decreased vitamin D action is associatedwithsecondary hyperparathyroidism and low phosphate levels. Thus hypocalcernia with hyperphosphatemia in the absence of phosphate load (exogenous or tissue lysis) and normal renal function suggests parathyroid insufficiency. Hypo­ magneserniashouldbeconsideredin patients withrefrac­ tory hypocalcernia and normal or low phosphate levels. 25-hydroxyvitamin D levels should be measured in children with rickets to identify vitamin D deficiency.

Management

In children with severe hypocalcernia (ionic calcium <0.8 mmol/1) parenteral calcium should be administered (2 ml/kg intravenously over 5-10 min) after obtaining blood sample for calcium. Calcium gluconate (10%, 9 mg calcium per ml) is the preparation of choice. Care should be taken to administer the drug slowly (to avoid cardiac effects) and avoidextravasation (to prevent skin necrosis). Parenteral calcium should be started at a dose of 80 mg/ kg/day and should be gradually tapered over two days.

Short course activated vitamin D (calcitriol or la.­ vitamin D, 20-40 ng/kg/day in three divided doses for 2 days) should be given to children with vitamin D deficiency and acute hypocalcemia. This should be combined with high dose vitamin D (300,000-600,000 IU) to replenish body stores of the vitamin. Longterm management for conditions with inefficient PTH action includes activated vitamin D (30-60 ng/kg/day) and

Serum phosphate

Renal failure

Phosphate load

Hypoparathyroidism

Pseudohypoparathyroidism

Vitamin D deficiency Hypomagnesemia Vitamin D dependent

rickets

Fig. 17.9: Evaluation of a child with hypocalcemia

calcium(50mg/kg/day)in theform ofcalciumcarbonate. Vitamin D dependent rickets is managed with activated vitamin D andcalciumphosphate. Higherdoses of vitamin D may be required in patients with calcitriol resistance.

Hypercalcemia

Hypercalcemia (serum calcium >11 mg/dl) is rare in children. Its causes include increased bone resorption (hyperparathyroidism, malignancy and immobilization) or excessive vitamin D action (iatrogenic excess and increased 1 a-hydroxylase activity).

Hyperparathyroidism is the commonest cause of chronic hypercalcemia in children. Homozygous inactivating mutations of the calcium sensing receptor present with severe neonatal hyperparathyroidism. Parathyroid adenoma is rare before the age of 10 yr. Rarely, hypercalcemia may be associated with other conditions, e.g. William syndrome (supravalvular aortic stenosis, abnormal facies) or hypophosphatasia (inactivating mutation of alkaline phosphatase). Vitamin D related hypercalcemia most commonly occurs in patients with overdose of vitamin D. Increased la-hydroxylase activity may occur in patients with granulomatous diseases (tuberculosis, sarcoidosis) or fat necrosis.

Clinical features are often nonspecific, including muscular weakness, anorexia, nausea, vomiting, consti­ pation, polydipsia and polyuria. Ectopic calcification in the kidney, basal ganglia and skin are common. Bony deformities and pathological fractures may be present. Infants present with failure to thrive, poor feeding, hypotonia and seizures. Serum total and ionized calcium levels are elevated with low levels of phosphate. Hyper­ parathyroidism is associated with elevated levels of PTH.

Treatment of acute hypercalcemia involves high fluid intakefollowedbydiuresis(frusemide1mg/kg).Bisphos­ phonates and antiresorptive agents are indicated if there is no response to these measures. Hemodialysis may be requiredinrefractorycases. Surgicalexplorationisindicated in all cases ofhyperparathyroidism. Short course ofgluco­ corticoids (prednisolone 2 mg/kg/day for 3 weeks) is indicated in children with iatrogenic vitamin D excess or increased la-alpha hydroxylase action (fat necrosis or sarcoidosis).

Endocrine and Metabolic Disorders -

Suggested Reading

Allgrove J. The parathyroid and disorders of calcium metabolism. In: Clinical Pediatric Endocrinology, 5th ednm Eds: Brook C, Clayton P, Brown R, Blackwell Publishing, Oxford, 2005;254-79

Hallick MF, Binkley NC, Bischoff-Ferrari HA et al. Evaluation, treat­ ment and prevention of vit D deficiency: Endocrine Society Clinical Practice Guidelines. J Clin Endocrinol Metab 2011;96:1911-30

Hallick MF. Vitamin D deficiency. New Engl J Med 2007;357:266-81

DISORDERS OF ADRENAL GLANDS

Physiology

Adrenal cortex produces three important groups of hormones-glucocorticoids, mineralocorticoids and androgens. The process of steroidogenesis involves conversion of cholesterol to steroid hormones through a series of enzymatic processes. Cholesterol is transferred into the mitochondria in a process mediated by the steroidogenic acute regulatory protein (StAR), an ACTH­ dependent protein. The most clinically relevant step in steroidogenesis is 21-hydroxylation mediated by the enzyme 21-hydroxylase (P450c21). This step is crucial for the production of cortisol and aldosterone.

Cortisol, the major glucocorticoid hormone has an important role in intermediary metabolism causing increased blood glucose levels and enhanced catabolism of proteins and lipids. Aldosterone acts on distal renal tubules andcollectingducts ofkidneysto promote sodium and fluid reabsorption. Aldosterone deficiency causes urinary salt wasting resulting in salt wasting crisis (hyponatremia, hyperkalemia and metabolic acidosis). Adrenal androgens are necessary for the development of pubic and axillary hair in girls.

Adrenocorticotropic hormone (ACTH), a polypeptide secre­ ted by the anterior pituitary, is the principle regulator of glucocorticoid and androgen synthesis. Intravascular volume, serum potassium levels and renin-angiotensin system are the chief regulators of aldosterone synthesis. ACTH has only a minor role in aldosterone regulation. ACTH deficiency as in secondary adrenal insufficiency is thereforenotassociatedwithsaltwasting.ACTHsecretion is stimulated by hypothalamic coriticotrophin releasing hormone and suppressed by cortisol as part of a feedback loop.

Adrenocortical Excess

The most common disorder of adrenocortical hyper­ function is Cushing syndrome. The term Cushing disease refers tohypercortisolismcaused by an ACTH-producing pituitary tumor. Classic features of Cushing syndrome such as central obesity, striae, moon facies and buffalo hump are rare in children (Fig. 17.10.) Growth failure and obesity are common; other features include hypertension, hirsutism, delayed puberty, behavioral problems, bone pain and muscle weakness.

Fig. 17.10: Cushing disease secondary to pituitary adenoma. Note the moon face and hypertrichosis over forehead and upper lip

Etiology

Cushing syndrome may be caused by increased endo­ genous production or exogenous administration (Table 17.15). Prolonged steroid treatment is the commonest cause of childhood Cushing syndrome. Increasedadrenal glucocorticoid production may be related to increased ACTH levels or represent autonomous adrenal hyper­ function. Adrenal pathology is more likely in young children, while pituitary causesarecommonafterpuberty. Ectopic ACTH production is rare.

Evaluation

Investigationsaredirectedtowardsconfirming thediagnosis of Cushing syndrome and finding the etiology. The

Table 17.15: Etiology of Cushing syndrome ACTH dependent causes

Hypothalamic lesions: Increased corticotrophin production Pituitary lesions: Microadenoma, macroadenoma

Ectopic lesions: Neuroblastoma, carcinoid tumor, Wilms tumor

ACTH independent causes

Adrenal carcinoma, adenoma

Pigmented nodular hyperplasia

McCune Albright syndrome

Exogenous administration

GIucocorticoids

ACTH

commonly used screening tests include assessment of diurnal cortisol rhythm, overnight dexamethasone suppressiontest (cortisollevelsafterasinglemidnightdose of dexarnethasone 0.3 mg/m2; maximum dose 1 mg) and 24 hr urine free cortisol (Table 17.16). Diagnosis can be confirmedwithlowdose dexarnethasone suppression test (serumcortisolafterdexamethasone5µg/kgevery6hrfor two days).

The most important part of evaluation of a child with Cushing syndrome is to differentiate ACTH-dependent causesfromautonomousadrenalsteroidproduction (Table 17.17). ACTH levels differentiate ACTH-independent (ACTHlevels <5pg/ml)fromACTH-dependentconditions (ACTHlevels>15pg/ml). Ectopic ACTHproductionshould besuspectedinchildren withextremelyhigh ACTHlevels (>100pg/ml).Highdose dexamethasonesuppressiontest is based on the principle that high doses of this agent suppress ACTH production in individuals with pituitary lesions but not in those with ectopic ACTH production.