ADRENOCORTICAL DEFICIENCY

Hasan AYDIN, MDEndocrinology and Metabolism

Yeditepe University Medical Faculty

Definition

Deficient adrenal production of

glucocorticoids or mineralocorticoids

SteroidogenesisCholesterol

Pregnenolone

Progesterone

11-Deoxycorticosterone

Corticosterone

Aldosterone

17-Hydroxypregnenolone

17-Hydroxyprogesterone

11-Deoxycortisol

Cortisol

DHEA

Androstenedione

Testosterone

Estradiol

3β hydroxysteroid dehydrogenase

21β-hydroxylase

11β-hydroxylase

Aldosterone synthase

Cholesterol desmolase

17α-hydroxylase 17,20 lyase

Glomerulosa

Fasciculata Reticularis

Primary Adrenal Insufficiency

Causes

• Anatomic destruction of gland

• Metabolic failure in hormone production

• ACTH-blocking antibodies

• Mutation in ACTH receptor gene

• Adrenal hypoplasia congenita

Secondary Adrenal Insufficiency

• Hypopituitarism due to hypothalamic-pituitary

disease

• Suppression of H-P-A axis

- By exogenous steroid

- By endogenous steroid from tumor

Causes of Adrenal Insufficiency

Primary adrenal insufficiency

• Autoimmune (70%of patients)

• Infections Tuberculosis (20% of patients) menincococcus,pnumococcus, fungal,HIV

• Medications (ketoconasole, dilantin,phenobarbital,rifampin,etomidate, metyrapone)

• Malignancy (Primary,metastatic)

• Adrenal hemorrhage (spontaneous, traumatic,coagulopathy/heparin/coumadin)

• Familial

• Infiltrative diseases (amyloidosis, sarcoidosis,hemochromatosis)

Secondary adrenal insufficiency

• Exogenous glucocorticoid withdawal

• Following cure of cushing’s sydrome

• Hypothalamic or pituitary disease

(Tumor,sarcoidosis,hemorrhage,

autoimmune,postoperative)

• Isolated adrenocorticotropic hormone

deficiency

Adrenal Insufficiency After Long-term Corticosteroid Therapy

• More than 20mg of prednisolone daily for more than 3 weeks, within the previous year

• Any patient who has clinical Cushing’s syndrome (from any steroid dose)

HPA axis suppresssion

Adrenal Insufficiency After Long-term Corticosteroid Therapy

• Dose equivalent to 5 mg/d or less of prednisolone given for any length of time once daily in the morning

• Any dose of glucocorticoid given for less than 3 weeks

Safe withdraw dose and duration

Primary Adrenal Insufficiency

(Addison’s disease)

- Involve > 90% of the glands

Pathophysiology

• Gradual adrenocortical destruction

- Initial phase: Decreased adrenal reserve

Basal steroid secretion- Normal

Not increase in stress response

- Further loss of cortical tissue

Impair basal secretion of glucocorticoid and

mineralocorticoid

• Plasma ACTH elevation- Earliest and most sensitive indication

Anatomic Destruction of Gland

• Idiopathic atrophy: Autoimmune, leukodystrophy

• Surgical removal

• Infection: TB, Fungus, Virus esp. in AIDS

• Hemorrhage

• Invasion: Metastasis eg. CA thyroid, breast, kidney, lymphoma

Idiopathic Atrophy

• Most common cause 70-80%

• Autoantibody: adrenal cortex Ab, 21-hydroxylase Ab

• Isolated or associated with polyglandular autoimmune syndrome

• PGA syndrome 2 types

• PGA type1- more common

• PGA type2

PGA Syndrome

• PGA type1 (Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dysplasia)

- Autosomal recessive (no HLA association)

- Childhood onset

- 2/3 of these clinicals

:Chronic mucocutaneous candidiasis

:Chronic hypoparathyroidism

:Autoimmune adrenal insufficiency

- Other: Hypogonadotropic hypogonadism, DM type1, Autoimmune thyroid disease, Lymphocytic hypophysitis, Pernicious anemia, Chronic active hepatitis, Vitiligo, Alopecia

PGA Syndrome

• PGA type2

- Polygenic, asso. with HLA DR3,DR4

- Adult onset

- Primary adrenal insufficiency, Grave’s disease,

Autoimmune thyroiditis, DM type1, Primary

hypogonadism, celiac disease

Metabolic Failure in Hormone Production

• Congenital adrenal hyperplasia

. Inborn error of cortisol synthesis

. 5 types ( classified by type of enz. deficiency)

- Most common: 21-hydroxylase deficiency

- 2nd most common: 11-hydroxylase deficiency

• Drugs

- Enzyme inhibitors: Metyrapone, phenytoin, barbiturate, ketoconazole, aminoglutethimide

- Cytotoxic agent: Mitotane

Slow Onset

• Auto-immune atrophy (cmst)• TBC• Metastatic CA (lung, breast, kidney) or lymphoma)

• Systemic fungal infections (histoplasmosis, cryptococcosis, blastomycosis)

• Amyloid• Granulomatous disease• Late stage of AIDS (CMV, bacterial or protozoal infection or Kaposi’s)• Schilder's disease (hereditary leucodystrophy and adrenocortical

atrophy)• Wolman's disease (adrenal insufficiency, HSM,steatorrhoea with lipid-

filled lysosymes)

Abrupt Onset

• Adrenal haemorrhage, necrosis or thrombosis in:

• meningococcal or other sepsis

• coagulation disorders

• as a result of warfarin therapy

• anti-phospholipid syndrome

Presentation

Highly variable

• Duration of disease

• Whether deficiency is primary or secondary

Potential Clinical Manifestations

Glucocorticoid deficiency• Cardiovascular hypotension ,impaired response to

catecholamines• Gastrointestinal anorexia, nausea, weight loss,

abdominal pain, diarrhea• Cutaneous hyperpigmentation (secondary to

ACTH precursors) vitiligo (secondary to autoimmune

disease)• Muscular fatigue,weakness,malasie• Neurologic confusion, apathy,

lethargy, psycosis

Mineralocorticoid Deficiency• Cardiovascular

hypovolemia, decreased cardiac output, impaired response to catecholamines

Clinical Features of Primary Adrenocortical Insufficiency

Percent Weakness, fatigue, anorexia, weight loss 100 Hyperpigmentation 92Hypotension 88Gastrointestinal disturbances 56 Salt craving 19 Postural symptoms 12

Other Autoimmune Endocrinopathies

• Hypo and hyperthyroidism

• Type 1 DM

• Premature ovarian failure with ovarian auto-antibodies

• Primary hypoparathyroidism

• Pernicious anaemia

• Alopecia

• Mucocutaneous candidiasis

Acute Adrenal Crisis

Acute adrenal insufficiency

occurs in patients with Addison’s disease who are exposed to the stress of infection,

trauma, surgery or dehydration

Clinical Features of Acute Adrenal Crisis

• Hypotension and shock • Fever • Dehydration, volume depletion • Nausea, vomiting, anorexia • Weakness, apathy, depressed mentation • Hypoglycemia

Laboratory Findings of Adrenal Insufficiency

Glucocorticoid deficiency

• Lymphopenia• Eosinophilia• Hypogycemia• Anemia

Minerolocorticoid deficiency

• Hyponatremia• Hyperkalamia• Acidosis• Azotemia• Hypercalcemia

ECG: features are low voltage,vertical QRS axis, nonspesific ST-T wave abnormalities

Diagnosis

Diagnosis of Adrenocortical Insufficiency

Since basal levels of adrenocortical steroids in either urine or plasma may be normal in partial adrenal insufficiency, tests of adrenal cortical reserve are necesseary to establish the diagnosis

Cortisol > 20 mg/day at any time of day -diagnosis very unlikely

Hemodynamic instability - cortisol < 20 mg/day - suspicious

ACTH Stimulation Test

• Performed at any time of day

• A baseline cortisol sample is obtained

• 250 mg/day synthetic ACTH (cosyntropin) is then administered

intravenously.

• Cortisol samples are drawn 30 and 60 min later.

• Plasma cortisol >18 mcg/dl excludes the diagnosis

Other Tests

• Insulin stress test,

• Corticotrophin releasing hormone test

• Metyrapone test

can be used to diagnose secondary adrenal

insufficiency

Tests to confirm 2ry adrenal insufficiency

• Prolong ACTH stimulation

- Baseline plasma cortisol

- Cosyntropin 250 ug iv q 8 hr for 48 hr.

: Primary adrenal insufficiency- plasma cortisol no change

: Secondary adrenal insufficiency- progressive increase in

plasma cortisol, and level >18 ug/dL

Tests to Confirm 2ry Adrenal Insufficiency

• Insulin induced hypoglycemia

- Suspected hypothalamic or pituitary disease

- Short acting insulin 0.05-0.1 u/kg at morning

- Blood for plasma glucose and cortisol at 30, 60, 90, and 120 min

Normal response- if BG <40 mg/dl---cortisol> 18 ug/dl

( Avoid when hypoglycemia is contraindicated, 1ry adrenal insufficiency, stroke, epilepsy)

Tests to Confirm 2ry Adrenal Insufficiency

• Short metyrapone test

- Metyrapone 30 mg/kg orally at 24.00 PM

- Blood for cortisol and 11-deoxycortisol at 8.00 AM

Normal- cortisol < 8 ug/dl

deoxycortisol > 7ug/dl

(Metyrapone not available in Turkey)

Plasma ACTH Level

Used to differentiate primary and secondary forms

Secondary adrenal insufficiency plasma ACTH <30 pg/mL ( 7pmol/L)

Primary adrenal insufficiency plasma ACTH >52 pg/mL

Suspected Adrenal InsufficiencyRapid ACTH stimulation test

Abnormal NormalDecreased ACTH reserve not excluded

Metyrapone or insulin hypoglycemia testing

Adrenocortical insufficiency

Plasma ACTH

Elevated Normal or low

1ry Adrenal insufficiency

2ry Adrenal insufficiency

Abnormal Normal

Exclude 2ry Adrenal insufficiency

Exclude 1ry Adrenal insufficiency

Differential Diagnosis

• CA• TB• Salt-losing nephropathy• Anorexia• Malnutrition• Severe GI disease• Malabsorption• Congenital adrenal hyperplasia

Treatment

Treatment of Acute Adrenal Crisis

• Glucocorticoid replacement • Administer hydrocortisone sodium phosphate or sodium

succinate, 100 mg IV every 6 hour for 24 hours. • When the patient is stable, reduce the dosage to 50 mg every

6 hours. • Taper to maintenance therapy by day 4 or 5 and add

mineralocorticoid therapy as required. • Maintain or increase the dose to 200-400 mg/d if

complications persist or occur.

• General and supportive measures • Correct volume depletion, dehydration, and hypoglycemia with

intravenous saline and glucose. • Evaluate and correct infection and other precipitating factors.

Regimen for Maintenance Therapy

• Hydrocortisone, 15-20 mg in AM and 10 mg orally at 4-5 pm

• Fludrocortisone, 0.05-0.1 mg orally in AM. • Clinical follow-up:

• Maintenance of normal weight, blood pressure, and electrolytes with regression of clinical features.

• Patient education plus identification card or bracelet. • Increased hydrocortisone dosage during "stress.''

If Adrenal Crisis Suspected

• Blood drawn for cortisol and start

hydrocortisone immediately without waiting the

result

Or

• Intravenous ACTH stimulation test done and

start hydrocortisone immediately without

waiting the result

In Acute Adrenal Failure 

• 100 mg hydrocortisone iv

• 100 mg iv every 6-8 hours

• Equivalent dose other corticosteroids

After 24 hours

• 25 mg hydrocortisone im every 8 hours

• Day 3 25 mg hydrocortisone im every 12 hours

• Day 4 oral replacement doses

Steroid Glucocorticoid Mineralocorticoid Equivalent dose

Cortisone 0.8 25 0.8

Hydrocortisone 1 20 1

Prednisone 4 5 0.8

Prednisolone 4 5 0.8

Methypprednisolone 5 4 0.5

Triamcinolone 5 4 0

Paramethasone 15 2 0

Dexamethasone 30 0.75 0

Bethametasone 30 0.75 0

Aldosterone 0 400 -

Fludrocortisone doses should be enough to abolish

• postural hypotension

• return Na and K to normal

• maintain plasma renin in upper normal range

• sustain well being

Fludrocortisone Doses

• Usually 50 - 200 mcg daily • Excessive doses of fludrocortisone or hydrocortisone

may result in:• unacceptable weight gain • edema • hypertension

Steroid and the surgical patient

Effect of Surgery

• Stress activates the HPA axis, increased plasma ACTH and cortisol concentration.

• The degree of activation depend on the type of surgery and anesthesia

• Cortisol increase to 75-150 mg/d,

normal: 15-20mg/d

Effect of Surgery

• The increase in cortisol: cariac output, sensitivity to catecholamine, work capacity of skeletal muscle, ability to mobilize energy source.

• Greatest ACTH secretion: reversal of anesthesia, during extubation, during the immediated postoperative recovery period.

Steroid Coverage for Major Surgery• Correct electrolytes, blood pressure, and hydration if necessary.

• Give hydrocortisone sodium phosphate or sodium succinate, 100 mg intramuscularly, on call to operating room.

• Give 50 mg intramuscularly or intravenously in the recovery room and then every 6 hours for the first 24 hours.

• If progress is satisfactory, reduce dosage to 25 mg every 6 hours for 24 hours and then taper to maintenance dosage over 3-5 days. Resume previous fludrocortison dose when the patient is taking oral medications.

• Maintain or increase hydrocortisone dosage to 200-400 mg/d if fever, hypotension, or other complications occur

Steroid Therapy Schedule For a Patient with Adrenal Insufficiency Undergoing Surgery---minor surgery

• 100 mg of hydrocortisone is given intravenously with the induction of anesthesia.

• followed by usual maintenance dose (approximately 20 mg/d of hydrocortisone)

Corticosteroid Insufficiency in Acutely Ill Patients

The Hypothalamic–Pituitary–Adrenal Axis in Acute illness

• During severe illness, many factors can impair the normal corticosteroid response.

Head injury;CNS depressants

Pituitary infarction

Ketoconazole

Adrenal hemorrhage in septicemia or coagulopathy

High level of inflammatory cytokines in sepsis p’t directly inhibit adrenal

cortisol synthesis

Extensive destruction by tumor or

infection

The Hypothalamic–Pituitary–Adrenal Axis in Acute illness

• Develop during an illness• Transient• “Functional adrenal insufficiency”

-- no obvious structral defects in HPA axis• “Relative adrenal insufficiency”

-- insufficient to control the inflammatory response

Diagnosis of Corticosteroid Insufficiency during Acute illness

• Corticosteroid insufficiency associated with acute illness

-- difficult to discern clinically, but there are some features that suggest the diagnosis.

Features suggesting corticosteroid insufficiency

common in patients with acute severe illness.

Easy been masked by fluid replacement, especially in ICU

Relatively uncommon

Laboratory Investigations

Randomly measured cortisol levels• More useful would be the identification of a

minimal threshold level and a maximal threshold level.

• 15 µg/dl (10 µg/dl to 34 µg/dl) best identifies persons with clinical features of corticosteroid insufficiency or who would benefit from corticosteroid replacement

Laboratory Investigations

Corticotropin stimulation test

IV or IM 250 µg of Cosyntropin

Check plasma cortisol levels

0, 30, ( 60 ) mins after administration

Laboratory Investigations

Corticotropin stimulation test

• Prognostic implications

-- < 9 µg /dl increased risk of death.

• > 34 µg /dl: unlike.

• <15 µg /dl: likely.

In Summary

• Adrenal failure can be primary or secondary

• Clinical features can be variable

• Diagnosed by basal cortisol and ACTH stimulation test

• Treated with glucocorticoids + mineralocorticoids