ADRENAL GLAND ADRENAL GLAND DISORDERSDISORDERS

Bereket FantahunPediatrics Endocrinology Fellow

December,2010

DISORDERS OF THE ADRENAL GLANDSDISORDERS OF THE ADRENAL GLANDS

1 Histology and Embryology• The adrenal gland is composed of 2 endocrine

tissues: the medulla and the cortex.• The cells of adrenal medulla are derived from

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

Histology and Embryology

• Mesodermal 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 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 GLANDPHYSIOLOGY OF THE ADRENAL GLAND

• 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 CORTEXREGULATION OF THE ADRENAL CORTEX

Cortisol 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 ActionsActions 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 ANDROGENSACTIONS OF THE ADRENAL ANDROGENS..

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 INSUFFICIENCYADRENOCORTICAL INSUFFICIENCY• In 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 INSUFFICIENCYADRENOCORTICAL INSUFFICIENCY

• Dysfunction 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 deficiency5.Disorder of cholesterol synthesis

1.INBORN DEFECTS OF STEROIDOGENESIS1.INBORN DEFECTS OF STEROIDOGENESIS

• 75% of Infants with 21-hydroxylase deficiency is the most common abnormality.

• 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

3.FAMILIAL GLUCOCORTICOID 3.FAMILIAL GLUCOCORTICOID DEFICENCYDEFICENCY

• This 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 • Inherited in an autosomal recessive manner.

Primary Adrenal Insufficency

Acquired Etiologies1.Autoimmune Addison disease2.Infection3.Drugs4.Hemorrage into adrenal glands

1.AUTOIMMUNE ADDISON DISEASE1.AUTOIMMUNE ADDISON DISEASE

The most common cause of Addison disease is autoimmune destruction of the glands

The 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 anti adrenal cytoplasmic antibodies in their plasma

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 , Rifampicin and anticonvulsants4.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.In infants, hyperkalemia, hypoglycemia and

hyponatremia are prominent presenting signs.

Clinical Manifestation

• In older children the onset is gradual and xized by muscle weakness, malaise, anorexia, vomiting, wt. loss and orthostatic hypotension.

• Hyper pigmentation• Hypoglycemia 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.

TreatmentTreatment 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 INSUFFICIENCYSECONDARY ADRENAL INSUFFICIENCY

EtiologyAbrupt 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) DEFICIENCY.CORTICOTROPIN (ACTH) 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.

Treatment

Use 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 .

ETIOLOGYThe 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 Manifestation

Truncal obesitymoon face growth retardation (short stature)purplish striaeHypertension, osteoporosis, glycosuriaAcne, 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 HYPERPLASIACONGENITAL ADRENAL HYPERPLASIA

Congenital 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 HYPERPLASIACONGENITAL ADRENAL HYPERPLASIA

Depending 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 Hyperplasia

• 21 alpha hydroxylase deficency is the commonest one

• 11 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 Tumors• In 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 MANIFESTATIONS• Symptoms 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