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Kimia klinik referat 1

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Adrenal Disorders in Childhood & Adolescence

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Kimia klinik referat 1

  1. 1. Adrenal Disorders in Childhood & Adolescence A N Gorsuch MA DM FRCP Consultant Endocrinologist KSS Deanery PLEAT Day, Conquest Hospital 8 July 2011
  2. 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. 3. Congenital Adrenal Hyperplasia A N Gorsuch August 1999, updated July 2011
  4. 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. 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. 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. 7. Side-chain cleavage 21 Cholesterol 20 11 HO 3 P450scc (CYP11A) 5 4 17 6 - Mitochondria - ACTH stimulates
  8. 8. Side-chain cleavage 21 Pregnenolone O 20 11 HO 3 5 4 6 17 HO
  9. 9. 17-α-hydroxylation 21 Pregnenolone O 20 11 17 P45017α HO 3 5 4 6 (17α-hydroxylase, CYP17) - smooth endoplasmic reticulum
  10. 10. 17-α-hydroxylation 17 α-hydroxy-pregnenolone 11 HO 3 5 4 6 21 O 20 17 OH
  11. 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. 12. 5 Formation of ∆ , 3-oxo group 17 α-hydroxy-progesterone 11 3 O 5 4 6 21 O 20 17 OH
  13. 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. 14. 21-hydroxylation OH 21 11-deoxycortisol O 20 11 3 O 5 4 6 17 OH
  15. 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. 16. 11-β-hydroxylation OH 21 Cortisol O 20 HO 11 3 O 5 4 6 17 OH
  17. 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. 18. Formation of 17-oxo group Dehydroepiandrosterone DHEA 11 HO 3 5 4 6 O 17
  19. 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. 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. 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. 22. Classical 21-hydroxylase deficiency Anatomy Cerebriform hyperplasia in an 18-day-old infant with salt-wasting congenital adrenogenital syndrome
  23. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 38. 21-hydroxylase deficiency: non-classical • • • • 16-year-old girl hirsutism labial thickening limited breast development
  39. 39. 21-hydroxylase deficiency: non-classical • Surgical correction of clitoromegaly in adolescent girl
  40. 40. 21-hydroxylase deficiency: non-classical • 20-year-old woman • shaves daily • mildly cushingoid due to glucocorticoid overreplacement
  41. 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. 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. 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. 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. 45. Addison’s disease Tutorial June 2000, updated July 2011 A N Gorsuch
  46. 46. Addison’s disease Scope of this session • • • • • • Definition & History Pathology Clinical features Investigations Long-term replacement therapy Management of addisonian crisis
  47. 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. 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. 49. Aetiology in early 19th century England Mainly tuberculosis (usually bovine) . ..
  50. 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. 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. 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. 53. Addisonian pigmentation III Woman aged 40 Weight loss Dehydrated Hypotensive
  54. 54. Addisonian pigmentation IV buccal pigmentation
  55. 55. Addisonian pigmentation V gingival pigmentation
  56. 56. Addisonian pigmentation VI extensor creases
  57. 57. Addisonian pigmentation VII recent scar
  58. 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. 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. 60. Investigations III Radiology • Chest • Abdomen
  61. 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. 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. 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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