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ADRENAL DISORDERS. Hasan AYDIN, MD Yeditepe University Medical Faculty Department of Endocrinology and Metabolism. Histologic Z ones of A drenal C ortex. Zona Glomerulosa Aldosterone Zona Fasiculata Cortisol and androgens Zona Reticularis Cortisol and androgens.

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adrenal disorders

ADRENAL DISORDERS

Hasan AYDIN, MD

Yeditepe University Medical Faculty

Department of Endocrinology and Metabolism

histologic z ones of a drenal c ortex
Histologic Zones of Adrenal Cortex
  • Zona GlomerulosaAldosterone
  • Zona FasiculataCortisol and androgens
  • Zona ReticularisCortisol and androgens
diseases of adrenal gland
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 sydrome vs disease
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 syndrome1
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
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
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 Cushing’s Syndrome
  • Adrenal neoplasm (adenoma,carcinoma)
  • Nodular adrenal hyperplasia
  • Primary pigmented nodular adrenal disease
  • Massive macronodular adrenonodular hyperplasia
  • Food-dependent (GIP-mediated )
diagnosis
Diagnosis
  • Urine free cortisol in 24 hour urine samples – 80-100 mg/24 h is normal
  • Used in screening
diagnosis1
Diagnosis
  • Absence of diurnal rhythm is the hallmark of diagnosis

Serum cortisol levels exceeding 7 mg/dL at midnight indicates absence of diurnal rhythm

diagnosis2
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
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%

i nferior p etrosal s inus s ampling
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
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

causes of adrenal insufficiency
Primary 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)

Secondary adrenal insufficiency

Exogenous glucocorticoid withdawal

Following cure of cushing’s sydrome

Hypothalamic or pituitary disease (Tumor,sarcoidosis,hemorrhage, autoimmune,postoperative)

Isolated adrenocorticotropic hormone deficiency

Causes of Adrenal Insufficiency
presentation
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,psycosis

Mineralocorticoid Deficiency

Cardiovascular

hypovolemia,

decreased cardiac output,

Potential Clinical Manifestations
acute adrenal crisis
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
Clinical Features of Acute Adrenal Crisis
  • Hypotension and shock
  • Fever
  • Dehydration,volume depletion
  • Nausea,vomiting,anorexia
  • Weakness, apathy, depressed mentation
  • Hypoglycemia
laboratory findings of adrenal insufficiency
Glucocorticoid deficiency

Lymphopenia

Eosinophilia

Hypoglycemia

Anemia

Minerolocorticoid deficiency

Hyponatremia

Hyperkalamia

Acidosis

Azotemia

Hypercalcemia

Laboratory Findings of Adrenal Insufficiency
diagnosis of adrenocortical insufficiency
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
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
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
Treatment ofAcute 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
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
slide30

Adrenal Hormone Synthesis

Cholesterol

Mineralocorticoids

Glucocorticoids

Sex hormones

Cholesteol desmolaz

17α-OH

17,20-liyaz

17-OH pregnenolon

DHEA

Pregnenolon

3β-HSD

3β-HSD

3β-HSD

17α-OH

17,20-liyaz

Δ-Androsteodione

Progesteron

17-OH progesteron

17β-HSD

21-OH

21-OH

11-Deoxycorticosterone

11-Deoxycortisol

Testosterone

5α-redüktaz

tip2

11β-OH

Aromataz

11β-OH

Corticosterone

Cortisol

Dihydrotestosterone

Estradiol

18-OH

18-OH B

18-HSD

Aldosterone

treatment1
Treatment
  • Corticosteroid replacement
  • Mineralocorticoid replacement
hyperaldosteronism
Hyperaldosteronism
  • Primary
    • Adrenal adenoma
    • Adrenal carcinoma
    • Bilateral hyperplasia
  • Secondary
    • Renal artery stenosis
    • Edematous states (cirrhosis, renal failure)
hyperaldosteronism1
Hyperaldosteronism
  • ↑BP + K+↓ or low normal K+
  • ↑BP in young person
  • ↑BP difficult to control
signs and l abs
Signs and Labs
  • Hypertension
  • Hypokalemia
  • Urine potassium wasting
  • Increased aldosterone
  • Low renin
hyperaldosteronism diagnosis
Hyperaldosteronism, Diagnosis
  • 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 diagnosis1
Hyperaldosteronism, Diagnosis
  • CT scan
  • Adrenal vein sampling
hyperaldosteronism treatment
Hyperaldosteronism, Treatment
  • Bilateral hyperplasia-medical, spironolactone, amiloride.
  • Unilateral adenoma- adrenalectomy.
catecholamine producing tumors
Catecholamine Producing Tumors

Neural Crest

Neuroblastoma

Sympathoadrenal Progenitor Cell

(Neuroblasts)

Chromaffin Cell

Sympathetic Ganglion Cell

Intra-adrenal Extra-adrenal

Pheochromocytoma

Ganglioneuroma

pheochromocytoma1
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:
      • 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
Pheo: Signs&Symptoms
  • The five P’s:
      • Pressure (HTN) 90%
      • Pain (Headache) 80%
      • Perspiration 71%
      • Palpitation 64%
      • Pallor 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
localization imaging
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
Pheochromocytoma, Treatment
  • Treatment is surgery
  • Must medically optimize prior to surgery
    • Treat HTN
    • Expand intravascular volume
    • Control cardiac arrhythmias
preop preperation regimens
Preop Preperation Regimens
  • Combined α + β blockade
      • Phenoxybenzamine
      • Selective α1-blocker (ex. Prazosin)
      • Propanolol
  • Metyrosine
  • Calcium Channel Blocker (CCB)
      • Nicardipine
incidentaloma1
Incidentaloma
  • Found on work up for another cause, not on cancer workup
    • US 0.1%
    • CT 0.4 to 4.4%
    • MRI
  • 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
incidentaloma2
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
Incidentaloma, Workup
  • Bioclinical examination
    • Dexamethasone suppression test
    • Urinary/plasma catecholamine/metanephrines
    • Serum potassium, plasma aldosterone concentration-plasma renin activity ratio (if hypertensive)
  • Rule out other malignancy
    • Stool for occult blood
    • CXR
    • Mammogram
incidentaloma who gets surgery
Incidentaloma, Who Gets Surgery?
  • 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
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.
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