Transcript
ENDOCRINE DISORDERS OF
ADRENAL GLAND
Dr Subhasish Deb
Burdwan Medical College And Hospital
Department of General Medicine
ADRENAL GLAND
STEROID HORMONE
BIOSYNTHSIS 5 hormones produced from cholesterol
Progesterone
Aldosterone
Glucocorticoids
Estrogen
Androgens
Active form of Vit D3 also considered a steroid hormone now a days
CHOLESTEROL
MOLECULECholesterol = 27C
Pregnanolone = 21C
Aldosterone
Glucocorticoids
ProgesteroneAndrogens = 19C
Oestrogens = 18C
Cholesterol
Pregnanolone
STAR protein
= Steroidogenic acute
Regulator proteinEnzyme = DESMOLASE
•Desmolase is the rate limiting enzyme
•Regulated by ACTH
•ACTH acts on Z.F and Z.R and stimulates
desmolase here to produce glucocorticoids
KETOCONAZOLE inibits desmolase
Cholesterol
Pregnanolone
STAR protein
= Steroidogenic acute
Regulator proteinEnzyme = DESMOLASE
Progesterone
DHEA
Glucocorticoids
Aldosterone
17 Hydroxylase 17 aOH
17-20 lyase
21 Hydroxylase
11 B Hydroxylase
3 B Hydroxy steroid dehydrogenase
Aldosterone synthase
& 11 OH deff
DHEA
Androstenidione
Testosteronein testis
Oesterogenin graafian follicle
and placentae
DHEA and androstenidione are also called 17 keto steroids
Weak androgens
2 functs in females:
•LIBIDO
•Secondary sexual charc – axl and pubic hair
Hydroxylations of hormones
from adrenal cortex
ALDOSTERONE:
21, 11, 18
GLUCOCORTICOIDS:
17, 21, 11
ADRENAL ANDROGENS:
17, and various modifications
CONGENITAL ADRENAL
HYPERPLASIA
AR
Also called adrenogenital syndrome due
to genital changes
Due to mutations in gene for enzymes
required in steroidogenesis
m/c 21hydroxylase deff
17 aOH defficiency
Sex hormones1. XY – female like genitilia
no secd. sexual charc.
2. XX – no secd sexual charac
Glucocorticoids
- hypogycemia
- ACTH increased
Aldosterone
-Na and water retension, inc BP
-hypokalemia
-alkalosis
PICSlide 6
21 B OH deff & 11 OH deff
Common:
• Glucocorticoid
• Adrenal androgens1. XY – precocious puberty
2. XX – masculinisation
21 OH def 11 OH def
• Salt and water wasting (bp dec)
• HYPERkalemia
• Acidosis
•BP normal or low
•11 OH cortisone produced
Which has mineralocorticoid act
Slide 6
Penis at 12 Syndrome: 5 alpha reductase deff
Lack of dihydrotestosterone
Small penis till age 12
Increase in testosterone at puberty after 12
HYPERADRENALISM
Hypercortisolism
(cortisol – ACTH)
Hyperadosteronism
(aldosterone – Angiotensin II)
High epinephrine
(epinephrine – Autonomic nervous sys)
CUSHING’S SYNDROME
• Any state of cortisol excess
• Cushing’s disease - excess cortisol due
to pituitary adenoma
• m/c/c – Iatrogenic use
• Mostly affects women
• Only 10% pts have adrenal cause
(ACTH independent)
ETIOLOGY
ACTH dependant ACTH independant
1. Cushing’s Disease
(ACTH producing pitu aden)
>1cm = macro
2. Ectopic ACTH syndrome
• Small cell lung CA
• Carcinoid
(bronchial,
pancreatic)
• Medullary thyroid
CA
1. Adrenocortical adenoma
2. Adrenocortical carcinoma
3. Other rare causes
CLINICAL FEATURES
Body fat: Weight gain
central obesity
moon facies
buffalo hump
Skin: Purple abdominal striae
easy bruising
Plethoric appearance
Bone: Osteopenia
Osteoporosis (vertebral fracture)
Muscle: proximal myopathy
CVS: diastolic hypertension
hypokalemia
oedema
atherosclerosisCortisol can stimulate mineralocorticoid receptors but an
enzyme 11B HSD2 rapidly converts it to inactive cortisone
without mineralocorticoid activity.
In cushing’s, excess cortisol overcomes the ability of 11b hsd2
to breakdown cortisol, hence mineralocorticoid effect seen- BP
& K
Reproductive sys: amenorrhea, libido
CNS: irritability, emotional liability, paranoid
psycosis
Blood: increased susceptibility to infections
WBC
hypercoagulation- DVT, P emboism
Metabolism: impaired glucose tolerance
dyslipidemia
Central obesity
Moon facies
Buffalo Hump
Purple striae
Diagnostic algorithm
according to the 2008 Endocrine Society clinical practice guideline
urinary free cortisol (UFC). Normal values
less than 220 to 330 nmol/24 hours (80 to 120 μg/24
hours
Low dose DXM supp test:Will only suppress normal physiological cortisol
release. Will not suppress any abnormal cortisol
release.
False positives seen in:Anti epileptics- carbamazepine, phenytoin
Rifampicin
Eating disorders
Depression
Alcohol withdrawl
(pseudo cushing’s)
The most discriminatory time of day to
measure ACTH is between 11 p.m. and 1
a.m., when ACTH/cortisol secretion is at a
nadir.
A midnight ACTH result >15 pg/mL in a
patient with biochemical hypercortisolism
confirms that the underlying disease is
ACTH dependent.
Inferior Petrosal Sinus Sampling is the most robust test to
distinguish Cushing’s disease from the ectopic ACTH
syndrome.
In virtually all patients with ectopic ACTH, ratio of ACTH in
IPS and in simultaneously drawn peripheral venous blood is
less than 1.4 : 1. In contrast, the ratio is elevated to greater
than 2.0 in Cushing’s disease.
However due to the problem of intermittent ACTH secretion, it
is useful to take measurements at 2, 5 and15 minutes, after iv
100 μg synthetic ovine CRH.
Treatment
ACTH independent : surgical resection
Cushing’s disease: transsphoidal removal of
tumour
In overt cushing’s: (difficult to control
hypokalemic htn or acute psychosis)
Medical therapy to treat cortisol excess before
surgery- Ketokonazole (200mg tds)
Metyrapone (500 mg tds)
Hydrocortisone at time of surgery and slowly tapered
following recovery.
HYPERALDOSTERONISM
m/c/c - b/l adrenal hyperplasia.
Carcinomas considered in younger individuals
Etiology:
Primary
hyperaldosteronism
Secondary
hyperaldosteronism
1. Adrenal adenoma
(Conn’s syndrome)
2. B/L (micronodular) adrenal
hyperplasia
3. Glucocorticoid remidiable
hyperaldosteronism
1. B/L renal artery stenosis
2. Cirrhosis of liver
3. CCF
4. Nephrotic syndrome
(Inc aldosterone only) (Inc aldosterone and Renin)
1. Syndrome of apparent mineralocorticoid excess:
Mutation of HSD 11B2
Cortisol cannot be converted to cortisone
Excess activation of MR by cortisol
2. Cushing’s syndrome
3. Glucocorticoid resistance – upregulation of cortisol
due to GR mutations
4. Adrenocortical CA
5. CAH – CYP 17A1 and CYP 11B1 deff
6. Liddle’s syndrome – mutant ENaC channels, resulting in
reduced degradation of ENaC, keeping the channel open,
enhancing mineralocorticoid action
Other rare causes:
Symptoms:
Often asymptomatic. Usually diagnosed in labs
while evaluating hypokalemia or evaluation of
hypertension in a young individual.
Labs: K
metabolic alkalosis
Na
Hypertension (Diastolic) without edema.
No features of hypervolemia due to ANP
mediated natriuresis (Aldosterone escape
mechanism)
ALGORITHM FOR
MINERALOCORTICOID
EXCESS
Saline infusion test:
It is positive when there is failure of aldosterone to
supress below 140 pmol/lit (5ng/dl) after saline
infusion, indicates autonomous mineralocorticoid
excess.
AVS (adrenal vein sampling):
Done to differentiate between B/L micronodular
hyperplasia and U/L adenoma in pts >40yrs if a
surgical procedure is feasible and required.
Treatment
U/L adrenal pathology: laparoscopic adrenalectomy
B/l pathology & not candidates for surg:
Medical therapy with MR antagoinsts
Spironotactone – started at 12.5- 50 bd max 400mg/day
Eplerenone – strt 25 bd titrated max to 200mg/day
Amiloride 5-10 mg bd
ADRENAL
INSUFFICIENCY m/c/c- suppression of HPA (exogenous
glucocorticoids)
Primary Secondary
1.Autoimune adrenalitis m/c
2. CAH
3. Adrenoleukodystrophy
4. Adrenal infections (tb, hiv,
cmv, cryptococcosis)
5. Adrenal haemorrhage
6. Drug induced (mitotane,
aminoglutethimide,
ketokonazole, RU486)
7. B/l adrenalectomy
1. Pituitar tumours
2. Pituitary irradiation
3. Pituitary apoplexy/Hg
4. Drug induced (chronic
glucocorticoid excess)
5. POMC deff
Chronic = Addison’s dis
Primary AI has defficency of both Gluc and
minlc, while seconday AI has only Gluc deff.
Hyponatremia is a characteristic biochem
feature of 1` AI. Can be seen in 2` AI due to
diminished inhibition of ADH by cortisol (SIADH)
1`AI – Hyperpigmentaion, excess POMC derived
peptides stimulate melanocytes.
2`AI associated with:
Inv of other endocrine axes (thyroid, gonad, GH,
prolactin)
Bitemporal hemianopia (chiasmal compression)
Primary vs Secondary AI
CLINICAL FEATURES
Due to glucocorticoid deff: Fatigue, lack of energy
Weight loss, anorexia
Fever
Anemia, lymphocytosis, eosinophilia
Slightly increased TSH (loss of feedback inhibition of TSH
release)
Hypoglycemia (more in children)
Hyponatremia (due to lack of feedback inhib of AVP
release)
Due to Mineralocorticoid Deff: (Primary
AI only) Nausea, vomiting, abdominal pain
Dizziness, postural hypotension
Salt craving
Low BP
Increased serum Cr (due to volume depletion)
Hyponatremia, hyperkalemia
Due to Adrenal Androgen Deff: Lack of energy
Loss of Libido
Loss of axilary and pubic hair
Diagnostic Algorithm
Treatment
Glucocorticoid replacement: Replacement of physiological daily gluc production ~
15-25mg hydrocortisone in two or three div doses
Pregnancy, increase dose by 50%
Long acting gluc not preffered such as Prednisolone
and dexamethasone.
Monitoring of replacement therapy with BP, 24 hr
UFC, plasma ACTH
Pt must be informed to take double the dose in
illness with fever.
100 mg iv dialy in case of prolonged vomiting,
surgery or trauma.
Mineralocorticoid replacement: In primary adrenal indufficiency
100-150 ug fludrocortisone
Monitoring by measuring Na, K, BP – sitting and standing (to detect postural drop indicative of hypovolemia), plasma renin.
Changes in glucocorticoid dose may impact mineralocorticoid dose. Ex: 40 mg hydrocortison = 100ug fludro
If travelling to hot tropical weather, dose of fludro inc by 50-100ug
Adrenal androgen replacement:An option in pts with lack of energy despite optimal gluc and
minc replacment.
OD 25-50 mg DHEA
Monitored by measuring DHEAS, androstenidione, 24 after
DHEA dose.
ACUTE ADRENAL
INSUFFICIENCY
a/k adrenal crisis
Its an endocrine emergency
Life threatening condition where body is
acutely deprived of cortisol and
sometimes aldosterone.
Who’s at risk for crisis?
1. Pts with Addison’s dis or other primary
hypoadrenalism in event of an acute stressor.
2. Pts with meningococcemia – Waterhouse
Fridreichsen Syndrome.
3. Sudden withdrawl of exo steroids
4. Pituitary necrosis (pit apoplexy)
5. Follwing b/l adrenalectomy
6. Follwing administration of ETOMIDATE.
Diagnosis
H/o and physical exam will help a ton!
Symptoms are not specific. Have to
differentiate it from other causes of shock
as AC will not respond to fluids and
pressors alone. Will need steroids.
Labs:
Na
K
Pre renal pic, Bun:Cr > 20:1 (due to
dehydration)
Treatment
Start treatment before the serum cortisolresults arrive.
Rehydration: NS @ 1lit/hr
continuous cardiac monitoring
Glucocorticoids: Hydrocortisone iv bolus 100mg
Followed by 100-200mh hyrocortisone over 24hrs by cotinous infusion or iv/im inj
Mineralocorticoid: Strated once daily hydrocortisone dose reduced to
<50mg (as high dose hydcor provides suff mincoraction)
PHEOCHROMOCYTOMA
“the great masquerader” as its presentation is
so variable.
Catecholamine producing tumours from ANS.
Name reflects the black coloured staining
caused by chromaffin oxidation of
catecholamines.
Rule of 10: 10% b/l
10% extraadrenal
10% malignant
10% not associated with HTN
Usually 10% are familial
Clinical features
Paroxysms or crisis:
Onset - Sudden
Ppt factors - Abdominal palpation, stress during
surgery, anaesthesia.
Feature - triad of episodic palpitation, sweating
and headache.
Hypertension:
Sustained sustained with some episodic peaks
normal
HTN
Diagnosis
To confirm diagnosis:
24 urinary vanillyl mandelic acid
Urinary metanephrins
To localize tumour:
CT, MRI of adrenal
In case of extra adrenal – mri chest, 131I
MIBG scan (metiodobenzyl guanidine),
Dopa PET
Treatment
Therapeutic goal is complete removal of the tumour. Proper fluid balance to be maintained during sx
Any htn crisis managed by iv phentolamine/ iv nitroprusside
Pre operative pre with alpha and then beta blockers
Metastaic tumour: chemo / Metyrosine (tyrosine hydroxylase inhibitor)
Supportive: For htn – phenoxybenzamine, start with 5-10mg tds
and gradually increase
For tachycardia – propranolo 10mg qds (but not before alpha blockade)
Thank you
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