Kimia klinik referat 1

Adrenal Disorders in Childhood & Adolescence

A N Gorsuch MA DM FRCPConsultant Endocrinologist

KSS Deanery PLEAT Day, Conquest Hospital8 July 2011

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

Congenital Adrenal Hyperplasia

A N GorsuchAugust 1999, updated July 2011

Case 1 – neonatal period 1968

First (only) child Parents young, healthy, unrelated, of Welsh descentPregnancy uneventfulBW 3.320 kg at 42/40, length 50cmAmbiguous genitalia (library photo)

• enlarged clitoris• partial fusion of labia

Comments, questions, suggestions?

(to be continued)

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

Cholesterol

HO

1

2

3 4

56

11

19

21

17

20 18

7

8 9

10

12

13

14 15

16

mitochondrial uptake

StAR

Steroidogenic acute regulatory protein

Side-chain cleavage

HO 3 4

56

11

21

17

20

P450scc (CYP11A)- Mitochondria

- ACTH stimulates

Cholesterol

Side-chain cleavage

HO 3 4

56

11

21

17

20 HOOPregnenolone

17-α-hydroxylation

HO 3 4

56

11

21

17

20

OPregnenolone

P45017α

(17α-hydroxylase, CYP17)

- smooth endoplasmic reticulum

17-α-hydroxylation

HO 3 4

56

11

21

17

20

O17 α-hydroxy-pregnenoloneOH

Formation of ∆5, 3-oxo group

HO 3 4

56

11

21

17

20

O17 α-hydroxy-pregnenolone

∆5,3β-hydroxysteroid dehydrogenase- Smooth endoplasmic reticulum

OH

Formation of ∆5, 3-oxo group

O3

4 5

6

11

21

17

20

O17 α-hydroxy-progesteroneOH

21-hydroxylation

O3

4 5

6

11

21

17

20

O17 α-hydroxy-progesteroneOH

P45021

(21-hydroxylase, CYP21)

-smooth endoplasmic reticulum

21-hydroxylation

O3

4 5

6

11

21

17

20

O11-deoxycortisolOH

OH

11-β-hydroxylation

O3

4 5

6

11

21

17

20

O11-deoxycortisolOH

OH

P45011β/18 (11β-hydroxylase, CYP11B1)

- mitochondrial membrane

11-β-hydroxylation

O3

4 5

6

11

21

17

20

OCortisolOH

OH

HO

Formation of 17-oxo group

HO 3 4

56

11

21

17

20

O17 α-hydroxy-pregnenoloneOH

P45017α

(17α-hydroxylase, CYP17)

Formation of 17-oxo group

HO 3 4

56

11 17

DehydroepiandrosteroneDHEA

O

Pathways of adrenal steroidogenesis

Glucocorticoid

Cholesterol

Cholesterol(mitochondrial)

StAR

Pregnenolone 17OH-Pregnenolone

17OH-Progesterone

Cortisol

P-45017α

3βHSD

P-45021

Progesterone

11-deoxycorticosterone

Corticosterone

Aldosterone

Mineralocorticoid

P-45011

P-450aldo

Dehydroepiandrosterone

Androstenedione

(Testosterone)

Oestradiol DHT

Androgen

P-45017α

17βHSD

P-450aro 5αR

ACTH_

+

11-deoxycortisol

21-hydroxylase deficiency

Glucocorticoid

Cholesterol


StAR


17OH-Progesterone

Cortisol

P-45017α

3βHSD

P-45021

Progesterone


Corticosterone

Aldosterone

Mineralocorticoid

P-45011

P-450aldo


Androstenedione

(Testosterone)

Oestradiol DHT

Androgen

P-45017α

17βHSD

P-450aro 5αR

ACTH_

+

one of the commonest known autosomal recessive disorders

11-deoxycortisol

Classical 21-hydroxylase deficiencyPathophysiology

Glucocorticoid



17OH-Progesterone

Cortisol

Progesterone


Aldosterone

Mineralocorticoid

P-45021


Androstenedione

(Testosterone)

Oestradiol DHT

Androgen

ACTH_

++

11-deoxycortisol

Classical 21-hydroxylase deficiencyAnatomy

Cerebriform hyperplasia in an 18-day-old infant with salt-wasting congenital adrenogenital syndrome

Classical CAH 21-hydroxylase deficiencyIncidence & effects

Incidence ~ 1 in 14 000 live birthshigher in some populations • Ashkenazy Jewish• ‘Celtic’

75%: salt-wasting adrenocortical insuff at ~7-10 daysOther 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

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 karyotypeGenotyping identifies ~95% of mutationsUSS pelvisUrinary steroid profile important in past, still useful in some cases

Ambiguous genitalia: diagnosis – 2

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

Gonadspalbable?

Uteruson USS?

Uteruson USS?

17-OHPhigh?

Karyotype XX Female CAH

Female pseudo-

hermaphrodite

True hermaphrodite

Mixed gonadal

dysgenesis

XY male pseudo-

hermaphrodite

Y

Y

Y

N

N

NN

XX

Y

X/XYX/XXY

XYXX/XY

Neonatal diagnosis of CAH

Ambiguous genitalia – see previous slidesAdrenal crisis (mainly in male babies at 7-10 days)

– biochemistry / genotyping as aboveNeonatal 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

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 genitaliaGenetic counselling & psychological support

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 resuscitationRx glucocorticoid and mineralocorticoid

Case 1: InfancySteroid 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

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

Case 1: Aged 20

• androgens not fully suppressed even on hydrocortisone totalling 40mg/day

• transferred to dexametasone 500mcg bdandrogens 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

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 …

Case 1: PregnancyAged 21 – 1st pregnancy 1989-90

– tired: dexametasone* increased to 250/500mcgthen 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

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)

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.

21-hydroxylase deficiency: non-classical

Glucocorticoid



17OH-Progesterone

Cortisol

Progesterone


Aldosterone

Mineralocorticoid

P-45021


Androstenedione

(Testosterone)

Oestradiol DHT

Androgen

ACTH_

++


Incidence ~ 1 in 500 – higher in some populations

• Askenazy Jews• ‘celtic’

Not salt-wasting or glucocorticoid-deficientNeonatal genitalia normal or mild clitoromegalyOften presents in adolescent/adult female with hirsutism etcPrecocious virilisation in some males


• 16-year-old girl• hirsutism• labial thickening• limited breast

development


• Surgical correction of clitoromegaly in adolescent girl


• 20-year-old woman• shaves daily• mildly cushingoid due

to glucocorticoid over-replacement

11β-hydroxylase deficiency

Glucocorticoid



17OH-Progesterone

Cortisol

Progesterone


Aldosterone

Mineralocorticoid

P45011β


Androstenedione

(Testosterone)

Oestradiol DHT

Androgen

ACTH_

++

11-deoxycortisol

11β-hydroxylase deficiency

Commonest CAH after 21-hydroxylase deficiencybut still <1 in 100 000 live births

Virilising but not salt-wasting at presentationHypertensionMay become salt-wasting with glucocorticoid treatment

Rare forms of CAH3β-hydroxysteroid dehydrogenase deficiency17α-hydroxylase deficiency (hypertensive)20,22 desmolase deficiencyStAR mutations - ‘lipoid CAH’

Incidence < 1 in 100 000Genitalia in neonate (no sex hormones)

– in female: female– in male: ambiguous, or female without uterus etc

Adrenocortical insufficiencySalt-wasting, except in 17α-hydroxylase deficiency

Last slide on CAHAny questions?

References• White PC. Congenital Adrenal Hyperplasias. Best Prac Res Clin Endocrinol Metab 2001; 15(1): 17-41• UpToDate

Addison’s disease

Tutorial

June 2000, updated July 2011

A N Gorsuch

Addison’s diseaseScope of this session

• Definition & History• Pathology• Clinical features• Investigations• Long-term replacement therapy• Management of addisonian crisis

Definition & History

Chronic primary adrenocortical insufficiencyDescribed 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.

Epidemiology

Nottingham, 1987-93 1Prevalence 110 10-6

Incidence 5-6 10-6 y-1

M:F ratio 1:3.5Age at onset 5-79 y; 63% 20-50 y

1Kong M-F & Jeffcoate W, Eighty-six cases of Addison’s disease. Clin Endocrinol (1994); 41: 757-761

Aetiology in early 19th century England

Mainly tuberculosis (usually bovine) . . .

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 0%

1 Kong M-F & Jeffcoate W. Eighty-six cases of Addison's disease.Clin Endocrinol 1994; 41:757-761

Polyendocrine AI disease

Primary hypothyroidism 25%Type 1 diabetes 10%Graves’ 11%Premature ovarian failure 13% of womenHypoparathyroidism 4%Pernicious anaemia 1%

Kong M-F & Jeffcoate W. Eighty-six cases of Addison's disease.Clin Endocrinol 1994; 41:757-761

Presentation & clinical featuresUsually 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.

Addisonian pigmentation III

Woman aged 40Weight lossDehydratedHypotensive

Addisonian pigmentation IV

buccal pigmentation

Addisonian pigmentation V

gingival pigmentation

Addisonian pigmentation VI

extensor creases

Addisonian pigmentation VII

recent scar

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

Investigations IIBiochemistry

• 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

Investigations III

Radiology• Chest • Abdomen

Long-term replacement therapy - IGlucocorticoid

• 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)2Nieman LK. Treatment of adrenal insufficiency in adults. UpToDate. Accessed online 9/6/11

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

Management of Addisonian crisis in adultBlood for cortisol, U&E, Cr, glucose, Ca, FBC

but don’t wait for resultGlucocorticoid parenterally

Known Addisons: Hydrocortisone 100mg IV (or IM) stat, then 100mg 6-hrly 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 casesMay need plasma expander & large amounts glucoseMonitor ECG, TPR, BP, glucose, U&E, CrTreat any underlying infection etc.When stable

Short synacthen test in new caseChange to oral hydrocortisone 20mg tds + (resume) fludrocortisone

Later back to maintenance doses

Health & Medicine

Kimia klinik referat 1