Adrenal gland diseases Done by Mayar - PowerPoint Presentation

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Adrenal gland diseases

Done by Mayar

Alatrash

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Anatomy

Pyramidal in shape. 3- 5 cm in height , 3 cm in width , less than 1 cm thick, Mass 3.5 - 5 g

The adrenal gland is divided into 2 areas, the cortex and medulla.

The cortex is divided into 3 areas: GFR

- the outer zone (glomerulosa): aldosterone synthesis

- the central zone (

fasciculata

): cortisol synthesis

- the inner zone (reticularis): androgen biosynthesis.

The adrenal medulla is an extension of the sympathetic nervous system that secretes

catecholamines

into capillaries rather than synapses.

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Physiology

Mineral corticosteroid

(most important is aldosterone )

Its function can explain as part of RAAS

K

+

& proton

excretion

The principle stimulus

hypovolemia or renal

artery stenosis

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Glucocorticoids

lipid-soluble hormones

, so most cortisol in the blood is bound to a special carrier protein, called

cortisol-binding globulin

, and only about

5% is unbound or free (

biologically active) , have to stay within the normal range, Using negative feedback .

it’s part of the circadian rhythm. Cortisol levels peak in the morning, when the body knows we need to “get up and go” and then

drop in the evening, when we’re preparing for sleep.

In times of stress, the body needs to have plenty of energy substrates around, so cortisol increases gluconeogenesis , proteolysis and lipolysis

.helps to maintain the blood pressure by increasing the sensitivity of peripheral blood vessels to catecholamines

, and this narrows the blood vessel lumen.helps to dampen the inflammatory and immune response

cortisol receptors are present in the brain, might influence mood and memory.

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Adrenal androgens ACTH

They are probably important in the initiation of puberty (

adrenarche

).

For males

 promote prostate growth and give masculine characteristic (hair growth and deep voice )

For females  important in libido

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Catecholamines SNS Small proportion of NA from medulla, remaining from sympathetic nerve endings

Major source of Adrenaline

Conversion of NA to Adrenaline by Catechol-O-

MethylTransferase

(COMT), which is induced by glucocorticoids.

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Cushing syndrome

named after the famous neurosurgeon,

Harvey Cushing

who first described it

Elevated cortisol levels in the blood , constantly higher than normal = loss of circadian rhythm.

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Clinical features 1) Increase breakdown of most types of tissues :

muscle wasting and thin extremities

skin thinning

Easy bruising

Abdominal

striae(Thick purple striae, greater than 1cm in diameter)

Bone thinning (osteoporosis)  increase risk of fractures2)Fat redistribution :

Round ,full moon shaped face

Buffalo hump Truncal obesity- central obesity

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3) Hypertension for two reasons.

First

, they amplify the effect of

catecholamines

on blood vessels.

Second, cortisol starts cross-reacting with mineralocorticoid receptors.

4) Hyperglycemia DM

5) Suppress immune system  increased risk for infection (

fungal)

6) inhibit the secretion of GRH, which messes up normal ovarian and testicular function.7) high levels of cortisol seem to impair normal brain function

but the exact mechanism of that is unclear.

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What are the causes ?

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Variation in clinical features !some common disorders can be confused with Cushing’s syndrome because they are associated with alterations in cortisol secretion, e.g. obesity and depression

Features that favor Cushing’s syndrome in an obese patient are bruising, myopathy and thin skin.

An 0800–0900-hr serum cortisol of < 100

nmol

/L (3.6

μ

g/

dL) in a patient with a normal sleep–wake pattern and Cushingoid appearance is consistent with exogenous synthetic glucocorticoid use (common) or cyclical secretion of cortisol from endogenous Cushing’s (uncommon).

Ectopic ACTH secretion not affected by negative feedback like Cushing disease , resulting in higher levels of both ACTH and cortisol

 marked pigmentation , hypokalemic alkalosis that aggravates myopathy and hyperglycemia (by inhibiting insulin secretion).Malignant  onset is usually rapid and may be associated with cachexia , the classical features of Cushing’s syndrome are less common in ectopic ACTH syndrome; if present, they suggest that a less aggressive tumor, such as a bronchial carcinoid

In Cushing’s disease, the pituitary tumor is usually a microadenoma (< 10 mm in diameter); hence other features of a pituitary macroadenoma

(hypopituitarism, visual failure or disconnection hyperprolactinemia

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First step

Second step

Some confirmations

To diagnose ..

Start with HX to exclude this

Third step

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First step ( Is it Cushing syndrome ?!)

1) Late night salivary cortisol level

>2 ng/ml

..BUT not best first choice for whom ??

2) 24h urinary free cortisol level - normal 3.5-45 mcg/24 hours –

> 3X the upper limit of normal

For 1 & 2 we need 2 abnormal result to confirm Cushing’s

3) Low – dose or overnight dexamethasone suppression test

LDDST  administration of 0.5 mg of dexamethasone( start at 9 am ) every 6 h for 48h (total 4 mg) then check serum cortisol level

ONDST administration of 1 mg dexamethasone at 11 pm

then checking cortisol serum level between 8 & 9 am

it’s Cushing when serum cortisol level in both >1.8mcg/dl

Keep in your mind

 any estrogens should be stopped 6 weeks prior to investigation , to avoid false positive response .

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Second step ( Ok It’s Cushing , but what is the cause ?)

* Serum ACTH level :

> 15 ng/L

 ACTH dependent

<5 ng/L

 ACTH independent

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Third step (ACTH dependent )

High dose dexamethasone suppression test

Measure serum cortisol at 8 am , then give 8 mg

Of dexamethasone at 11 pm , then measure

Serum cortisol at 8 am of the following morning.

Serum cortisol 50% lower than the previous day

indicative of Cushing disease.

But , its recommended to confirm the DX - CRH stimulation test

- Bilateral inferior petrosal sinus sampling- Brain MRI

or thorax abdomen and pelvis CT or MRI

The idea here that high doses of dexamethasone are able to suppress pituitary ACTH secretion, but not ectopic ACTH

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CRH stimulation test Administration of 100 mg

hCRH

IV , serum ACTH and cortisol samples obtained before and 45min after the injection.

>20% rise in cortisol or > 50% rise in ACTH

indicative of Cushing disease.

BIPSS

Catheter is inserted in the LT & RT jugular or femoral veins , and advanced all the way up to LT&RT inf. Petrosal sinuses ( drain the blood from the pituitary ) , CRH injected , ACTH samples obtained from peripheral veins and petrosal sinus before and 10min after the injection

Inf. Petrosal sinus ACTH : peripheral veins ACTH > 2:1 before the injection or > 3:1 after the injection

indicative of Cushing disease.

Brain MRI if Cushing disease is suspected or thorax abdomen and pelvis CT or MRI if ectopic ACTH is suspected

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Third step (ACTH independent )

Adrenal adenoma or carcinoma

- Clinical signs

-

abd.CT

Some

clinical signs of an adrenal carcinoma include age below 10, or over 50, as well as signs of androgen excess in women - like acne, hirsutism, and deepening of the voice, which are not usually present with adenomas.

Also, on an abdominal CT, adrenal carcinomas usually have necrosis, hemorrhage, and calcifications, whereas adenomas typically don’t.

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Management

Cushing disease

the tumor can be removed through

transsphenoidal

resection

If the entire tumor can’t be removed, then

radiation therapy may also be used to eliminate the tumor.However, it may take anywhere between 6 months and three years for hypercortisolism to disappear

, and during this time, drugs that block the adrenal synthesis of cortisol, like metyrapone may be used to control the symptoms.If medications aren’t sufficient to block cortisol effects

, a last resort is to surgically remove both adrenal glands. In that situation,

lifelong substitution therapy with glucocorticoid and mineralocorticoid hormones is needed.Ectopic ACTH secretiontreatment here depends on the kind of tumor it is, and its stage.

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Adrenal adenoma laparoscopic adrenalectomy of the affected adrenal gland.

Adrenal carcinoma

usually an open adrenalectomy, and nearby lymph nodes are often removed as well.

If the carcinoma is invasive, then surgical resection of nearby organs, like the kidney, liver, or spleen may be needed.

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Exogenous  tapering of glucocorticoids

** when surgery contraindicated or unsuccessful , or pt. is awaiting surgical treatment , medical therapy is appropriate (Adrenal enzyme inhibitors like ketoconazole)

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Hyperaldosteronism

the adrenal gland produces above normal levels of the hormone

aldosterone

.

Primary hyperaldosteronism

 independent of RAAS

- bilateral adrenal hyperplasia (idiopathic hyperaldosteronism)- aldosterone-producing adenoma (APA; Conn’s syndrome)- Glucocorticoid-suppressible hyperaldosteronism (rare)

Secondary hyperaldosteronism

Renin induced - Inadequate renal perfusion (diuretic therapy, cardiac failure, liver- failure, nephrotic syndrome, renal artery stenosis)- Renin-secreting renal tumor (very rare)

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Clinical features

- Usually asymptomatic

- Hypertension, but accelerated phase hypertension is rare.

- HTN related symptoms ( headache , fascial flushing , fatigue)

- Hypokalemia related symptoms (

weakness

, polyuria (secondary to renal tubular damage, which produces nephrogenic diabetes

insipidus) and occasionally tetany (because of associated metabolic alkalosis and low ionized calcium).

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Diagnosis 1- primary or secondary ?

2- confirm primary

3- the cause of primary

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primary or secondary ? (plasma aldosterone to renin ratio)

confirm primary ( saline infusion test or oral sodium loading )

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the cause of primary

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Management

Mineralocorticoid receptor antagonists

(spironolactone and eplerenone) are valuable in treating both hypokalemia and hypertension in all forms of mineralocorticoid excess.

Up to 20% of males develop

gynecomastia

on spironolactone.

Amiloride(10–40 mg/day), which blocks the epithelial sodium channel regulated by aldosterone, is an alternative.

In patients with an APA, medical therapy is usually given for a few weeks to normalize whole-body electrolyte balance before unilateral adrenalectomy. Laparoscopic surgery cures the biochemical abnormality but, depending on

the pre-operative duration, hypertension remains in as many as 70% of cases, probably because of irreversible damage to the systemic microcirculation.

Bilateral hyperplasia is treated with spironolactone.

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Adrenal insufficiently

adrenal glands don't produce enough adrenal hormones - particularly cortisol, but sometimes aldosterone can be deficient as well.

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Primary adrenal insufficiency causes

1) Autoimmune

most common cause in industrialized countries .

by

its own or part of polyglandular autoimmune syndrome

type 1 or 2 rare immune endocrinopathies characterized by the coexistence of at least two endocrine gland insufficiencies that are based on autoimmune mechanisms. Associations with

nonendocrine immune diseases may occur. Three subtypes , two of them have adrenal involvement Type 1

: usually appears in childhood at age 3–5 yr. or in early adolescence and, therefore, is also called juvenile autoimmune polyendocrinopathy , It is defined by a persistent fungal infection

(chronic mucocutaneous candidiasis), the presence of acquired hypoparathyroidism, and adrenal failure (Addison’s disease) most individual have primary hypogonadism .-

Type 2 :more common and occurs in adulthood, mainly in the third or fourth decade, It is characterized by primary adrenal failure (Addison’s disease) with autoimmune thyroid disease (

Schmidt’s syndrome) and/or type 1 diabetes (Carpenter’s syndrome). other disorders like

immunogastritis , pernicious anemia, and alopecia areata.

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2) Infectious most common cause

worldswide

TB / HIV / disseminated fungal infection 3) Adrenal metastases

from lung, breast, stomach and colon cancer, or lymphoma.4) Iatrogenic : Bilateral

adrenalectomy5) Adrenoleukodystrophy is an inherited disease that predominantly affects young males. In this disease, very long chain fatty acids accumulate in various tissues

, and they particularly affect the central nervous system and the adrenal cortex, causing learning disabilities, seizures, and the development of blindness and

quadriparesis 6) Congenital adrenal hyperplasia.7) Drugs: metyrapone, ketoconazole, etomidate8) Intra-adrenal hemorrhage

(Waterhouse–Friderichsen syndrome following meningococcal sepsis)9) Amyloidosis10) Haemochromatosis

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Secondary adrenal insufficiency causes

patients on long tem steroid therapy (chronic CRH and ACTH inhibition )

Hypopituitarism

Tertiary

adrenal insufficiency

causesHypothalamic causes

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Most frequently, individuals have chronic symptoms which may or may not go unnoticed, and then some sort of stress ,like: serious illness/ during febrile / after trauma / during surgery etc.

precipitates an

Adrenal crisis

.

Its presentation

circulatory shock with severe hypotension, hyponatremia, hyperkaliemia and, in some instances, hypoglycemia and hypercalcemia. Muscle cramps, nausea, vomiting, diarrhea, unexplained fever and mental status changes.

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Patients with suspected acute adrenal crisis and with circulatory compromise treatment SHOULD NOT be delayed

random blood sample should be stored for subsequent measurement of serum cortisol and, if possible, plasma ACTH, then start your treatment!

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if the patient’s clinical condition permits or present with features suggestive of chronic adrenal insufficiency , it may be appropriate to spend 30 minutes performing a short ACTH stimulation test

before administering hydrocortisone

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ACTH stimulation test

give 250 mcg of

Cosyntropin

, which is the synthetic analog of ACTH, and the serum cortisol is taken before ACTH is given, and 30 min later.

Serum cortisol levels

> 18 mcg/dl

before or after the ACTH injection

rule out adrenal insufficiency.On the other hand, if serum cortisol is < 18 mcg/dl

, and cortisol levels stay the same following Cosyntropin

administration, that confirms primary adrenal insufficiency.If they rise, that means the adrenals are responding properly to ACTH, so the issue is central, either with the

pituitary or the hypothalamus.

CRH stimulation test Give a CRH injection, and ACTH is measured four times -

5 minutes before the CRH injection, then again when the injection is given, and then 15 minutes later

, and finally

30 minutes later.

No rise

in serum ACTH compared to the basal value points towards a pituitary, or

secondary adrenal insufficiency

.

if serum ACTH

increases

, then the hypothalamus is to blame - so

tertiary adrenal insufficiency

.

-----------------------------------------------------

Head MRI for further identification of each one cause

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OK , consider it is Addison's disease , what is the cause?To know we will do the following work up

1) serum anti-adrenal antibodies, particularly anti-21-hydroxylase

Autoimmune

2)Chest X-ray and a tuberculin skin test

TB

anti tuberculosis medications

3) Screening for an HIV infection with PCR or with antibody-antigen tests. If an HIV infection is the cause, antiretroviral therapy should be initiated.4) abdominal CT can identify

enlarged adrenal glands that may have calcifications - which is evidence of a disseminated fungal infection

, like with Histoplasma capsulatum, which causes histoplasmosis, or Paracoccidioides brasiliensis, which causes paracoccidioidomycosis

Treatment here is antifungal medication.A CT scan can also identify identify adrenal metastases

 treatment depends on the source of the primary tumor.

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Management

Patients with adrenocortical insufficiency always need glucocorticoid replacement therapy and usually, but not always, mineralocorticoid therapy.

There is some evidence that adrenal androgen replacement may also be beneficial in women.

Other treatments depend on the underlying cause.

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Glucocorticoid replacement

Adrenal replacement therapy consists of oral

hydrocortisone (cortisol) 15–20 mg daily

in divided doses, typically

10 mg on waking and 5 mg at around 15:00 hrs

. These are physiological replacement doses

that should not cause Cushingoid side-effects.The dose may need to be adjusted for the individual patient but this is subjective.

Excess weight gain usually indicates overreplacement.while persistent lethargy or hyperpigmentation may be due to an inadequate dose or lack of absorption.

Measurement of serum cortisol levels is not usually helpful.

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Mineralocorticoid replacement

Fludrocortisone

(9α-

fluoro

-hydrocortisone) is administered at the usual dose of

0.05–0.15 mg daily.

Adequacy of replacement may be assessed by measurement of blood pressure, plasma electrolytes and plasma renin

. It is indicated for virtually every patient with primary adrenal insufficiency but is not needed in secondary adrenal insufficiency.

Androgen replacement

Androgen replacement with DHEAS (50 mg/day) is occasionally given to women with primary adrenal insufficiency who have symptoms of reduced libido and fatigue, but the evidence in support of this is not robust Treatment may be associated with side-effects such as acne and hirsutism.

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Thank you