ADRENAL INSUFFICIENCY BY DR UMENZEKWE CHUKWUDI

OUTLINE INTRODUCTION ANATOMY AND PHYSIOLOGY EPIDEMIOLOGY AETIOLOGY TYPES OF ADRENAL INSUFFIENCY TREATMENT CONCLUSION

Intro cont They are lobulated retroperitoneal glands Greyish yellow in color, soft, pyramidal in shape Cortex is 90% of the gland, made of 3 layers Z. glomerulosa, Z. fasciculata and Z. reticularis.

HORMONES OF ADRENAL CORTEX ZONA GLOMERULOSA……ALDOSTERONE,11 DEOXYCORTICOSTERONE. ZONA FASICULATA CORTISOL ZONA RETICULARIS………ANDROGENS.

CORTISOL A glucocorticoid Frequently referred to as the ‘stress hormone’ Released in response to physiological or psychological stress: exercise, illness, injury, starvation, extreme dehydration, electrolyte imbalance, emotional stress, surgery, etc.

FXNS OF CORTISOL Critical actions on many physiologic systems, including: Maintains cardiovascular function Provides blood pressure regulation Enables carbohydrate metabolism acts on the liver to maintain normal glucose levels Immune function actions Reduces inflammation Suppresses immune system

FXNS OF CORTISOL CONT When cortisol is not produced or released by the adrenal glands, humans are unable to respond appropriately to physiologic stressors Rapid deterioration resulting in organ damage and shock/coma/death can occur, especially in children

ALDOSTERONE A mineralocorticoid Regulates body fluid by influencing sodium balance The human body requires certain amounts of sodium and water in order to maintain normal metabolism of fats, carbohydrates and proteins

ALDOSTERONE CONT Water/sodium balance is maintained by aldosterone Without aldosterone, significant water and sodium imbalances can result in organ failure/death

ALDOSTERONE CONT Aldosteron secretion is stimulated by; -Renin-angiotensin system. -ACTH. -Hyperkalemia. -Hypovolemia. -Hypotension. -congestive heart failure. -Surgery.

PHYSIOLOGY OF THE GLAND

ADRENAL INSUFFICIENCY Adrenal glands produce inadequate amount of steroid hormones,primarily cortisol. Also there is inadequacy of aldosterone that regulate Na retention,potasium secretion and water retention.

TYPES OF ADRENAL INSUFFICIENCY Basicaly three types; 1’ Primary adrenal insufficiency; -idiopathic or of unknown cause. -80% due to autoimmune disease(addisons or autoimmune adrenalitis. -Congenital adrenal hyperplasia or adenoma of adrenal gland. 2; 2ndry adrenal insufficiency (pituiitory)

Examples;exogenous steroid use, - pituitary adenoma/microadenoma ----Sheehans syndrom; 3 Tertiary adrenal insufficiency is due to hypothalamic disease.

CLINICAL PRESENTATION HYPOGLYCEMIA DEHYDRATION WT LOSS DISORIENTATION WKNESS,TIREDNESS,LOW BP,ORTHOSTATI HYPOTENSION,CVS COLLAPSE,MUSCLE ACHES,NAUSEA,VOMITING,DIARHOEA TANNING of the skin that may be patchy or generalised.seen commonly on the hands and buccal mucosa. GOITER AND VERTILIGO MAY BE PRESENT.

C/P CONT CHRONIC ADRENAL INSUFFICIENCY ACUTE ADRENAL INSUFFICIENCY PPTED BY; -Waterhouse-friderickson syndrom. -Sudden withdrawal of long term steroid therapy Stress;surgery,infection,emotional sress

ADDISONS DISEASE Thomas Addison first described the clinical presentation of primary adrenocortical insufficiency (Addison disease) in 1855 in his classic paper, On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules.

Pathophysiology of addisons dx Addison disease is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed.

EPIDEMIOLOGY OF ADDISONS DX Age;The most common age at presentation in adults is years. Sex;Idiopathic autoimmune Addison disease tends to be more common in females and children. Incidence;3-4/million/year. Prevalence;40-60/million/year.

Aetiology cont 1- idiopathic autoimmune adrenocortical insufficiency. 2- Chronic granulomatous diseases; TB, sarcoidosis, histoplasmosis. 3- Hematologic malignancies; as Hodgkin and non-Hodgkin lymphoma and leukemia. Haemorhage/infarctiion -meningococcal septisaemia -venography

Aetiology cont 4- Metastatic malignant disease; as metastatic cancer of the lung, breast, colon or renal cell carcinoma. 5-Infiltrative metabolic disorders; Amyloidosis and hemochromatosis. Schilders dx(adrenal leucodystrophy). AIDS. Surgical removal Type 2 polyglandular syndrom

CF OF ADDISONS DISEASE C\P Patients usually present with features of both glucocorticoid and mineralocorticoid deficiency. The predominant symptoms vary depending on the duration of disease. -Hyperpigmentation of the skin and mucous membranes due to high ACTH. - vitiligo, which most often is seen in idiopathic autoimmune Addison disease. A

-clinical manifestations due to aldosteron deficiency; hyponatremia, hypovolemia, hypotension, hyperkalemia and metabolic acidosis

-clinical manifestations due to cortisol deficiency; weakness, fatigue, hypoglycemia, hypotension, and weight loss.

CF CONT Prominent gastrointestinal symptoms may include nausea, vomiting, and occasional diarrhea. - acute adrenal crisis;a life threatening emergency.may be pri or sec.presents basicaly as hypotension resistant to catecholamine and IVF resuscitation.

INVESTIGATIONS Laboratory Studies; Single cortisol measurement;100nmol/l is suggestive but when >550nmol/l makes the diagnosis unlikely. -Short ACTH(tetracosactide) stimulation test; In patients with Addison disease, both cortisol and aldosterone show minimal or no change in response to ACTH. Am plasma ACTH levels;>80ng/l with low/lownormal cortisol>pri hypoaldosteronism. -hyponatremia Hyperkalemia metabolic acidosis

INVEST CONT -elevated (BUN) and creatinine due to the hypovolemia with decreased glomerular filtration rate. -Hypoglycemia -adrenal autoantibodies may be present Plasma renin levels >very high due to low aldosterone

TREATMENT ACUTE; IV HYDROCORT 100mg(bolus),then200mg in infusion over 24hours. Correct volume deficit and hypoglycaemia.

ADDISON DISEASE AND PREGNANCY Addison Disease and Pregnancy -Before glucocorticoid replacement therapy became available, pregnancy in patients with adrenal insufficiency was associated with a maternal mortality rate of 35-45%. -The usual glucocorticoid and mineralocorticoid replacement dosages are continued throughout pregnancy.

ADDISONS AND PREGNANCY CONTD During labor, adequate saline hydration and 25 mg of intravenous cortisol (ie, hydrocortisone sodium succinate) should be administered every 6 hours. At the time of delivery or if the labor is prolonged, high-dose parenteral hydrocortisone should be administered (100 mg q6h or as a continuous infusion).

ADDISONS AND PREGNANCY CONTD After delivery, the dosage can be quickly tapered to a maintenance dose in 3 days.

CONGENITAL ADRENAL HYPERPLASIA An autosomal recessive deficiency of enzyme in the cortisol synthetic pathway. 5 major Enzymes deficiency are clinically important 21-Hydroxylase 11-b-Hydroxylase 17-a-Hydroxylase 3-b-Hsteroid hydrogenese 20,22 Desmolase deficiency

Result of a 21-Hydroxylase Deficiency

21 HYDROXYLASE DEFICIENCY Most common type, accounts for >80% of cases. Incidence is 1:5000 to 1:15000 live birth. Gene is located on the short arm of chromosome 6 near the C4 locus in close association with HLA genes. Heterozygous carriers can be detected by ACTH stimulation test.

21 OHLASE DEF CONT It is characterized by reduced production of cortisol and aldosterone and increased production of progesterone; 17-OH-progesterone, and sex steroids. The urinary steroid metabolites (17-ketosteroids and pregnanetriol) are elevated above normal levels.

21 OHLASE DEF CONT 2 forms, classic early virilization type with or without salt-losing crisis and non-classic type with late-onset virilization. Male babies with non salt-losing non-classic type remains asymptomatic till late childhood when they may show signs of sexual precocity.

11-b-Hydroxylase Deficiency Accounts for 5-10% of cases of CAH. Gene is located on the long arm of chromosome 8. It is characterized by low plasma renin activity & elevation of serum 11-Deoxycortisol and 11- deoxycorticosterone. Because of the strong mineralocorticoid activity of deoxycorticosterone, the condition is characterized by salt retention, hypertension & hypokalemic alkalosis. The elevated plasma androgens may cause virilization of the female fetus.

17-a-Hydroxylase deficiency Genetic defect is on chromosome 10. Presents with similar features of those of 11- Hydroxylase deficiency except that Androgens are low, so no virilization in girls & genitalia is ambiguous in boys.

3-b-hydroxysteroid dehydrogenase deficiency This is a very rare disorder that results in accumulation of DHEA, which is converted to testosterone in peripheral tissues. It can cause virilization of female fetus and leads to ambiguous genitalia in the newborn.

C/F The clinical phenotype depends upon the nature and severity of the enzyme deficiency. Approximately 50% of patients with classic congenital adrenal hyperplasia due to 21- hydroxylase (CYP21) deficiency have salt wasting due to inadequate aldosterone synthesis. Girls are usually recognized at birth because of ambiguous genitalia.

GIRLS WITH CAH Have ambiguous genitalia at birth: complete fusion of the labioscrotal folds and a phallic urethra. clitoromegaly and partial fusion of the labioscrotal folds In less severe forms, genitalia is normal at birth. Precocious pubic hair & clitoromegaly and excess facial or body hair appear later in childhood, often accompanied by tall stature.

BOYS WITH CAH Are unrecognized at birth because their genitalia are normal. They are not diagnosed until later, often with a salt wasting crisis resulting in dehydration, hypotension, hyponatremia and hyperkalemia or later in childhood with early pubic hair & phallic enlargement accompanied by accelerated linear growth and advancement of skeletal maturation. High blood pressure & hypokalemia may occur in those with 11-b-hydroxylase deficiency and 17-a-hydroxylase deficiency due to the accumulation of the mineralocorticoid desoxycorticosterone

INVESTIGATION BASAL ACTH LEVELS ARE RAISED. 17-HYDROXYPROGESTERONE LEVELS ARE RAISED. URINARY PREGNANTRIOL EXCRETION IS INCREASED. ALDOSTERONE LEVELS ARE RAISED.

IMAGING STUDIES A pelvic ultrasound: in the infant with ambiguous genitalia to demonstrate the presence or absence of a uterus or associated renal anomalies A urogenitogram is often helpful to define the anatomy of the internal genitalia. A CT scan of the adrenal gland to R/O bilateral adrenal hemorrhage in the patient with signs of acute adrenal failure A bone age study is useful in the evaluation of the child who develops precocious pubic hair, clitoromegaly, or accelerated linear growth.

TREATMENT PRINCIPLE Treatment is life-long Treatment goals are: to maintain growth velocity & skeletal maturation. to normalize electrolytes & hormone levels using the smallest dose of glucocorticoids that will suppress the  ACTH to normal. Mineralocorticoid replacement may be needed to sustain normal electrolyte homeostasis.

ACUTE MEDICAL MGT Fluid therapy in babies with salt losing crisis 0.9% sodium chloride 20 ml/kg as IV bolus, followed by a continuous IV infusion of 0.9% or 0.45% saline 3200 ml/m2/day. If the patient is hypoglycemic, 2-4 ml of 10% dextrose will correct the hypoglycemia. Patients with 11-b-hydroxylase and 17-alpha- hydroxylase deficiency, may be hypokalemic and require potassium.

LONG TERM THERAPY Glucocorticoids Replacement Hydrocortisone mg/m2/day divided in 3 oral doses. Dose should doubled during crisis & stressful conditions. The goals of therapy are: To replace the body's requirement under normal conditions and during stress. To suppress ACTH secretion, which drives the adrenal gland to overproduce adrenal androgens in virilizing forms of congenital adrenal hyperplasia.

LONG TERM THERAPY CONT Mineralocorticoids Treatment Fludrocortisone acetate mg once daily orally is indicated for patients who have salt-wasting forms of CAH to replace the aldosterone that is insufficiently produced by the adrenal cortex. It will restore the sodium- potassium balance.

SURGICAL MGT Infants with CAH may require surgical evaluation and, if needed, corrective surgery. Traditional approach is clitroplasty early in life, followed by vaginoplasty after puberty. Some female infants with adrenal hyperplasia are only mildly virilized and may not require corrective surgery if they receive adequate medical therapy to prevent further virilization.

PATIENT EDUCATION Educate the caretakers and patients about the nature of the disease. Patients & parents must understand the need for additional glucocorticoids in times of illness and stress in order to avoid an adrenal crisis which may be life-threatening.

PROGNOSIS Is good and complications like short stature, sexual precocity & metabolic effects are not seen with early adequate therapy. However, children with CAH are at  risk of developing mesodermal tumours e.g. osteogenic sarcoma, pulmonary liposarcoma, uterine leiomyomata and brain tumours.

PROGNOSIS 2 Late diagnosis & inadequate therapy may cause: Death of newborns with salt-losing types & if patients are not provided with stress doses of glucocorticoid in times of illness, trauma, or surgery. Psychological problems in girls with ambiguous genitalia. Short stature and infertility.