Urgenţe Endocrinologice

2

Cetoacidoza Diabetică (CAD)

CAD este o urgenţă endocrinologică determinată de deficitul absolut sau relativ al insulinei, caracterozată prin hiperglicemie, deshidratare şi acidoză metabolică. CAD este o complicaţie a diabetului zaharat decompensat şi necesită tratament imediat

• Diabetul zaharat este una din cele mai frecvente afecţiuni la copii • CAD este adesea modul de prezentare al diabetului zaharat la copil• La copii, CAD determină 70 % din decesele prin boală

Epidemiologie

• CAD este precipitat de factori variaţi:- în majoritatea cazurilor CAD este precipitat de o infecţie sau de neadaptarea dozelor de insulină în cursul infecţiilor intercurente severe (creşterea dozei) (pneumonie, gripă, gastroenterită, infecţie de tract urinar)- noncomplianţa la insulină – omiterea dozelor, din cauza problemelor psihologice, tulburărilor de comportament; teama de creştere în greutate la fete; teama de manifestările hipoglicemice, etc. - stress (emotional, intrevenţii chirurgicale pentru pseudoabdomen acut)

3

• Deficitul de insulină imposibilitatea utilizării glucozei de către celule (fatigabilitate, cefalee) hiperglicemie (în CAD aproape întotdeauna >300 mg/dL) hiperosmolaritate: osmolaritatea serică (mosm/L)= 2[Na (mEq/L)] + glucoză (mg/dL)/18; normal 297 ± 2 mosm/L) poliurie (diureză osmotică), pierdere urinară de Na, K, Cl, Mg, Ca, P

• “Foamea” celulară hormonilor contrareglatori (glucagon, epinefrină, cortizol, hormon de creştere) cu instalarea unei stări hipercatabolice:

ficat: gluconeogeneză and glicogenoliză ţesut muscular: proteoliză ţesut adipos: lipoliză, sursă de cetogeneză hepatică (acid acetoacetic, acid -hidroxibutiric); halenă acetonemică; acidoză metabolică cu polipnee sau respiraţie Kussmaul, greaţă şi vărsături; dureri abdominale care pot mima un abdomen acut chirurgical

• Deshidratare (diureză osmotică, vărsături) – prezentă la toţi bolnavii, poate apare rapid (în ore de la debut) şi este severă; deshidratarea cu pierderea apei şi electroliţilor depletion of water and electrolytes from both intra- and extracellular fluid compartments• Cerebral edema is the most feared and most lethal complication of DKA, accounting for at least half of DKA-related deaths; factors implicated but not proved to be associated: rapid fall in blood glucose, failure of the actual serum sodium to rise during treatment, and the use of bicarbonate

Fiziopatologie

4

• The clinical manifestations of DKA depend primarily on the severity of metabolic imbalance and the degree of intravascular volume depletion• Fatigue, loss of weight, polyuria, polydispsia, nausea, vomiting • Virtually all patients have signs of significant dehydration (most patients with DKA are at least 10 % dehydrated): tachycardia, dry mucous membranes, poor skin turgor; poor peripheral perfusion is indicated by cool extremities with delayed capillary refill• The metabolic acidosis induces hyperventilation in order to decrease PCO2; therefore most patients are tachypneic; patients with severe acidosis may demonstrate Kussmaul breathing, characterized by deep, sighing respirations and fruity odor to their breath (ketotic odor)• Some patients may develop abdominal pain severe enough to resemble an acute abdomen (acute pancreatitis, apendicitis, gastrointestinal perforation)• Mental status ranges from normal to lethargy and (in severe cases) coma• Cerebral edema: headache, coma, loss of the pupillary light reflex (0.3 – 1% of children with DKA, 20 – 50% mortality)

• The physical examination always includes a careful search for an infection that may have precipitated DKA

Clinical Manifestations

5

• At presentation, the magnitude of specific deficits in an individual patient varies depending upon the duration and severity of illness, and the extent to which the patient was able to maintain intake of fluid and electrolytes• Hyperglycemia 11 mmol/L (200 mg%); a bedside glucose test can quickly confirm the presence of hyperglycemia; in DKA, the serum glucose is almost always >300 mg/dL; Glucosuria • Metabolic acidosis: venous pH 7.3 or sodium bicarbonate 15 mmol/L• Ketonemia and ketonuria• Serum electrolytes (Na, K, Ca, Mg, P)• Serum osmolality • Kidney function: urea and creatinine• CBC, CRP, urine, blood cultures, pulmonary x-Ray (infection)• Cerebral edema: CT scan to assess the severity and to exclude other causes

During the resuscitation (approximately the first 12 hours):- serum glucose levels are monitored every hour- serum ketones every 2 hours- serum electrolytes and pH every 4 hours- urine is monitored for ketones at every void- flowsheet with accurate estimates of input and output

Laboratory Studies

6

Replacing the fluid and electrolyte deficit Administration of exogenous insulin

Fluid Resuscitation• The initial fluid resuscitation: normal saline or Ringer's lactate at a dose of 20 mL/kg over 1 to 2 hours in stable patients; shock - administration as fast as possible• After the initial bolus, the patient's cardiovascular status is reevaluated; if perfusion is not adequate, a second bolus of 20 mL/kg is administered• After the initial resuscitation, rehydration is continued with 0.45 NS or 0.9 NS depending

on state of hydration, serum Na, and hemodynamic status of the patient; if significant hyponatremia is present, the first 6-8 hrs of correction should occur with 0.9 NS; corrected serum Na should not be allowed to drop faster than 10 to 12 mEq/L/24 h• Total fluid volume for 24 hrs:

• 5 % dehydration - 3000 mL/m2; • 7.5 % dehydration - 3750 mL/m2

• 10 % dehydration - 4000 mL/m2 (no more than 4 L/m2/24 h)• Hydration status and serum osmolality must be monitored carefully• Serum osmolality (mosm/L) may be estimated using the following formula: 2[Na (mEq/L)] + glucose (mg/dL)/18; normal 297 ± 2 mosm/L

Management

7

Potassium• Virtually all patients with DKA are K-depleted: metabolic acidosis - intracellular K is exchanged for extracellular H+ to buffer the metabolic acidosis, and extracellular K is lost through the kidney. • Depending on multiple factors, including the severity and acuity of acidosis and the degree of dehydration, the initial serum K can be low, normal, or high; both severe hypo- and hyperkalemia can cause life-threatening cardiac arrhythmias• Hypokalemia is most common several hours after rehydration is initiated• Replacement therapy is started once a normal or low serum K is ensured and urine output is established• The usual dose of K is twice-daily maintenance, or 3-4 mEq/kg/24 h, provided as 40 mEq/L in the IV fluids

Sodium• The osmotic diuresis usually induces Na depletion in patients with DKA; laboratory studies do not reflect actual serum Na concentration, since both the hyperglycemia and the hyperlipidemia of DKA cause false low values• Some of the depleted Na is replaced during the initial resuscitation with NS or Ringer's lactate; during the continuing resuscitation, Na levels are monitored every 4 hours; as the glucose falls, the reported level of Na should rise; a fall in serum Na during continued fluid resuscitation may indicate excess accumulation of free water and may be a risk factor for the development of cerebral edema.

8

Bicarbonate• The use of sodium bicarbonate in the treatment of DKA remains extremely controversial• Clinical studies have failed to demonstrate improved outcome in patients treated with supplemental bicarbonate• Its use can be considered in patients with:

- severe acidosis (pH <7.1 or serum bicarbonate < 5 mEq/L)- associated with insulin resistance or cardiovascular collapse

• For a serum bicarbonate level 5 mEq/L, correction to one-third of the total deficit rapidly, as a resuscitation procedure only

- assume total bicarbonate equals 25 mEq/L- total deficit = [normal bicarbonate – actual bicarbonate] x 0.5 x weight in kg- discontinue bicarbonate therapy when bicarbonate reaches 7 to 10 mEq/L

9

Insulin administration • As soon as the diagnosis of DKA is made and fluid resuscitation instituted, supplemental insulin is administered• Current recommendations are for low-dose, continuous, IV insulin infusion, the starting dose is 0.1 U/kg/h; on occasion, the infusion may have to be increased to 0.15 to 0.2 U/kg/h to lower the serum glucose and reverse the ketosis if the patient's serum glucose is unresponsive to the initial starting dose of 0.1 U/kg/h after the first 1 to 2 hours of insulin therapy; an initial bolus of insulin is not necessary and can precipitate rapid fluid exchanges that may be dangerous• The goal of therapy is to decrease the serum glucose by 75 to 100 mg/L/h; when the serum glucose reaches 250 mg/dL, 5 % glucose is added to the infusing fluid ; if the serum glucose is dropping precipitously, a glucose solution of 10 % may need to be administered• It is dangerous to discontinue the insulin infusion completely if the patient has moderate to large serum ketones, since this can worsen the ketoacidosis; it is necessary to decrease the insulin infusion to 0.03 to 0.06 U/kg/h only in situations in which acidosis is minimal and glucose is dropping excessively • During the initial resuscitation phase the patient should be given nothing by mouth; as the patient improves, sips of water or ice may be provided and advanced to clear liquids as tolerated

10

Insulin administration • When the serum glucose normalizes, metabolic acidosis improves, and serum ketones decrease to trace, the insulin infusion is discontinued in concert with a switch to SC insulin and enteral intake of liquids or solids. • SC insulin is administered 30 minutes prior to discontinuing the insulin infusion to allow for absorption of the SC insulin dose; not administering SC insulin prior to discontinuing the infusion can predispose to rebound hyperglycemia and ketoacidosis.• Children in mild DKA or "day after resuscitation" can be managed by providing SC insulin using their baseline or "home" dose; this typically amounts to 0.5 to 1.5 U/kg/d, depending on age and pubertal status. • The ongoing presence of ketones may be managed by providing additional insulin at approximately 6-hour intervals, in the form of regular insulin at a dosage of 5-10% of the total daily requirement for small, 10 - 15 % for moderate, and 25 % for large ketones.• Additional insulin may be administered as often as every 2 to 3 hours if rebound acidosis occurs. • If ketones persist, doses are increased by 5 - 10 % until improvement is evident.

11

• Hypoglycemia is common, especially in young diabetics, who tend to be labile; it often occurs 6 to 8 hrs after the initiation of therapy for DKA; treatment consists of adjusting the insulin infusion and providing supplemental IV and oral glucose according to the principles outlined above; toddlers appear to be unusually sensitive to insulin, requiring lower initial insulin infusion doses and greater vigilance regarding hypoglycemia; this is thought to be secondary to suboptimal counterregulatory hormone responses during DKA.• Hypokalemia is the most common electrolyte abnormality and occurs within several hrs

of initiation of therapy; since it can lead to arrhythmias, cardiac monitoring is essential until metabolic parameters have stabilized; treatment is with supplemental potassium, as discussed above.• Cerebral edema is the most feared and most lethal complication of DKA, accounting for at least half of DKA-related deaths. It usually occurs as the patient's metabolic parameters are improving and is often heralded clinically by complaints of headache, dizziness, changes in behavior, incontinence, and alterations in pulse and blood pressure, all of which can indicate increased intracranial pressure. • It seems to be more common in young diabetics and in cases of new-onset diabetes.

Complications

12

• Cerebral edema • At present, the etiology of cerebral edema is unknown and its occurrence unpredictable. Factors implicated but not proved to be associated with cerebral edema include

• a rapid fall in blood glucose, • hypoglycemia, • fluid volume replacement, • a failure of the actual serum sodium to rise during treatment, • and the use of bicarbonate.

• A recent study confirmed that children with cerebral edema had lower initial pCO2 levels

and higher blood urea nitrogen levels than controls; also, treatment with bicarbonate was associated with cerebral edema; however, this study did not answer the question of whether cerebral edema results from the severity of metabolic disturbance before presentation to the ED or the requisite intensive treatment during the resuscitation period; treatment with bicarbonate nevertheless must be done with close monitoring and conservatively.

• The treatment of cerebral edema consists of hyperventilation, mannitol, and fluid restriction, all of which decrease intracranial pressure; given the unpredictable nature of cerebral edema, careful attention to neurologic status with hourly mental status checks in a critical care setting is mandatory in the treatment of all patients with DKA.

Complications

13

Hypoglycemia

• Hypoglycemia is defined as a decrease in the plasma glucose level below 55 mg/dL in children and below 35–45 mg/dL in neonates. • A plasma glucose level <45 mg/dL (blood glucose <40 mg/dL) in association with symptoms requires intervention. • A plasma glucose 25–35 mg/dL requires intervention in an asymptomatic infant only if the infant is at risk of hypoglycemia (e.g., infant of diabetic mother or fetal malnutrition) and the glucose value does not rise to 45 mg/dL or more with feeding.

• The actual glucose level at which obvious signs and symptoms of hypoglycemia are manifest is variable; the clinical diagnosis of hypoglycemia involves:

- demonstrating a cause-and-effect relationship between symptoms, - laboratory evidence of hypoglycemia, - and a demonstrable resolution of symptoms following the administration of

glucose.

Definition

14

Patophisiology• Glucose is the main energy substrate for the central nervous system and most other organs in the body. • There must be an exogenous supply of glucose by food intake. The endogenous supply

of glucose from liver and muscle stores is regulated by a complex interaction of hormones, including:

• insulin (inhibitory) • and glucagon, epinephrine, cortisol, and growth hormone (stimulatory)

• In the presence of an adequate supply of glucose, insulin promotes the uptake of glucose and amino acids into muscle and adipose tissue, where they undergo anabolic conversion, including the formation of glycogen and protein. Insulin lowers blood glucose levels. • Glucagon, epinephrine, cortisol, and growth hormone oppose the effects of insulin in an attempt to increase the serum level of glucose. They stimulate glycogenolysis in the liver as well as the mobilization of amino acids (especially alanine and glycine) for gluconeogenesis, and they promote lipolysis, generating free fatty acids and glycerol, which can be used in limited amounts as energy substrates. • The cumulative effect is to maintain glucose levels in the normal range.

15

Signs and Symptoms

• The wide variety of signs and symptoms of hypoglycemia usually results from the sympathetic stimulation driven by the insulin-antagonizing hormones that function to increase serum glucose. • Newborns and young infants may be asymptomatic or may manifest nonspecific symptoms such as irritability, pallor, cyanosis, tachycardia, tremors, lethargy, apnea, or seizures.• Older children exhibit more classic symptoms of hypoglycemia, including diaphoresis, tachycardia, tremor, anxiety, tachypnea, and weakness; parodoxically, refusal of food and vomiting may be present. • Prolonged hypoglycemia can cause confusion, stupor, ataxia, seizures, and coma. In the early phase, many patients will complain of headache. • Particularly after insulin misadventures or lack of substrate, prolonged, severe hypoglycemia may present as a stroke-like state with a Todd's paralysis. This condition, termed neuroglycopenia, takes several hours to resolve even after the glucose is restored to normal. The etiology of this particular presentation of hypoglycemia is not known.

16

Differential Diagnosis• Hypoglycemia can be due to:

• inadequate substrate supply, • accelerated glucose utilization, • toxic ingestion, • and disorders of endogenous glucose storage, release, and synthesis.

• Hypoglycemia secondary to lack of exogenous glucose is common in acutely ill infants and children, since oral intake is often decreased during an acute illness. Diarrheal diseases may cause malabsorption of substrate and result in hypoglycemia. Deliberate fasting due to anorexia in an older child may present as hypoglycemia.• Idiopathic ketotic hypoglycemia - usually seen in a previously healthy, slender young child, aged 2 - 7 years (typically male), often with a history of normal to low birth weight,

with normal growth and development who presents with episodic bouts of symptomatic

fasting hypoglycemia, ketosis and ketonuria, without hepatomegaly. It may be associated with an intercurrent illness. It is the most common cause of hypoglycemia beyond infancy. The pathogenesis is unknown, but it is thought to be due to an exaggeration of the normal childhood inefficiency of gluconeogenesis. Hepatic glycogen stores are depleted at presentation, so there is no glycemic response to glucagon. In the acute phase, patients respond promptly to glucose. Avoidance of prolonged fasting is the only treatment necessary. The disorder is outgrown by late childhood.

17

Differential Diagnosis

• Conditions leading to hyperinsulinemia can result in hypoglycemia. • most commonly occurs in a diabetic patient who has taken insulin but does not ingest sufficient calories; hypoglycemia is the most common acute problem suffered by patients with diabetes. • autosomal recessive persistent hyperinsulinemic hypoglycemia of infancy (formerly known as nesidioblastosis)• infant of the diabetic mother• -cell hyperplasia of Beckwith-Wiedemann syndrome• in older children, one might consider islet cell adenomas • "Munchausen by proxy syndrome," i.e., exogenous insulin administration by a caregiver; the earliest reported case involved an infant 2 months of age.

• Inborn errors of metabolism can result in hypoglycemia by disrupting endogenous glucose metabolism:

• defects in amino acid metabolism • glycogen storage diseases• fatty acid oxidation (FAO) disorders• enzyme deficiencies in gluconeogenic pathways• and activating mutations of glucose transporters

18

Differential Diagnosis• The most common FAO disorder is medium chain acyl-CoA dehydrogenase deficiency (MCADD). It can be asymptomatic or present as unexplained death during infancy. It is inherited as an autosomal recessive disease. The allele frequency varies in different

populations ranging from 1:40 in Northern Europeans to 1:15,000 in Caucasian Americans. Recent data show that MCADD accounts for 1 % of sudden infant death syndrome; 19 % of children with MCADD are diagnosed after death. For this reason it has been recommended for newborn screening and must be considered when entertaining the diagnosis of ketotic hypoglycemia.

• Hormonal disorders such as hypopituitarism and adrenal insufficiency can also cause hypoglycemia.

19

Diagnosis

• A rapid screen for the serum glucose level at the bedside is possible using a glucose oxidase reagent strip. • More accurate confirmation is achieved by direct measurement done on an initial venous sample. This is the "critical sample" and should include not only a sample for glucose obtained in a gray top tube and placed on ice but important additional studies: insulin, C-peptide, growth hormone, cortisol, and glucagon levels. • Urine is tested stat for ketones. The presence or absence of ketonuria is important for the differential diagnosis of hypoglycemia:

- negative ketones indicate - hyperinsulinism - fatty acid oxidation abnormalities,

- the presence of ketones is characteristic of:- ketotic hypoglycemia, - adrenal insufficiency- growth hormone deficiency - other inborn errors of metabolism.

• Measurements of urinary amino acids, ammonia and energy substrates, lactate, pyruvate, and ketone bodies should be obtained if the etiology of hypoglycemia remains obscure.

20

Management

• Treatment of hypoglycemia should be started while awaiting laboratory results.• IV glucose is the first line of therapy. Glucose is administered to symptomatically hypoglycemic patients in a dose of 0.5 g/kg/dose0.5 g/kg/dose. Dextrose 25% at a dose of 2-4 mL/kg is appropriate therapy. • In neonates and preterm infants, dextrose 10% at a dose of 5-10 mL/kg/dose is used to avoid sudden hyperosmolarity. • In older children and adolescents, dextrose 50% at a dose of 1-2 mL/kg/dose is used. • If hypoglycemia persists, a continuous infusion of D5W or D10W at 5 mg/kg/min is indicated.

• The amount of IV glucose required to elevate blood glucose levels and to ameliorate symptoms may provide clues to the etiology of hypoglycemia; if glucose needs in an infant exceed 12 mg/kg/min, the diagnosis is most likely hyperinsulinemia; If time permits prior to the administration of IV glucose, or in the event that IV access is not possible, glucagon at a dose of 0.3 mg/kg is given.

21

Management

• A glucagon challenge is useful for both diagnosis and treatment: -a negative challenge (blood glucose rise <40 mg/dL over baseline), suggests poor glycogen stores (undernutrition, ketotic hypoglycemia, liver failure, or glycogen storage disease)- a positive challenge (glycemic increment rising 40 mg/dL over baseline), suggests hyperinsulinism.

• Patients with mild hypoglycemia who are capable of eating or drinking are treated with orange juice or some other age-appropriate source of calories.• After an episode of hypoglycemia, glucose levels are monitored every 1 to 2 hours until the patient is alert and capable of eating and drinking.

22

Adrenal Insufficiency (AI)

General aspects• The symptoms of adrenal insufficiency (AI) result from deficiencies of two classes of hormones secreted by the adrenal cortex:

glucocorticoid deficiency results from lack of cortisol mineralocorticoid deficiency results from lack of aldosterone

• Glucocorticoid deficiency impairs gluconeogenesis and glycogenolysis, resulting in fasting hypoglycemia. It also resets the "osmostat" and causes dilutional hyponatremia via the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). • Aldosterone deficiency results in decreased sodium retention by the kidney, resulting in osmotic diuresis, hyponatremia, hypovolemia, and vascular collapse. In addition, it causes a decreased distal renal tubular exchange of potassium and hydrogen ions for sodium ions, leading to hyperkalemia and acidosis. • AI is classified into primary (adrenocortical failure itself), secondary (pituitary), or tertiary (hypothalamic) types. Primary and tertiary AI, due to withdrawal from exogenous

steroid administration and suppression of cortisol synthesis, are the two most common

causes of adrenal crisis presenting to a pediatric emergency facility.

23

Etiology

Primary AIOnly the primary type of AI is characterized by hyperpigmentation, hyperkalemia, and severe vascular collapse.

Primary AI results from congenital or acquired adrenal gland dysfunction. • Clinical signs and symptoms do not become manifest until at least 90% of the adrenocortical tissue from both glands is destroyed; the onset of primary AI is usually gradual, resulting in partial corticoid deficiencies and vague symptoms of fatigue, anorexia, occasional mild postural hypotension, or polyuria. • However, primary AI in the presence of intercurrent illness or stress, can present as shock, especially in infants.• The most common cause of primary AI in infants is congenital adrenal hyperplasiahyperplasia (CAH)

- the female newborn presents with genital ambiguity secondary to virilization in utero. Hypotension, hyponatremia, hyperkalemia, natriuresis, and shock typically do not develop until about 7-14 days postnatally- boys, therefore, characteristically present at this time in cardiovascular collapse.

• 17-Hydroxyprogesterone is usually on the neonatal screen; this identifies infants who escape diagnosis at birth and prior to acute presentation in the emergency department.

24

• CAH results from a block in the enzymatic activity of one of five enzymes in the cortisol biosynthetic pathway. Each enzyme deficiency results in a characteristic alteration in steroidogenic precursors, resulting in a particular clinical syndrome. • Of the several types of CAH, 21-hydroxylase deficiency accounts for over 90% of cases. This type causes cortisol and aldosterone deficiency with androgen overproduction. The incidence varies from 1 in 12,000 in the general population.Test for 21-hydroxylase deficiency must be in the differential diagnosis of the shocky infant in the first month of life.• Congenital adrenal hypoplasiahypoplasia is a rare cause of primary AI in infancy; it has been reported to occur as an isolated defect with or without a familial tendency. There are two hereditary forms:

- the cytomegalic form is an X-linked disease in which the normal adrenal architecture is replaced by large, vacuolated cells; this form classically presents in the first 6 months of life with AI and is caused by DAX-1 mutation or contiguous gene deletions that are associated with hypogonadotropic hypogonadism, Duchenne's muscular dystrophy, and/or mental retardation

- the "miniature" form occurs as an autosomal recessive disorder and may be secondary to isolated ACTH deficiency.• Congenital primary AI can also result from adrenal aplasia or hemorrhage associated with a traumatic delivery.

25

• Familial isolated glucocorticoid deficiency is a heterogeneous group of autosomal recessive disorders.. 50% of the cases have inactivating mutations of the ACTH receptor. The "triple A syndrome," is a distinct clinical syndrome consisting of AI, alacrima, and achalasia of the esophagus, often associated with various neurologic defects, plus ACTH insensitivity or resistance. The mineralocorticoid system is usually intact, thus cardiovascular collapse is rare

• Progressive granulomatous, degenerative, or storage diseases involve the adrenal gland (tuberculosis, histoplasmosis, or lysosomal acid lipase deficiency - Wolman's disease), and occur in infancy. Wolman's disease - autosomal recessive, abnormal storage of triglycerides and cholesterol esters that cannot be degraded by the adrenal, spleen, liver, or other affected organs; vomiting, diarrhea, failure to thrive, hepatosplenomegaly, and adrenal calcification. Patients invariably die at a few months of age despite corticosteroid therapy.

•Adrenoleukodystrophy (ALD) is a rare cause of childhood primary AI. It is an X-linked recessive familial disorder, characterized by fatty acid accumulation in adrenocortical and neural cells, associated with progressive central demyelination, resulting in blindness, deafness, dementia, quadriparesis, and death.

26

• Acquired causes of primary AI in children are less common than congenital disorders, and results from autoimmune, infectious, infiltrative, hemorrhagic, or ablative disorders:

- autoimmune adrenalitis, which accounts for 80% of all cases of acquired primary AI, is often associated with immune destruction of other glands and is encountered in both types of polyglandular autoimmune syndromes. The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome

(type I, or APECED) is more commonly found during childhood, with a mean age at diagnosis of 12 years; type II (primary AI, hypothyroidism, and diabetes mellitus) is more common and typically occurs in middle life (mean age of onset 30 years).

- infection of the adrenal gland with tuberculosis or fungi; HIV has been also reported as a cause of primary AI

- infiltrative diseases, such as sarcoidosis, hemochromatosis, or malignancy- acute adrenal hemorrhage in fulminating sepsis (the Waterhouse-

Friderichsen syndrome)- surgical removal of the adrenal glands

27

Secondary and tertiary AI• Secondary and tertiary AI result from pituitary or hypothalamic underfunction, respectively. Both lead to isolated cortisol deficiency (and in females, androgen deficiency); because ACTH is decreased, hyperpigmentation does not occur; the mineralocorticoid system is intact, thus, hyperkalemia and shock do not occur; dilutional hyponatremia may be encountered, however, secondary to SIADH• Secondary AI

- tumors, craniopharyngioma, infections, infiltrative diseases of the pituitary,- lymphocytic hypophysitis, head trauma, - and intracranial aneurysms, - or in association with cerebral malformation. - extremely low birth weight newborns may experience transient glucocorticoid

deficiency due to a sluggish HPA axis; neonatal ACTH deficit also occurs as part of the congenital hypopituitarism syndrome of hypoglycemia and cholestatic jaundice, with micropenis in males. • Tertiary AI is most commonly caused by withdrawal from chronic administration of glucocorticoid pharmacotherapy, which suppresses the hypothalamic-pituitary-adrenal axis. Hyponatremia and hyperkalemia do not occur. It also occurs after cure of Cushing's syndrome, trauma, or any process that disrupts hypothalamic CRH secretion (e.g., intracranial tumor or its treatment).

28

Clinical Presentation and Laboratory FindingsPrimary AI• Crisis is typically encountered in a child with newly diagnosed primary AI subjected to the stress of an acute illness/in a patient with previously established AI who has not increased the prescribed steroid dose appropriately during the stress of an intercurrent illness.• Acute cardiovascular collapse is the most common presentation of AI. • In impending AI, patients may complain of anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, or lethargy; diffuse myalgia and arthralgias may occur.• Hypoglycemia may be the presenting symptom. • In the most severe cases, a child may present in coma or suffer from severe mental confusion. • Fever may be present.• Signs of primary AI include hyperpigmentation, most notably in areas exposed to the sun (face, neck, and hands), areas subject to friction (elbows, knees, and knuckles), the buccal mucosa, areolae, and anal mucosa.

• Vitiligo secondary to melanocyte destruction suggests an underlying autoimmune disorder. • Moniliasis is associated with the AI of polyglandular autoimmune syndrome type • Severe or long-standing AI has associated psychiatric abnormalities, including organic brain syndrome, depression, or psychosis.

29

Primary AI• Laboratory findings in primary AI include

- hypoglycemia- hyponatremia, - hypochloremia, - hyperkalemia, - and metabolic acidosis (low serum bicarbonate levels)- urinary sodium excretion is elevated, approaching the osmolality of serum.- increased blood urea nitrogen:creatinine ratio occurs as the result of dehydration- mild to moderate eosinophilia, lymphocytosis, and anemia are common. - electrocardiographic abnormalities that occur as the result of hyperkalemia include

peaked T waves, low P waves, and wide QRS complexes; rarely, asystole or intraventricular heart block results- low cortisol levels, elevated ACTH levels, low aldosterone, increased plasma renin activity, and low dehydroepiandrosterone-sulfate levels (in pubertal children) are confirmatory

30

Management of AI crisis

Primary AI• If sepsis is suspected, blood, urine, and cerebrospinal fluid cultures • Blood samples for cortisol and ACTH levels• Urine electrolytes, serum electrolytes, glucose, blood urea nitrogen, and creatinine levels, as well as a urinalysis • Aldosterone level and plasma renin activity may prove to be helpful for later diagnosis

. Fluid therapy should begin by giving a 20 mL/kg bolus of 5% dextrose/normal saline or colloid rapidly IV. After the initial resuscitation, normal saline (NS)is usually required at a rate appropriate for severe dehydration; an appropriate rate is twice the normal maintenance rate (200 mL/kg/day for children weighing less than 10 kg and 2250-3000 mL/m2/day for older children) to replenish sodium stores and keep up with ongoing losses of salt and water. • Input and output must be monitored closely, with close attention to sodium losses in the urine. • Hypoglycemia should be treated with 0.5 to 1.0 g/kg/dose (using boluses) of 50% dextrose in water, and 10% glucose should be included in replacement fluids as needed.

31

Management of AI crisis

Primary AI Specific treatment requires initiating glucocorticoid therapy with cortisol (hydrocortisone, Solu-Cortef), 50 mg/m2/dose, IV every 6 hours. • Mineralocorticoid need not be given in acute adrenal crisis, as high-dose hydrocortisone has mineralocorticoid-like action.

• Antibiotics should be initiated IV if septic shock is suspected.