Download Adrenal disorders - University of Yeditepe Faculty of Medicine, 2011

ADRENAL DISORDERS
Hasan AYDIN, MD
Yeditepe University Medical Faculty
Department of Endocrinology and Metabolism
Histologic Zones of Adrenal Cortex
• Zona Glomerulosa
Aldosterone
• Zona Fasiculata
Cortisol and androgens
• Zona Reticularis
Cortisol and androgens
Diseases of Adrenal Gland
• Diseses of Adrenal Cortex
– Cushing syndrome
– Adrenal failure
– Congenital adrenal hyperplasia
• Diseases of Adrenal Medulla
– Pheochromocytoma
– Hyperaldosteronism (Conn’s syndrome)
Cushing’s Syndrome
Cushing’s Sydrome vs. Disease
• Chronic glucocorticoid excess, whatever it’s
cause
• Cushing’s diasease: a spesific type of Cushing’s
sydrome due to excessive pituitary ACTH
secretion from a pituitary tumor.
Cushing’s Syndrome
• ACTH dependent
– Pituitary adenoma (Cushing’s Disease)
– Nonpituitary neoplasm (ectopic ACTH)
• ACTH independent
– Iatrogenic (glucocorticoid,megestrol acetate)
– Adrenal neoplasm (adenoma,carcinoma)
– Nodular adrenal hyperplasia
primary pigmented nodular adrenal disease
massive macronodular adrenonodular hyperplasia
food-dependent (GIP-mediated )
Cushing’s Disease
• 70 % of cases of Cushing’s sydrome
• Female/male 8:1
• Age at diagnosis : childhood –70 years
Etiology:
Corticotroph-cell pituitary adenomas
Corticotroph cell hyperplasia
Tumors are typically smaller than 10 mm
Ectopic ACTH Hypersecretion
• 15-20 % of patients with ACTH dependent Cushing’s
Sydrome
• Tumors causing the ectopic ACTH syndrome
– Small cell carcinoma of the lung (50% of cases)
– Pancreatic islet tumors
– Carcinoid tumors (lung,thymus,gut,pancreas,ovary)
– Medullary carcinoma of the thyroid
– Pheochromocytoma
Adrenal Cushing’s Syndrome
– Adrenal neoplasm (adenoma,carcinoma)
– Nodular adrenal hyperplasia
– Primary pigmented nodular adrenal disease
– Massive macronodular adrenonodular hyperplasia
– Food-dependent (GIP-mediated )
Clinical Aspects of Cushing's Syndrome
Diagnosis
• Urine free cortisol in 24 hour urine samples – 80-100
mg/24 h is normal
• Used in screening
Diagnosis
• Absence of diurnal rhythm is the hallmark of
diagnosis
Serum cortisol levels exceeding 7 mg/dL at
midnight indicates absence of diurnal rhythm
Diagnosis
• Dexametasone supression test
Low dose –for screening
1 mg dexametasone at bedtime (23 00hour)
Determine plasma cortisol early following morning
Plasma cortisol < 1.8 mcg/dl - normal
Dexamethasone 4 x 0.5 mg for two days
17 hydroxycorticosteroid excretion greater than 4 mg/24 h on the
second day of dx administration= Cushing syndrome
Differential Diagnosis
• Plasma ACTH:
Differentiate ACTH dependent and non dependent
forms
Patients with ACTH –secreting neoplasms usually have
plasma ACTH levels > 10 pg/ml frequently greater
than 52 pg/ml.
• Pituitary MRI
ACTH-dependent patients adenoma on MRI likehood of
cushing disease 98-99%
Incidentaloma 10%
Inferior Petrosal Sinus Sampling
• Distinguishing pituitary from non pituitary ACTH
dependent Cushing’s syndrome
• Simultaneous inferior petrosal sinus and peripheral
ACTH measurements before and after CRH stimulation
• IPS/P > 2
pituitary ACTH secreting tumor
• IPS/P < 1.8 ectopic ACTH
• Diagnostic accuracy 100% in the differential diagnosis of
ACTH dependent Cushing’s syndrome
Treatment
Remove or destroy the basic lesion
Correct the hypersecretion of adrenal
hormones
• microsurgery
• radiation therapy
• pharmocologic inhibition of ACTH secretion
ketoconasole,metyrapone,amimoglutethimide,
mitotane
Adrenocortical Insufficiency
(Addison’s Disease)
Causes of Adrenal Insufficiency
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Primary adrenal insufficiency
Secondary adrenal insufficiency
Autoimmune (70%of patients)
Infections
Tuberculosis (20% of patients)
menincococcus,pnumococcus,
fungal,HIV
Medications (ketoconasole,
dilantin,phenobarbital,rifampin,
etomidate, metyrapone)
Malignancy (Primary,metastatic)
Adrenal hemorrhage (spontan,traumatic,
coagulopathy/heparin/coumadin)
Familial
Infiltrative diseases
(amiloidosis,sarcoidosis,
hemochromatosis)
• Exogenous glucocorticoid
withdawal
• Following cure of cushing’s
sydrome
• Hypothalamic or pituitary disease
(Tumor,sarcoidosis,hemorrhage,
autoimmune,postoperative)
• Isolated adrenocorticotropic
hormone deficiency
Presentation
Highly variable
Duration of disease
Whether deficiency is primary or secondary
Potential Clinical Manifestations
Glucocorticoid deficiency
• Cardiovascular
–
hypotension
• Gastrointestinal
–
anorexia,nausea,weight loss,
abdominal pain, diarrhea
• Cutaneous
–
–
hyperpigmentation (secondary
to ACTH precursors)
vitiligo(secondary to
autoimmune disease)
• Muscular
–
fatigue,weakness,malasie
• Neurologic
–
confusion,apathy,lethargy,psyc
osis
Mineralocorticoid Deficiency
• Cardiovascular
–
hypovolemia,
–
decreased cardiac output,
Acute Adrenal Crisis
occurs in patients with Addison’s
disease who are exposed to the stress
of infection, trauma,surgery or
dehydration
Clinical Features of Acute Adrenal Crisis
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Hypotension and shock
Fever
Dehydration,volume depletion
Nausea,vomiting,anorexia
Weakness, apathy, depressed mentation
Hypoglycemia
Laboratory Findings of Adrenal Insufficiency
Glucocorticoid deficiency
Minerolocorticoid deficiency
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Lymphopenia
Eosinophilia
Hypoglycemia
Anemia
Hyponatremia
Hyperkalamia
Acidosis
Azotemia
Hypercalcemia
Diagnosis of Adrenocortical Insufficiency
Since basal levels of adrenocortical steroids in
either urine or plasma may be normal in partial
adrenal insufficiency, tests of adrenal cortical
reserve are necesseary to establish the diagnosis
Cortisol > 20 mg/day at any time of day - diagnosis very unlikely
Hemodynamic instability - cortisol < 20 mg/day - suspicious
ACTH Stimulation Test
Performed at any time of day
A baseline cortisol sample is obtained and 250 mg
synthetic ACTH (cosyntropin) is then
administered intravenously. Cortisol samples
are drawn 30 and 60 min later.
Plasma cortisol >18 mcg/dl excludes the diagnosis
Plasma ACTH Level
• Used to differentiate primary and secondary
forms
Secondary adrenal insufficiency
plasma ACTH <30 pg/mL ( 7pmol/L)
Primary adrenal insufficiency
plasma ACTH >52 pg/mL
Treatment of Acute Adrenal Crisis
• Glucocorticoid replacement
Administer cortisol (hydrocortisone 100 mg i.v. Every 6 hours for 24
hours
When patient stable reduce dosage to 50 mg every 6 hours
Taper the maintenance therapy by day 4 or 5 and add minerolocorticoid
therapy as required
Maintain or increase the dose to 200-400 mg/day if complications persist
or occur
• General and supportif measures
Correct volume depletion,dehydration and hypoglycemia
With i.v. saline and glucose
Evaluate and correct infection and other precipitating factors
Maintenance Therapy
• Cortisol 15-20 mg in AM. and 10 mg at 4-5 PM
• Fludrocortisone, 0.05-0.1 mg orally in AM
• Clinical follow-up : maintenance of normal weight,
blood pressure, and electrolytes
• Patient education, identification card or bracelet
• Increase cortisol dosage during stress
Congenital Adrenal Hyperplasia
Adrenal Hormone Synthesis
Cholesterol
Cholesteol
desmolaz
Mineralocorticoids
Glucocorticoids
Sex hormones
17α-OH
17,20-liyaz
17-OH pregnenolon
Pregnenolon
3β-HSD
3β-HSD
3β-HSD
17α-OH
Progesteron
21-OH
11-Deoxycorticosterone
11β-OH
Corticosterone
18-OH
18-OH B
18-HSD
Aldosterone
DHEA
17-OH progesteron
17,20-liyaz
Δ-Androsteodione
17β-HSD
21-OH
11-Deoxycortisol
11β-OH
Testosterone
5α-redüktaz
Aromataz
tip2
Cortisol
Dihydrotestosterone
Estradiol
State
11 beta-hydroxylase
17 alpha-hydroxylase
3 beta-hydroxysteroid
dehydrogenase
Aldosterone synthase
StAR
Incidence
Clinical Picture
~1 in 100,000 livebirth
Virilization in women;
salt wasting rare
rare
Virilization in men; no
puberty in women. No
salt wasting
rare
Virilization in men; mild
virilization in women.
Salt wasting possible
rare
Cortisol concentration
normal; no virilisation.
Salt wasting
rare
Virilization in men;no
puberty in women. salt
wasting
Treatment
• Corticosteroid replacement
• Mineralocorticoid replacement
Hyperaldosteronism
(Conn’s Syndrome)
Hyperaldosteronism
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Primary
1. Adrenal adenoma
2. Adrenal carcinoma
3. Bilateral hyperplasia
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Secondary
1. Renal artery stenosis
2. Edematous states (cirrhosis, renal failure)
Hyperaldosteronism
• ↑ BP + K+ ↓ or low normal K+
• ↑ BP in young person
• ↑ BP difficult to control
Signs and Labs
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Hypertension
Hypokalemia
Urine potassium wasting
Increased aldosterone
Low renin
Hyperaldosteronism, Diagnosis
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Serum K < 3.6 mEq/L
Plasma renin activity (PRA) < 1 ng/ml
Plasma aldosterone >22 ng/dL
Urine aldosterone > 14 mcg/24hrs
Urine K > 40 mEq/24 hrs
Plasma aldosterone:PRA ratio > 50:1
Hyperaldosteronism, Diagnosis
• CT scan
• Adrenal vein sampling
Hyperaldosteronism, Treatment
• Bilateral hyperplasia- medical,
spironolactone, amiloride.
• Unilateral adenoma- adrenalectomy.
Pheochromocytoma
Catecholamine Producing Tumors
Neural Crest
Sympathoadrenal Progenitor Cell
(Neuroblasts)
Chromaffin Cell
Neuroblastoma
Sympathetic Ganglion Cell
Intra-adrenal Extra-adrenal
Pheochromocytoma
Ganglioneuroma
Pheochromocytoma
• 0.01-0.1% of HTN population
• Found in 0.5% of those screened
• M=F
• 3rd to 5th decades of life
• Rare, investigate only if clinically suspicion:
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Signs or Symptoms
Severe HTN, HTN crisis
Refractory HTN (> 3 drugs)
HTN present @ age < 20 or > 50 ?
Adrenal lesion found on imaging (ex. Incidentaloma)
Pheo: Signs & Symptoms
• The five P’s:
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Pressure (HTN)
Pain (Headache)
Perspiration
Palpitation
Pallor
90%
80%
71%
64%
42%
» Paroxysms (the sixth P!)
• The Classical Triad:
• Pain (Headache), Perspiration, Palpitations
• Lack of all 3 virtually excluded diagnosis of pheo in a series
of > 21,0000 patients
Biochemical Tests: Summary
SEN
SPEC
Ucatechols
83%
88%
Utotal metanephrines
76%
94%
Ucatechols+metaneph
90%
98%
UVMA
63%
94%
Plasma catecholamines
85%
80%
Plasma metanephrines
99%
89%
Localization: Imaging
• CT abdomen
• Adrenal pheo SEN 93-100%
• Extra-adrenal pheo SEN 90%
• MRI
• > SEN than CT for extra-adrenal pheo
• MIBG Scan
• SEN 77-90% SPEC 95-100%
Pheochromocytoma, Treatment
• Treatment is surgery
• Must medically optimize prior to surgery
– Treat HTN
– Expand intravascular volume
– Control cardiac arrhythmias
Preop Preperation Regimens
• Combined α + β blockade
• Phenoxybenzamine
• Selective α1-blocker (ex. Prazosin)
• Propanolol
• Metyrosine
• Calcium Channel Blocker (CCB)
• Nicardipine
Incidentaloma
Incidentaloma
• Found on work up for another cause, not on
cancer workup
– US 0.1%
– CT 0.4 to 4.4%
– MRI
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70-94% are benign and nonfunctional
>3cm more likely to be functional
Up to 20% may be subclinically active
Increase with age, no change in sex
5-25% will increase in size by at least 1cm
Incidentaloma
• Increased risk of adrenocortical
carcinoma with increasing size
<4cm
2%
4.1-6cm
6%
>6cm
25%
• No change with age or sex
Incidentaloma, Workup
• Bioclinical examination
– Dexamethasone suppression test
– Urinary/plasma catecholamine/metanephrines
– Serum potassium, plasma aldosterone concentrationplasma renin activity ratio (if hypertensive)
• Rule out other malignancy
– Stool for occult blood
– CXR
– Mammogram
Incidentaloma, Who Gets Surgery?
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Unilateral, functioning tumors.
>6cm; 4-6 cm is a grey area.
Rapid growth rate.
Imaging not suitable with benign adenoma.
No surgery if workup reveals metastasis.
?Younger patients (increased lifetime cancer
risk, longer f/u, lower incidence of adrenal
masses).
Incidentaloma, Watchful Waiting
• <4cm, nonfunctioning tumors.
• CT in 3 and 12 months. If no increase in size, no
data to support further imaging.
• ? Periodic hormonal testing. If a tumor will start
to hyperfunction, this will most likely happen in
3-4 yrs.