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Kimia klinik referat 1

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Adrenal Disorders in Childhood & Adolescence

Adrenal Disorders in Childhood & Adolescence

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  • 1. Adrenal Disorders in Childhood & Adolescence A N Gorsuch MA DM FRCP Consultant Endocrinologist KSS Deanery PLEAT Day, Conquest Hospital 8 July 2011
  • 2. Adrenal Disorders Scope of this session Congenital adrenal hyperplasia (CAH) illustrated by a case followed through 43 years – – – – – steroid biochemistry pathology clinical features investigations management Addison’s disease
  • 3. Congenital Adrenal Hyperplasia A N Gorsuch August 1999, updated July 2011
  • 4. Case 1 – neonatal period 1968 First (only) child Parents young, healthy, unrelated, of Welsh descent Pregnancy uneventful BW 3.320 kg at 42/40, length 50cm (library photo) Ambiguous genitalia • enlarged clitoris • partial fusion of labia Comments, questions, suggestions? (to be continued)
  • 5. Corticosteroid biosynthesis • Supply of cholesterol • Transport to inner mitochondrial membrane – StAR (steroidogenic acute regulatory) protein • Hydroxylases – – – – Cytochrome P450 family NADPH-linked Mitochondrial & microsomal 5 types involved (4 in adrenal cortex) • Dehydrogenases – NADP+-linked – Microsomal
  • 6. Cholesterol 21 18 20 12 17 11 13 16 1 19 10 HO 14 9 2 3 8 7 5 4 15 6 StAR Steroidogenic acute regulatory protein mitochondrial uptake
  • 7. Side-chain cleavage 21 Cholesterol 20 11 HO 3 P450scc (CYP11A) 5 4 17 6 - Mitochondria - ACTH stimulates
  • 8. Side-chain cleavage 21 Pregnenolone O 20 11 HO 3 5 4 6 17 HO
  • 9. 17-α-hydroxylation 21 Pregnenolone O 20 11 17 P45017α HO 3 5 4 6 (17α-hydroxylase, CYP17) - smooth endoplasmic reticulum
  • 10. 17-α-hydroxylation 17 α-hydroxy-pregnenolone 11 HO 3 5 4 6 21 O 20 17 OH
  • 11. 5 Formation of ∆ , 3-oxo group 17 α-hydroxy-pregnenolone 11 HO 3 21 O 20 17 OH 5 4 6 ∆5,3β-hydroxysteroid dehydrogenase - Smooth endoplasmic reticulum
  • 12. 5 Formation of ∆ , 3-oxo group 17 α-hydroxy-progesterone 11 3 O 5 4 6 21 O 20 17 OH
  • 13. 21-hydroxylation P45021 17 α-hydroxy-progesterone 11 3 O 5 4 6 21 O (21-hydroxylase, CYP21) 20 17 OH -smooth endoplasmic reticulum
  • 14. 21-hydroxylation OH 21 11-deoxycortisol O 20 11 3 O 5 4 6 17 OH
  • 15. 11-β-hydroxylation OH 21 11-deoxycortisol O 20 11 3 O 5 4 6 P45011β/18 (11β-hydroxylase, CYP11B1) - mitochondrial membrane 17 OH
  • 16. 11-β-hydroxylation OH 21 Cortisol O 20 HO 11 3 O 5 4 6 17 OH
  • 17. Formation of 17-oxo group 17 α-hydroxy-pregnenolone 11 21 O 20 17 OH P45017α HO 3 5 4 6 (17α-hydroxylase, CYP17)
  • 18. Formation of 17-oxo group Dehydroepiandrosterone DHEA 11 HO 3 5 4 6 O 17
  • 19. Pathways of adrenal steroidogenesis Cholesterol StAR Cholesterol (mitochondrial) + P-45017α Pregnenolone P-45017α 17OHPregnenolone Dehydroepiandrosterone 17OH-Progesterone Androstenedione 3βHSD Progesterone 17βHSD P-45021 (Testosterone) 11-deoxycorticosterone 11-deoxycortisol P-450aro ACTH _ Corticosterone P-450aldo Aldosterone Mineralocorticoid 5αR Oestradiol P-45011 DHT Cortisol Glucocorticoid Androgen
  • 20. 21-hydroxylase deficiency one of the commonest known autosomal recessive disorders Cholesterol StAR Cholesterol (mitochondrial) + P-45017α Pregnenolone P-45017α 17OHPregnenolone Dehydroepiandrosterone 17OH-Progesterone Androstenedione 3βHSD Progesterone 17βHSD P-45021 (Testosterone) 11-deoxycorticosterone 11-deoxycortisol P-450aro ACTH _ Corticosterone P-450aldo Aldosterone Mineralocorticoid 5αR Oestradiol P-45011 DHT Cortisol Glucocorticoid Androgen
  • 21. Classical 21-hydroxylase deficiency Pathophysiology Cholesterol (mitochondrial) ++ Pregnenolone 17OHPregnenolone Dehydroepiandrosterone Progesterone 17OH-Progesterone Androstenedione P-45021 11-deoxycorticosterone 11-deoxycortisol (Testosterone) Oestradiol ACTH DHT _ Aldosterone Mineralocorticoid Cortisol Glucocorticoid Androgen
  • 22. Classical 21-hydroxylase deficiency Anatomy Cerebriform hyperplasia in an 18-day-old infant with salt-wasting congenital adrenogenital syndrome
  • 23. Classical CAH 21-hydroxylase deficiency Incidence & effects Incidence ~ 1 in 14 000 live births higher in some populations • Ashkenazy Jewish • ‘Celtic’ 75%: salt-wasting adrenocortical insuff at ~7-10 days Other effects Female – ambiguous external genitalia – internal (müllerian) organs usually normal – hirsutism, delayed menarche, subfertility, polycystic ovaries Male – genitalia usually normal – precocious ‘pubarche’ (adrenarche) – testicular adrenal rests, usually benign
  • 24. Ambiguous genitalia: diagnosis – 1 Examination – identify urethral meatus – gonads Blood biochemistry (NOT in first 24h; special reference ranges in prematurity) – U&E – at least, random 17-hydroxyprogesterone (17-OHP) . Result >100 nmol/l diagnostic. False –ve possible if mother on glucocorticoid treatment. – ideally, also cortisol, 11-deoxycortisol, 17-OH-pregnenolone, androstenedione, maybe deoxycorticosterone & dehydroepiandrosterone – borderline results: repeat pre- and 1-hr-post synacthen 250mcg – (plasma renin activity / aldosterone not helpful – overlap with normal) Rapid karyotype Genotyping identifies ~95% of mutations USS pelvis Urinary steroid profile important in past, still useful in some cases
  • 25. Ambiguous genitalia: diagnosis – 2 Gonads palbable? Uterus on USS? N Y Uterus on USS? N XY male pseudohermaphrodite 17-OHP high? Y N N Karyotype Y XX X/XY X/XXY Mixed gonadal dysgenesis Y XX Female CAH XY XX/XY True hermaphrodite Female pseudohermaphrodite Assign the baby’s sex only when diagnostic information is available (multidisciplinary team, with parents) White PC. Congenital Adrenal Hyperplasias. Best Prac Res Clin Endocrinol Metab 2001; 15(1): 17-41
  • 26. Neonatal diagnosis of CAH Ambiguous genitalia – see previous slides Adrenal crisis (mainly in male babies at 7-10 days) – biochemistry / genotyping as above Neonatal screening – ‘Guthrie’ cards for 17-OHP Not currently offered in UK under review – report expected March 20121 Standard in USA since 2008, also in NZ etc +ve in ~0.5% of all tests, specificity only 2% – normal result after mult antenatal glucocorticoid Rx: repeat after 2 wks – borderline result: repeat, or genetic testing – high result: U&E and 17-OHP etc on fresh blood 1 http://www.screening.nhs.uk/policydb.php?policy_id=65 accessed 4/7/11
  • 27. Management of CAH Glucocorticoid replacement / androgen suppression – – – – – children: hydrocortisone 10-20mg/m2 per day, divided doses adults: usually dexametasone larger dose at bed-time to suppress ACTH beware over-replacement monitor 17-α-progesterone and androstenedione (?testosterone, cortisol, ACTH etc) growth, bone age, BP, U&E, skin; osteoporosis scans in adults Correction of salt-wasting – 9-a-fludrocortisone 100-400mcg/day (long-acting) – plus sodium chloride supplements until able to select saltier foods – monitor BP, U&E, oedema (?renin) Corrective surgery to genitalia Genetic counselling & psychological support
  • 28. Case 1 – neonatal period 1968 (continued) Initial (?timing) urinary steroid profile ‘normal’ Aged 9 days: vomiting, hypotensive, Na+↓, K+↑ Repeat steroid profile abnormal: CAH (21-hydroxylase deficiency) IV resuscitation Rx glucocorticoid and mineralocorticoid
  • 29. Case 1: Infancy Steroid replacement – – – – various regimens tried poor growth, hypertensive crises when tried without mineralocorticoid finally settled on hydrocortisone 5mg tds fludrocortisone 50mcg bd Corrective surgery aged 2yr 9 mth – partial clitoridectomy (preserving glans) & vaginoplasty library photos © Endopics
  • 30. Case 1: Childhood to mid-teens • • • • • • • on hydrocortisone 10/5/10 mg + fludro 100/50 mcg satisfactory growth up 10th centile from age 9 menarche at 13 ht 1.545m wt 52.0kg BMI 21.8 at age 15 lively, ‘a tomboy’ gynae review: ‘tidying up’ suggested when fully mature moved to Hastings from Surrey 1983
  • 31. Case 1: Aged 20 • androgens not fully suppressed even on hydrocortisone totalling 40mg/day • transferred to dexametasone 500mcg bd androgens then well controlled • fludrocortisone 200 mcg daily • gynae opinion – menstruating normally so internal organs functioning – full examination not possible – consider EUA & laparoscopy in due course
  • 32. Case 1: Aged 21 (1989) • • • • 17-hydroxyprogesterone & androstenedione normal BP 130/90, K+ 3.9, dermal atrophy, weight up dexametasone 500mcg reduced from bd to od fludrocortisone reduced from 200 to 150mcg daily – BP then 110/70, andro & 17-OHP well controlled, weight down • thinking of getting married at some time in the future – considering OCP & referral back to gynaecologist – soon afterwards …
  • 33. Case 1: Pregnancy Aged 21 – 1st pregnancy 1989-90 – tired: dexametasone* increased to 250/500mcg then developed purple striae so reduced to 250mcg bd – – – – Na+ <140: fludrocortisone increased to 100mcg x12 /wk div androgens remained well suppressed ELCS at 39/40, glucocorticoid cover baby normal & well pre-discharge 17-OHP sample lost; 10-day 17-OHP normal. Age 26: 2nd pregnancy 1994-5 – similar, but dexametasone* 250/500mcg needed to control androgens, ?leading to excess weight-gain – baby normal – reduced weight subsequently on Dex 250mcg on * hydrocortisone or prednisolone now recommended in pregnancy
  • 34. CAH and Pregnancy • Pregnancy in a woman with CAH 1999: the placenta blocks androgens, prednisolone & hydrocortisone, but passes dexametasone – reassure that CAH unlikely to affect baby unless parents related or Ashkenazy Jews etc – preferably use hydrocortisone tds or prednisolone – continue fludrocortisone – monitor as in non-pregnant state; doses may need adjusting • Prenatal diagnosis & treatment where fetus at risk – amniocyte/chorionic villus genetic analysis – amniotic fluid 17-OHP has been used – dexamethasone to mother (crosses placenta)
  • 35. Case 1: Current status Age 42 (2010) – – – – – – Well on dexametasone 250mcg on fludrocortisone recently increased to 200mcg as renin up 17OHP, Andro, DHEA, ACTH, Testo, renin all normal clinic BP up, awaiting monitoring Mirena coil.
  • 36. 21-hydroxylase deficiency: non-classical Cholesterol (mitochondrial) ++ Pregnenolone 17OHPregnenolone Dehydroepiandrosterone Progesterone 17OH-Progesterone Androstenedione P-45021 11-deoxycorticosterone (Testosterone) Oestradiol ACTH DHT _ Aldosterone Mineralocorticoid Cortisol Glucocorticoid Androgen
  • 37. 21-hydroxylase deficiency: non-classical Incidence ~ 1 in 500 – higher in some populations • Askenazy Jews • ‘celtic’ Not salt-wasting or glucocorticoid-deficient Neonatal genitalia normal or mild clitoromegaly Often presents in adolescent/adult female with hirsutism etc Precocious virilisation in some males
  • 38. 21-hydroxylase deficiency: non-classical • • • • 16-year-old girl hirsutism labial thickening limited breast development
  • 39. 21-hydroxylase deficiency: non-classical • Surgical correction of clitoromegaly in adolescent girl
  • 40. 21-hydroxylase deficiency: non-classical • 20-year-old woman • shaves daily • mildly cushingoid due to glucocorticoid overreplacement
  • 41. 11β-hydroxylase deficiency Cholesterol (mitochondrial) ++ Pregnenolone 17OHPregnenolone Dehydroepiandrosterone Progesterone 17OH-Progesterone Androstenedione 11-deoxycorticosterone 11-deoxycortisol ACTH _ Oestradiol P45011β Aldosterone Mineralocorticoid (Testosterone) DHT Cortisol Glucocorticoid Androgen
  • 42. 11β-hydroxylase deficiency Commonest CAH after 21-hydroxylase deficiency but still <1 in 100 000 live births Virilising but not salt-wasting at presentation Hypertension May become salt-wasting with glucocorticoid treatment
  • 43. Rare forms of CAH 3β-hydroxysteroid dehydrogenase deficiency 17α-hydroxylase deficiency (hypertensive) 20,22 desmolase deficiency StAR mutations - ‘lipoid CAH’ Incidence < 1 in 100 000 Genitalia in neonate (no sex hormones) – in female: female – in male: ambiguous, or female without uterus etc Adrenocortical insufficiency Salt-wasting, except in 17α-hydroxylase deficiency
  • 44. Last slide on CAH Any questions? References • White PC. Congenital Adrenal Hyperplasias. Best Prac Res Clin Endocrinol Metab 2001; 15(1): 17-41 • UpToDate
  • 45. Addison’s disease Tutorial June 2000, updated July 2011 A N Gorsuch
  • 46. Addison’s disease Scope of this session • • • • • • Definition & History Pathology Clinical features Investigations Long-term replacement therapy Management of addisonian crisis
  • 47. Definition & History Chronic primary adrenocortical insufficiency Described by Thomas Addison (1795-1860)1 – from Newcastle & Cumberland – MD (Edin) 1815 – on staff of Guy’s Hospital. 1Addison T, “On the Constitutional and Local Effects of Disease of the Suprarenal Capsules”, 1855.
  • 48. Epidemiology Nottingham, 1987-93 1 Prevalence Incidence M:F ratio Age at onset 1Kong 110 10-6 5-6 10-6 y-1 1:3.5 5-79 y; 63% 20-50 y M-F & Jeffcoate W, Eighty-six cases of Addison’s disease. Clin Endocrinol (1994); 41: 757-761
  • 49. Aetiology in early 19th century England Mainly tuberculosis (usually bovine) . ..
  • 50. Aetiology now Frequency England 1987-93 1 Organ-specific autoimmunity 93% Metastatic malignancy 2% Adrenoleukodystrophy 3% X-linked recessive, consider in boys under 15 Tuberculosis 1 0% Kong M-F & Jeffcoate W. Eighty-six cases of Addison's disease.Clin Endocrinol 1994; 41:757-761
  • 51. Polyendocrine AI disease Primary hypothyroidism Type 1 diabetes Graves’ Premature ovarian failure Hypoparathyroidism Pernicious anaemia 25% 10% 11% 13% of women 4% 1% Kong M-F & Jeffcoate W. Eighty-six cases of Addison's disease.Clin Endocrinol 1994; 41:757-761
  • 52. Presentation & clinical features Usually present: insidious … – – – – – Anorexia, nausea, weight-loss Fatigue, weakness, lethargy Postural dizziness & hypotension Pigmentation Recurrent hypoglycaemia / falling insulin requirement in DM May occur – – – – – – – – – – Nocturia Abdominal pain, dyspepsia, back pain Vitiligo Supine hypotension Diarrhoea Loss of body hair Erectile failure or amenorrhoea Mental disturbances Addisonian crisis: vomiting, dehydration, hypoglycaemia, shock. Death.
  • 53. Addisonian pigmentation III Woman aged 40 Weight loss Dehydrated Hypotensive
  • 54. Addisonian pigmentation IV buccal pigmentation
  • 55. Addisonian pigmentation V gingival pigmentation
  • 56. Addisonian pigmentation VI extensor creases
  • 57. Addisonian pigmentation VII recent scar
  • 58. Investigations I Serum cortisol (09:00) • Addison’s excluded if >500nmol/l • adrenocortical insufficiency if <200 at 09:00 • SACTH test needed if 200-500 Short tetracosactrin (Synacthen) test • high-dose (250mcg); – normal if baseline >250 and 30-min >600 nmol/l • low-dose (1 mcg) may be better for CENTRAL adrenocortical insufficiency of recent onset
  • 59. Investigations II Biochemistry • • • • • • • • Na+ low or normal, 120-140 mmol/l K+ high or high-normal, 4.5-8 Glucose may be low Urea may be raised Calcium may be raised Plasma renin activity elevated Plasma aldosterone low (esp upright) Hypothyroidism may coexist Haematology • Normocytic anaemia usual when hydrated • Pernicious anaemia may coexist
  • 60. Investigations III Radiology • Chest • Abdomen
  • 61. Long-term replacement therapy - I Glucocorticoid • • • • hydrocortisone (formerly cortisone acetate) first dose on waking, +1-2 further doses up to 18:00 hr) maintenance doses e.g. 10/5mg to 15/10/5mg adjust on clinical grounds; may do cortisol day curves Mineralocorticoid • 9a-fludrocortisone 50-300mcg daily • adjust using BP, U&E, ?PRA (plasma renin activity) Androgen? • DHEA may help some otherwise optimally-treated women with persisting lethargy, low libido or low mood1 • not prescribable, available OTC • ?try 25-50mg od for 3-6 months, stop if no clear benefit2 1Arlt et al, NEJM 1999; 341: 1013-1020) LK. Treatment of adrenal insufficiency in adults. UpToDate. Accessed online 9/6/11 2Nieman
  • 62. Long-term replacement therapy - II Education • • • • Double hydrocortisone during illness, then back to usual Medic-Alert or similar Vomiting is dangerous Vial of hydrocortisone injection & syringe in fridge Other points • Depriving of fludrocortisone to treat essential hypertension is unkind (postural hypotension) • Beware osteoporosis due to over-replacement • Consider DEXA scan
  • 63. Management of Addisonian crisis in adult Blood for cortisol, U&E, Cr, glucose, Ca, FBC but don’t wait for result Glucocorticoid parenterally Known Addisons: Hydrocortisone 100mg IV (or IM) stat, then 100mg 6hrly im or 4-hrly iv Suspected new case: Dexametasone 4mg IV (or IM) - does not affect cortisol assay IVI 0.9% saline, preferably with added glucose; ?1 litre in first 30-60min, total up to 6 litres CVP line in most cases May need plasma expander & large amounts glucose Monitor ECG, TPR, BP, glucose, U&E, Cr Treat any underlying infection etc. When stable Short synacthen test in new case Change to oral hydrocortisone 20mg tds + (resume) fludrocortisone Later back to maintenance doses

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