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ADRENAL GLAND: Congenital adrenal hyperplasia & adrenal insufficiency Dr. Amnon Zung Pediatric Endocrinology Unit Kaplan Medical Center

ADRENAL GLAND: Congenital adrenal hyperplasia & adrenal insufficiency

Jan 01, 2016




ADRENAL GLAND: Congenital adrenal hyperplasia & adrenal insufficiency. Dr. Amnon Zung Pediatric Endocrinology Unit Kaplan Medical Center. Congenital Adrenal hyperplasia – the beginning. 21-hydroxylase deficiency Classic: female pseudohermaphroditism (DSD): - PowerPoint PPT Presentation
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  • 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)


  • 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)