ADRENAL GLAND: Congenital adrenal hyperplasia & adrenal insufficiency

ADRENAL GLAND: Congenital adrenal hyperplasia & adrenal insufficiencyDr. Amnon ZungPediatric Endocrinology UnitKaplan Medical Center

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/LAndrostenedione: 20 nmol/LTestosterone: 8 nmol/L

Congenital Adrenal hyperplasia the beginning21-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: 1:27Hispanics: 1:40Slavs: 1:50Italians: 1:30011- hydroxylase deficiencyFrequency: 1:100,000 (highest in Moroccan Jews)

CAH Molecular Genetics21-hydroxylase encoding gene:Short arm of chromosome 6Two homologous genes: Cyp21B & Cyp21A (pseudogene)98% homology in exons (n=10); 96% in intronsAbout 50 mutations known todayCorrelation & none-correlation of genotype\phenotype

CAH: genotype-phenotype correlation due to 21-hydroxylase deficiencyPatients are often compound heterozygotesPhenotype is likely to reflect less severely alleleMutation classification based on reduced activity:SevereModerateMildSevere SW SV NCModerate SV SV NCMild NC NC NC

CAH: Clinical features of different typesS W S VNon-CAge at DxM: 0-6mM:1.5-4yM: 0-18 yF: 0-1 mF: 0-2 yF: 0-18 yGenitalia:M: normalM: normalM: normalF: ambiguousF: ambig.F: clitorisAldosterone normalnormalRenin= or normal17-OH P>600nmol/L300-60045-300TestosteroneSomatic growth-2 to 3 SD-1 to 2 SD nl to 1SDEnzymatic activity0%1%20-50%

Classical CAH due to 21OH deficiency: clinical featuresPostnatal periodM & F: rapid somatic growth, bone age advancement early pubarche, early body odor, acne true precocious pubertyM: increased penile size without testicular enlargmentF: hirsutism, ovarian dyfunction (amenorrhea, dysmenorrhea)

Classical CAH: Salt wastingclinical featuresMay lead to adrenal crisis by the 2nd week of lifePoor appetite, failure to thriveVomitingLethargy

Adrenal hyprplasia due to 21 hydroxylase deficiency: DiagnosisDiagnosisSynacten (ACTH) stimualtion test: especially important to detect NC adrenal hyperplasiaAldosterone, renin, Na, K: for CAH (SV/ SW)

Case report [2]ACTH (Synacten) stimulation test17-hydroxyprogesterone: > 75 nmol/L over the studyCortisol levels: up to 46 nmol/LSkeletal age: 10 years & 3 months (with sesamoid bone !)Plasma renin activity: 13.4

Adrenal hyprplasia due to 21 hydroxylas deficiency: TreatmentChildren: hydrocortisone 10-20 mg/m2/d BID-TIDAdolescents & adults: prednisone 5-7.5 mg/d BID or dexamethasone 0.25-0.5 mg QDFludrocortisone (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

Adrenal hyprplasia due to 21 hydroxylase deficiency: treatment & follow-upAims of treatmentKeeping 17OH-P at the upper normal limits (sometimes add MC for better suppression)Avoid liquid hydrocortisone better crush tabletsAvoid GC side effect: compromised growth, rapid weight gain, pigmented striae, osteopeniaAvoid MC side effects: hypertension, edema, tachycardia.

Adrenal hyprplasia due to 21 hydroxylase deficiency: treatment & follow-upMonitoring treatmentCheck periodically 17OH-P, androstenedione (testosterone in girls & prepubertal boys)PRA (for children treated with flurinef)Doses during stressWear warning braceletTriple GC dose on moderate to severe stressWhen p.o. is not possible: IM/IV Solu-CortefAt major surgery: IV hydrocortisone 100 mg/m2/day QID for 24 hr, than tapering over several days

Case report [3]

10 days before clinic visit, he stopped prednisone treatment7 days before clinic visit, he developed high fever1 day before clinic visit, he was brought to ER pulseless & with respiratory arrest. His BG was 4 mg%.

Adrenal insufficiencyPrimary adrenal insufficiency (Addison disease)Low cortisol, low aldosterone, high ACTH

Secondary adrenal insufficiency Low cortisol, normal aldosterone, low ACTH

Adrenal insufficiencyGlucocorticoids:Modulate ACTH secretion ACTH elevationInotropy of heart muscle tachycardia, low stroke volumeVascular response to beta agonists low vascular resistanceAntagonize insulin action hypoglycemia

Mineralocorticoids:Distal tubule sodium retention hyponatremiaDistal tubule potassium & hydrogen excretion hypokalemia & matabolic acidosis

Primary adrenal insufficiencyAutoimmune adrenal insufficiency65%Tuberculosis20%Other causes15%Fungi (histoplasmosis, blastomycosis, coccidio, crypto)Adrenal hemorrhage (anti coagulants, DIC, trauma)Metastases (breast, lung, stomach, colon, melanoma, lymphomaSarcoidosisAmyloidosisAdrenoleukodystrophyAIDSCongenital adrenal hyperplasiaCongenital unresponsiveness to ACTHMedications (fluconazole, ketoconazole, phenytoin, rifampin)

Secondary adrenal insufficiencyHypothalamic pituitary adrenal suppressionGlucocorticoidsCushing syndrome

Lesions of the hypothalamus or pituitary glandNeoplasm (pituitary tumor, metastases)CraniopharyngiomaInfection (tuberculosis, actinomycosis, nocardia)Head trauma

Glucocorticoid induced 2nd adrenal insufficiencyDepends on dose & durationShould 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 40Adrenal suppression can last up to 1 year !

Symptoms of adrenal insufficiencyWeakness & fatigue 100%Anorexia100%Nausea, vomiting, diarrhea50%Muscle, joint & abdominal pain10%Postural dizziness10%Craving for saltHeadacheMemory impairmentdepression

Signs of adrenal insufficiencyWeight loss100%Orthostatic hypotension90%TachycardiaFeverHyperpigmentation90%Vitiligo5%

Laboratory finding in adrenal insufficiencyHyponatremiaHyperkalemiaMetabolic acidosis (mild)HypoglycemiaNormochromic-normocytic anemiaLymphocytosisEosinophiliaElevated TSH levels

Adrenal insufficiency - treatmentIn glucocorticoid-induced adrenal suppression:Maintenance dose x 3 to x 6: depends on severity of diseaseIn shock: 5% dextrose in normal salineHydrocortisone 50 100 mg qid(Florinef 0.05 mg/ day)

CAH due to 11-HYDROXYLASE DEF About 5-8% of CAH casesPrevalence: 1:100,000 live birthsIn Jews from Morocco: 1;5000-1:7000 (R448H)Two 11-hydroxylase isoenzymes:CYP11B1: 11 hydroxylase11 deoxycortisol to cortisol/ 11-DOC to corticosteroneCYP11B2: aldosterone synthase11-DOC to corticsterone 18-hydroxylase / 18 oxidase activity

CAH due to 11-HYDROXYLASE DEFRegulation of the 2 isoenzymes:CYP11B1: ACTHCYP11B2: Renin Aldosterone System + K

11 hydroxylase defucuency: Lab & ClinicMild to moderate hypertension (66%)HyperandrogenismNo correlation between hypertension & hyperandrogenism

High ACTH stimulated 11-DOC & 11-deoxycortisol (S)Suppressed PRA + aldosteroneHypokalemia/ muscle weakness (minority)

11 hydroxylase defucuency: TreatmentGlucocorticoidsFor long-standing hypertension:K-sparing diuretics: spironolactoneCalcium-channel blockers: nifedipine (NO: Thiazides, ACE inhibitors)