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Page 1: ADRENAL GLAND:    Congenital adrenal hyperplasia &    adrenal insufficiency

ADRENAL GLAND: Congenital adrenal hyperplasia & adrenal insufficiency

Dr. Amnon Zung

Pediatric Endocrinology Unit

Kaplan Medical Center

Page 2: ADRENAL GLAND:    Congenital adrenal hyperplasia &    adrenal insufficiency

case report [1]

M.R., a 4 y.o. boy

Previous history: Born in Kaplan, BW 3000, to healthy parents.

At 3.5 years was referred to ER , where tonsillitis was diagnosed. Incidental finding: pubic hair Tanner 3.

Basal androgens levels:

17-hydroxyprogesterone: 89 nmol/L

Androstenedione: 20 nmol/L

Testosterone: 8 nmol/L

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Congenital Adrenal hyperplasia – the beginning

21-hydroxylase deficiencyClassic: female pseudohermaphroditism (DSD):At birth: urogenital sinus, labial fusion, clitoromegaly75% are salt wasters Frequency: 1:13,000 to 1:15,000 live births (based on 6.6

million newborn screened) Carrier state: 1:63New York city: 1:100 / 1:7Ashkenazi Jews: 1:27 Hispanics: 1:40Slavs: 1:50 Italians: 1:300 11-ß hydroxylase deficiencyFrequency: 1:100,000 (highest in Moroccan Jews)

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CAH – Molecular Genetics 21-hydroxylase encoding gene: Short arm of chromosome 6 Two homologous genes: Cyp21B & Cyp21A

(pseudogene) 98% homology in exons (n=10); 96% in introns About 50 mutations known today Correlation & none-correlation of genotype\

phenotype

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CAH: genotype-phenotype correlation due to 21-hydroxylase deficiency

Patients are often compound heterozygotes Phenotype is likely to reflect less severely allele Mutation classification based on reduced activity:

Severe Moderate Mild

Severe SW SV NC

Moderate SV SV NC

Mild NC NC NC

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CAH: Clinical features of different typesS W S V Non-C

Age at Dx M: 0-6m M:1.5-4y M: 0-18 yF: 0-1 m F: 0-2 y F: 0-18 y

Genitalia: M: normal M: normal M: normalF: ambiguous F: ambig. F: clitoris

Aldosterone normal normalRenin = or normal17-OH P >600nmol/L 300-600 45-300TestosteroneSomatic growth -2 to –3 SD -1 to –2 SD nl to –1SDEnzymatic activity 0% 1% 20-50%

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Classical CAH due to 21OH deficiency: clinical features

Postnatal period

M & F: rapid somatic growth, bone age advancement early pubarche, early body odor, acne

true precocious puberty

M: increased penile size without testicular enlargment

F: hirsutism, ovarian dyfunction (amenorrhea, dysmenorrhea)

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Classical CAH: Salt wastingclinical features

May lead to adrenal crisis by the 2nd week of life Poor appetite, failure to thrive Vomiting Lethargy

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Adrenal hyprplasia due to 21 hydroxylase deficiency: Diagnosis

Diagnosis Synacten (ACTH) stimualtion test: especially

important to detect NC adrenal hyperplasia Aldosterone, renin, Na, K: for CAH (SV/ SW)

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Case report [2]

ACTH (Synacten) stimulation test

17-hydroxyprogesterone: > 75 nmol/L over the study

Cortisol levels: up to 46 nmol/L Skeletal age: 10 years & 3 months (with

sesamoid bone !) Plasma renin activity: 13.4

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Adrenal hyprplasia due to 21 hydroxylas deficiency: Treatment

Children: hydrocortisone 10-20 mg/m2/d BID-TID Adolescents & adults: prednisone 5-7.5 mg/d BID or

dexamethasone 0.25-0.5 mg QD Fludrocortisone (florinef) 0.1-0.2 md/day + Nacl

1-2gr/day (1gr = 17 meq Na)

TREATMENT: PREDNISONE 1.25 BID + FLORINEF 0.1 mg + CLINIC VISIT A MONTH LATER

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Adrenal hyprplasia due to 21 hydroxylase deficiency: treatment & follow-up

Aims of treatment Keeping 17OH-P at the upper normal limits

(sometimes add MC for better suppression) Avoid liquid hydrocortisone – better crush tablets Avoid GC side effect: compromised growth, rapid

weight gain, pigmented striae, osteopenia Avoid MC side effects: hypertension, edema,

tachycardia.

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Adrenal hyprplasia due to 21 hydroxylase deficiency: treatment & follow-up

Monitoring treatment Check periodically 17OH-P, androstenedione (testosterone

in girls & prepubertal boys) PRA (for children treated with flurinef)

Doses during stress Wear warning bracelet Triple GC dose on moderate to severe stress When p.o. is not possible: IM/IV Solu-Cortef At major surgery: IV hydrocortisone 100 mg/m2/day QID

for 24 hr, than tapering over several days

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Case report [3]

10 days before clinic visit, he stopped prednisone treatment

7 days before clinic visit, he developed high fever

1 day before clinic visit, he was brought to ER pulseless & with respiratory arrest. His BG was 4 mg .%

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Adrenal insufficiency

Primary adrenal insufficiency (Addison disease)

Low cortisol, low aldosterone, high ACTH

Secondary adrenal insufficiency

Low cortisol, normal aldosterone, low ACTH

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Adrenal insufficiencyGlucocorticoids: Modulate ACTH secretion ACTH elevation Inotropy of heart muscle tachycardia, low stroke volume Vascular response to beta agonists low vascular resistance Antagonize insulin action hypoglycemia

Mineralocorticoids: Distal tubule sodium retention hyponatremia Distal tubule potassium & hydrogen excretion hypokalemia

& matabolic acidosis

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Primary adrenal insufficiency Autoimmune adrenal insufficiency 65% Tuberculosis 20% Other causes 15%• Fungi (histoplasmosis, blastomycosis, coccidio, crypto)• Adrenal hemorrhage (anti coagulants, DIC, trauma)• Metastases (breast, lung, stomach, colon, melanoma, lymphoma• Sarcoidosis• Amyloidosis• Adrenoleukodystrophy• AIDS• Congenital adrenal hyperplasia• Congenital unresponsiveness to ACTH• Medications (fluconazole, ketoconazole, phenytoin, rifampin)

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Secondary adrenal insufficiency Hypothalamic – pituitary – adrenal suppression Glucocorticoids Cushing syndrome

Lesions of the hypothalamus or pituitary gland Neoplasm (pituitary tumor, metastases) Craniopharyngioma Infection (tuberculosis, actinomycosis, nocardia) Head trauma

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Glucocorticoid induced 2nd adrenal insufficiency

Depends on dose & duration Should be anticipated in any patient who has been

receiving > 30 mg of hydrocortisone per day for > 3 wPrednisolone (solomedrol) x 4Prednisone (meticorten) x 5Dexamethasone x 40

Adrenal suppression can last up to 1 year !

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Symptoms of adrenal insufficiency Weakness & fatigue 100% Anorexia 100% Nausea, vomiting, diarrhea 50% Muscle, joint & abdominal pain 10% Postural dizziness 10% Craving for salt Headache Memory impairment depression

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Signs of adrenal insufficiency

Weight loss 100% Orthostatic hypotension 90% Tachycardia Fever Hyperpigmentation 90% Vitiligo 5%

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Laboratory finding in adrenal insufficiency Hyponatremia Hyperkalemia Metabolic acidosis (mild) Hypoglycemia Normochromic-normocytic anemia Lymphocytosis Eosinophilia Elevated TSH levels

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Adrenal insufficiency - treatment

In glucocorticoid-induced adrenal suppression:

Maintenance dose x 3 to x 6: depends on severity of disease In shock: 5% dextrose in normal saline Hydrocortisone 50 – 100 mg qid (Florinef 0.05 mg/ day)

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CAH due to 11ß-HYDROXYLASE DEF About 5-8% of CAH cases Prevalence: 1:100,000 live births In Jews from Morocco: 1;5000-1:7000 (R448H) Two 11ß-hydroxylase isoenzymes:

CYP11B1: 11ß hydroxylase

11 deoxycortisol to cortisol/ 11-DOC to corticosterone

CYP11B2: aldosterone synthase

11-DOC to corticsterone

18-hydroxylase / 18 oxidase activity

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CAH due to 11ß-HYDROXYLASE DEF

Regulation of the 2 isoenzymes: CYP11B1: ACTH CYP11B2: Renin – Aldosterone System + K

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11ß hydroxylase defucuency: Lab & Clinic

Mild to moderate hypertension (66%) Hyperandrogenism No correlation between hypertension &

hyperandrogenism

High ACTH stimulated 11-DOC & 11-deoxycortisol (S)

Suppressed PRA + aldosterone Hypokalemia/ muscle weakness (minority)

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11ß hydroxylase defucuency: Treatment

Glucocorticoids For long-standing hypertension:

K-sparing diuretics: spironolactone

Calcium-channel blockers: nifedipine

(NO: Thiazides, ACE inhibitors)


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