Adrenal gland Adrenal gland disordersdisorders

Bereket FantahunPediatrics Endocrinology Unit

May 17, 2012

Disorders of the Adrenal Disorders of the Adrenal GlandsGlands1 Histology and EmbryologyThe adrenal gland is composed of

2 endocrine tissues: the medulla and the cortex.

The chromaffin cells of the adrenal medulla are derived from neuroectoderm, whereas the cells of the adrenal cortex are derived from mesoderm.

Histology and EmbryologyHistology and EmbryologyMesodermal cells also

contribute to the development of the gonads.

The adrenal glands and gonads have certain common enzymes involved in steroid synthesis; an inborn error in steroidogenesis in one tissue may also be present in the other.

Histology and EmbryologyHistology and Embryology

The adrenal cortex consists of 3 zones:

The zona glomerulosa, the outermost zone located immediately beneath the capsule;

The zona fasciculata, the middle zone; and

The zona reticularis, the innermost zone, lying next to the adrenal medulla.

Physiology of the Adrenal Physiology of the Adrenal glandgland

The zona glomerulosa synthesizes aldosterone, the most potent natural mineralocorticoid in humans.

The zona fasciculata produces cortisol, the most potent natural glucocorticoid in humans, and

the zona fasciculata and zona reticularis synthesize the adrenal androgens.

The medulla produce physiologically active catecholamines (dopamin , NEP and EP).

Regulation of the adrenal Regulation of the adrenal cortexcortexCortisol secretion is regulated by

ACTHAldosterone secretion is regulated

mainly by Renine Angiotensin system and by potassium levels

Adrenal androgen secretion-adrenarche is a maturational process in the adrenal gland that results in adrenal androgen secretion b/n 5-20 yrs.

Adrenal Steroid Hormone Actions

Actions of glucocorticoids *Metabolic Effects and growth *Circulatory and Renal Effects. *Immunologic Effects *Effects on Skin, Bone, and Calcium. *Central Nervous System Effects.ACTIONS OF MINERALOCORTICOIDS. *Their major function is to maintain

intravascular volume by conserving sodium and eliminating potassium and hydrogen ions.

ACTIONS OF THE ADRENAL ACTIONS OF THE ADRENAL ANDROGENSANDROGENS..

Adrenal androgens contribute to the physiologic development of pubic and axillary hair during normal puberty.

They also play an important role in the pathophysiology of congenital adrenal hyperplasia, premature adrenarche, adrenal tumors, and Cushing syndrome

Adrenocortical Adrenocortical InsufficiencyInsufficiencyIn primary adrenal insufficiency,

congenital or acquired lesions of the adrenal cortex it prevents production of cortisol and often aldosterone.

Acquired primary adrenal insufficiency is termed as Addison disease.

Adrenocortical Adrenocortical InsufficiencyInsufficiencyDysfunction of the hypothalamus or anterior pituitary gland may cause a deficiency of corticotropin (ACTH) and lead to hypofunction of the adrenal cortex; this is termed secondary adrenal insufficiency .

Primary Adrenal InsufficencyPrimary Adrenal Insufficency

Inherited Etiologies1.Inborn defects of steroidogenesis2.Adrenal hypoplasia congenita3.Adrenoleukodystrophy4.Familial Glucocorticoid deficency5.Disorder of cholestrol synthesis

1.Inborn defects of 1.Inborn defects of steroidogenesissteroidogenesis75 % of Infants with 21-hydroxylase

deficiency, Almost all infants with lipoid adrenal

hyperplasia, and Most infants with a deficiency of

3β-hydroxysteroid dehydrogenase manifest salt-losing symptoms in the newborn period because they are unable to synthesize either cortisol or aldosterone.

2.Adrenal hypoplasia 2.Adrenal hypoplasia CongenitaCongenita.. Hypoadrenalism usually presents

acutely in the neonatal period but may be delayed until later childhood or even adulthood with a more insidious onset.

Histologic examination of the the adrenal gland reveals hypoplastic adrenal cortex

The disorder affects primarily boys and is caused by mutation of the DAX1 gene,

Boys with adrenal hypoplasia congenita (AHC) do not undergo puberty owing to hypogonadotropic hypogonadism

3.Adrenoleukodystrophy3.AdrenoleukodystrophyAdrenocortical deficiency is associated with

demyelination in the central nervous system

The most frequent form of ALD is an X-linked disorder with various presentations.

The most common clinical picture is of a degenerative neurologic disorder appearing in childhood or adolescence and progressing to severe dementia and deterioration of vision, hearing, speech, and gait, with death occurring within a few years.

There is no correlation between the degree of neurologic impairment and severity of adrenal insufficiency.

4.Familial Glucocorticoid 4.Familial Glucocorticoid deficencydeficencyThis form of chronic adrenal insufficiency

is characterized by isolated deficiency of glucocorticoids , elevated levels of ACTH, and normal aldosterone production.

The salt-losing manifestations present in most other forms of adrenal insufficiency do not occur; instead, patients mainly have hypoglycemia, seizures, and increased pigmentation during the 1st decade of life.

Both sexes are affected equally and is Inherited in an autosomal recessive

manner.

Primary Adrenal Primary Adrenal InsufficencyInsufficencyAcquired Ethiologies1.Autoimmune Addison disease2.Infection3.Drugs4.Hemorrage into adrenal glands

1.Autoimmune Addison 1.Autoimmune Addison diseasediseaseThe most common cause of Addison disease

is autoimmune destruction of the glandsThe glands may be so small that they are

not visible at autopsy, and only remnants of tissue are found in microscopic sections.

Marked lymphocytic infiltration All adrenocortical function is lost, but early

in the clinical course, isolated cortisol deficiency may occur.

Most patients have antiadrenal cytoplasmic antibodies in their plasma; 21-hydroxylase (CYP21) is the most frequently occurring autoantigen.

2.Infection2.Infection

Tuberculosis is a common cause of adrenal destruction

The most frequent infectious etiology for adrenal insufficiency is meningococcemia

RVI patients

3.Drugs3.Drugs

Ketoconazol , Rifampicine and anticonvulsants

4.Hemorrage into adrenal glands• This may occur in the neonatal period as

a consequence of a difficult labor An abdominal mass, anemia,

unexplained jaundice, or scrotal hematoma may be the presenting sign. Often, the hemorrhage is asymptomatic initially and is identified later by calcification of the adrenal gland.

Clinical ManifestationClinical Manifestation

Depends on the age of the patient , whether both cortisol and

aldosterone secretion are affected and to some extent

on the underling etiology.Hyperkalemia,hypoglycemia and

hyponatremia are prominanat presenting signs in infants.

Clinical ManifestationClinical ManifestationIn older children the onset is gradual

and xized by muscle weakness ,malaise anorexia ,vomiting ,wt.loss and orthostatic hypotension.

Hyper pigmentationHypoglycemia and ketosis are

common.Hyponatremia and hyperkalemia will

occur later in the course of the disease.

Laboratory findingsLaboratory findings Na + and K+ is high, cortisol level

is decreased and ACTH is increased in case of primary adrenal insufficiency.

The most definitive test for adrenal insufficency is measurment of serum levels of cortisol before and after adminstration of ACTH.

TreatmentTreatmentTreatment of acute adrenal

insufficiency must be immediate and vigorous.

Give 5 % D/W with 0.9 % N/S to correct hypoglycemia, hyponatremia and hypotension.

If the hyperkalemia is sever it needs treatment. IV hydrocortisone should be given.

After the acute manifestation is under control most patients require chronic replacement therapy for their cortisol and aldosterone deficencies

Secondary Adrenal Secondary Adrenal insufficiencyinsufficiencyEtiologyAbrupt cessation of steroid

treatment.Secondary adrenal insufficiency most

commonly occurs when the hypothalamic-pituitary-adrenal axis is suppressed by prolonged administration of high doses of a potent glucocorticoid and that agent is suddenly withdrawn or the dose is tapered too quickly.

CORTICOTROPIN (ACTH) CORTICOTROPIN (ACTH) DEFICIENCY.DEFICIENCY.Pituitary or hypothalamic dysfunction can cause corticotropin deficiency, usually associated with deficiencies of other pituitary hormones such as growth hormone and thyrotropin.

Destructive lesions in the area of the pituitary, such as craniopharyngioma and germinoma, are the most common causes of corticotropin deficiency

CLINICAL PRESENTATION.CLINICAL PRESENTATION.Aldosterone secretion is unaffected in secondary adrenal insufficiency because the adrenal gland is, by definition, intact and the renin-angiotensin system is not involved.

Thus, signs and symptoms are those of cortisol deficiency.

Newborns often have hypoglycemia.

CLINICAL PRESENTATION.CLINICAL PRESENTATION.Older children may have orthostatic

hypotension or weakness. Electrolytes are usually normal.Acquired anatomical defect

involving the pituitary there may be signs of associated deficiency of other pituitary hormones.

TreatmentTreatmentUse smallest effective doseSlow tapering may allow the

adrenal cortex to recover

Cushing SyndromeCushing Syndrome Cushing syndrome is the result of

abnormally high blood levels of cortisol or other glucocorticoids.

This can be iatrogenic or the result of endogenous cortisol secretion, due either to an adrenal tumor or to hypersecretion of corticotropin (adrenocorticotropic hormone [ACTH]) by the pituitary (Cushing disease) or by a tumor .

ETIOLOGYETIOLOGYThe most common cause of Cushing

syndrome is prolonged exogenous administration of glucocorticoid hormones.

Endogenous Cushing syndrome is most often caused in infants by a functioning adrenocortical tumor, usually a malignant carcinoma but occasionally a benign adenoma.

Cushing SyndromeCushing SyndromeThe most common etiology of

endogenous Cushing syndrome in children older than 7 yr of age is Cushing disease, in which excessive ACTH secreted by a pituitary adenoma causes bilateral adrenal hyperplasia.

Such adenomas are often too small to detect by imaging techniques and are termed microadenomas.

Clinical ManifestationClinical ManifestationTruncal obesitymoon face growth retardation(short stature)purplish striaeHypertension, osteoporosis,

glucosuriaAcne, hirsutism and

musculization

LABORATORY FINDINGS.LABORATORY FINDINGS.• Cortisol levels in blood are normally

elevated at 8 A.M. and decrease to less than 50% by midnight.

• Elevated night time salivary cortisol levels raise suspicion for Cushing syndrome.

• ACTH:-Decreased in case of adrenal tumors

• dexamethasone suppression test • Urinary cortisol level increased.Rx – mainly surgery.

Congenital Adrenal Congenital Adrenal HyperplasiaHyperplasiaCongenital adrenal hyperplasia

(CAH) is a family of autosomal recessive disorders of cortisol biosynthesis .

Cortisol deficiency increases secretion of corticotropin (ACTH), which in turn leads to adrenocortical hyperplasia and overproduction of intermediate metabolites.

Congenital Adrenal Congenital Adrenal HyperplasiaHyperplasiaDepending on the enzymatic step

that is deficient, there may be signs, symptoms, and laboratory findings of mineralocorticoid deficiency or excess; incomplete virilization or premature puberty in affected males; and virilization or sexual infantilism in affected females.

Congenital Adrenal Congenital Adrenal HyperplasiaHyperplasia21 alpha hydroxylase deficency

is the commonest one11 beta hydroxylase deficency

and 3- betadehydoxylase enzyme deficency

Primary AldosteronismPrimary Aldosteronism

Primary aldosteronism encompasses disorders caused by excessive aldosterone secretion independent of the renin-angiotensin system.

These disorders are characterized by hypertension, hypokalemia, and suppression of the renin-angiotensin system

Aldosterone-secreting adenomas are unilateral and have been reported in children as young as 3½ yr of age

The treatment of an aldosterone-producing adenoma is surgical removal

Adrenal TumorsAdrenal TumorsAdrenocortical tumors are rare in childhood. They occur in all age groups but most

commonly in children younger than 10 yr of age.

In 2–10% of cases, the tumors are bilateral.Symptoms of endocrine hyperfunction are

present in more than 90% of children with adrenal tumors

Tumors may be associated with hemihypertrophy, usually occurring during the first few years of life.

They are also associated with the Beckwith-Wiedemann syndrome and other congenital defects, particularly genitourinary tract and central nervous system abnormalities and hamartomatous defects.

Virilizing Adrenocortical Tumors Virilizing Adrenocortical Tumors

CLINICAL MANIFESTATIONS. Virilization is the most common

presenting symptom in children with adrenocortical tumors.

In males, the clinical picture is similar to that of simple virilizing congenital adrenal hyperplasia: accelerated growth velocity and muscle development, acne, penile enlargement, and the precocious development of pubic and axillary hair.

Virilizing Adrenocortical TumorsVirilizing Adrenocortical TumorsIn females, virilizing tumors of the

adrenal gland cause masculinization of a previously normal female with clitoral enlargement, growth acceleration, acne, deepening of the voice, and premature pubic and axillary hair development.

In addition to virilization, 20–40% of children with adrenocortical tumors also have Cushing syndrome.

Although virilization may occur alone (50–80%), children with adrenal tumors usually do not have Cushing syndrome alone.

Treatment is surgical.

Feminizing Adrenal Tumors Feminizing Adrenal Tumors Feminizing adrenocortical tumors may

be either carcinomas or benign adenomas.

They may produce only estrogens or, in addition, androgens, cortisol, or mineralocorticoids.

High levels of aromatase activity is found in these tumors.

Feminizing Adrenal Tumors Feminizing Adrenal Tumors CLINICAL MANIFESTATIONS. Such tumors may become symptomatic at

any age after 6 mo. Gynecomastia in males or premature

thelarche in girls is often the initial manifestation.

Growth and development may be otherwise normal, or concomitant virilization may occur, evidenced by acne, deep voice, penile or clitoral enlargement, and advanced skeletal maturation.

Hypertension is common in affected adults but has not been observed in children.

Treatment is surgical

PheochromocytomaPheochromocytoma Pheochromocytomas, catecholamine-secreting

tumors, arise from chromaffin cells. The most common site of origin approximately 90%

is the adrenal medulla; however, tumors may develop anywhere along the abdominal sympathetic chain

Ten per cent occur in children, in whom they present most frequently between 6 and 14 yr of age.

Tumors vary from 1 to 10 cm in diameter; they are found more often on the right side than on the left.

In more than 20% of affected children, the adrenal tumors are bilateral; in 30–40% of children, tumors are found in both the adrenal and extra-adrenal areas or only in an extra-adrenal area.

Pheochromocytoma may be inherited as an autosomal dominant trait

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS The clinical features of pheochromocytoma

result from excessive secretion of epinephrine and norepinephrine.

All patients have hypertension at some time. The hypertension is sustained hypertension

in children. During attacks, the patient complains of

headache, palpitations, abdominal pain, and dizziness; pallor, vomiting, and sweating also occur.

Convulsions and other manifestations of hypertensive encephalopathy may occur

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONSSymptoms may be exacerbated by

exercise. The child has a good appetite but because

of hypermetabolism does not gain weight, and severe cachexia may develop.

Polyuria and polydipsia can be sufficiently severe to suggest diabetes insipidus.

Growth failure may be striking. The blood pressure may range from 180 to

260 mm Hg systolic and from 120 to 210 mm Hg diastolic, and the heart may be enlarged.

TREATMENT-Removal of these tumors results in cure