Adrenal disorders
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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

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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 syndrome

Cushing’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 )


Adrenal disorders

Clinical Aspects of Cushing's Syndrome


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


Adrenocortical insufficiency addison s disease

Adrenocortical Insufficiency(Addison’s Disease)


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


Congenital adrenal hyperplasia

Congenital Adrenal Hyperplasia


Adrenal disorders

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 conn s syndrome

Hyperaldosteronism(Conn’s Syndrome)


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.


Pheochromocytoma

Pheochromocytoma


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%

      • Perspiration71%

      • Palpitation64%

      • Pallor42%

        • 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

    Biochemical Tests: Summary


    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


  • Incidentaloma

    Incidentaloma


    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

      <4cm2%

      4.1-6cm6%

      >6cm25%

    • 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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